Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

CDK5

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101554

Synonyms

Historical Background

Cyclin-dependent kinase 5 (CDK5), a proline-directed serine/threonine-protein kinase, was originally purified from bovine brain and defined as a neuronal CDC2 (CDK1)-like kinase (NCLK) (Roder and Ingram 1991; Hellmich et al. 1992). Later on, CDK5 demonstrated capability to induce the Alzheimer-like characteristics by phosphorylation of tau protein (Baumann et al. 1993). p35 (CDK5R1) was then characterized as a regulatory subunit of CDK5 to activate its kinase activity, with subsequent identification of its isoform p39 (CDK5R2) (Tsai et al. 1994; Tang et al. 1995). CDK5/p35 is the first example of a CDC2-like kinase with neuronal function. A truncated form of p35, p25, was purified with CDK5 as a hetero-dimer exhibiting activity in vitro and regarded as a novel regulatory subunit of CDK5 (Lew et al. 1994). Accumulation of p25 is found in brains of AD patients and conversion of p35 to p25 plays a major role in triggering pathological events, leading to neurodegeneration (Patrick et al. 1999; Cruz et al. 2003). Inhibition of CDK5 prevents β-amyloid (Aβ)-induced neuronal death (Alvarez et al. 1999). CDK5/p35 kinase is found essential for neurite outgrowth, neuronal migration, laminar configuration of the cerebral cortex, as well as dynamics of actin skeleton reorganization (Nikolic et al. 1996, 1998). The Phosphorylation of DARPP-32 indicates the involvement of CDK5 in dopamine signaling pathway, neurotransmission, and cocaine addiction (Bibb et al. 1999, 2001). Nowadays, apart from neuronal functions, CDK5 signaling is also involved in cardiometabolic disorders and cancer events. CDK5 can regulate insulin expression and secretion in β-cell (Ubeda et al. 2004; Lee et al. 2008) and affect insulin sensitivity by phosphorylation of PPARγ (peroxisome proliferator-activated receptor γ) in obesity (Choi et al. 2010, 2011). CDK5-mediated hyperphosphorylation of SIRT1 contributes to endothelial senescence and atherosclerosis (Bai et al. 2012). Tumorgenesis and metastasis are also affected by CDK5 (Goodyear and Sharma 2007; Bisht et al. 2015).

Expression and Regulation

Human CDK5 gene is located on chromosome 7q36 and encodes a 31 kD polypeptide containing 292 amino acids. CDK5 belongs to the cyclin-dependent kinase (CDK) family and can bind to cyclin D1, D2, D3, and E (Miyajima et al. 1995; Malumbres et al. 2009; Nagano et al. 2013). Unlike other family members, the enzymatic activity of mammalian CDK5 is mainly dependent on noncyclin proteins, including p35 and p39 (Baumann et al. 1993). Cyclin I is also indicated to activate CDK5 in kidney podocytes (Nagano et al. 2013). In contrast to cell cycle CDKs, CDK5 does not require phosphorylation of its activation loop (T-loop). Both p35 and p39, containing 307 and 369 amino acids respectively, have CDK5 activation domains in their C-terminal region (Tsai et al. 1994; Tang et al. 1995). The crystal structure has explained the ability of p35 to activate CDK5 and that the activation domain has a tertiary structure which resembles cyclin A in the CDK2-cyclin A complex (Tarricone et al. 2001). Binding to regulatory subunits is sufficient for CDK5 to get fully stretched and activated. The available amount of p35 and p39 determines CDK5 kinase activity. p35 and p39 are short-lived proteins, with half-life of 30 and 120 min respectively, and are degraded by ubiquitin-protease system (Patrick et al. 1998; Patzke and Tsai 2002; Minegishi et al. 2010). This degradation is stimulated by CDK5-mediated phosphorylation of p35 at threonine138 (Kamei et al. 2007). When encountering oxidative stress or under pathological stimuli, increased influxes of Ca2+ induce protease calpain activity, facilitating cleavage of p35 and p39 to N-terminal truncated forms, p25 and p29 (Patzke and Tsai 2002; Smith et al. 2006). Because p25 has about five fold longer half-life than p35, CDK5/p25 complex is more stable with prolonged activity (Patrick et al. 1999). The nuclear protein SET can enhance CDK5 activity by its physical interaction with the N-terminal regions of p35 and p39 (Qu et al. 2002). By contrast, C42 can form a complex with p35 and specifically inhibits CDK5 activation (Ching et al. 2002). A C-terminal 172 amino acid domain of the DNA-binding protein, dbpA, also binds to CDK5 but inhibits its activity (Moorthamer et al. 1999). Ribosomal protein L34 is discovered as a novel inhibitor of CDK5, suggesting role of CDK5 in translational regulation (Moorthamer and Chaudhuri 1999). Despite wide expression in different cell and tissue types, CDK5 is mainly active in postmitotic neurons due to predominant expression of p35 and p39 in nervous system (Tsai et al. 1994; Tang et al. 1995). In neuronal cells, the subcellular distribtuion of CDK5 is determined by binding with different subunit. p39 localizes the active CDK5 complex in the perinuclear region and at the plasma membrane as does p35 (Asada et al. 2008, 2012). In addition, CDK5 also shows nuclear/cytoplasm translocation, which is critically involved in cell cycle control. CDK5 has no intrinsic nuclear localization signal (NLS) but contains two weak nuclear export signals (NES). Its nuclear localization relies on its binding to the cyclin-dependent kinase inhibitor p27, whereas its cytoplasmic localization is achieved through the NES-CRM-1 nuclear export mechanism (Zhang et al. 2010a). Structurally, CDK5/p27 interaction requires two protein faces involving threonine 17 on CDK5 (Zhang et al. 2010a) and tryptophan 60 on p27 (Kawauchi et al. 2006).

Biological Functions

Cell Cycle Control

Ectopic expressed CDK5 does not promote cell cycle progression or change cell cycle distribution in several mammalian cell lines, so roles of CDK5 in cell cycle regulation are questioned (van den Heuvel and Harlow 1993). However, CDK5 plays crucial roles for neuronal cell cycle arrest. Postmitotic neurons cannot reenter a new cell cycle (Herrup and Yang 2007). Deficiency of CDK5 in neurons leads to loss of cell cycle arrest and cell death (Cicero and Herrup 2005). Latter studies reveal that dynamic nuclear/cytoplasmic translocation of CDK5 determines cell cycle arrest. β-amyloid peptide-treated primary neurons reenter a new cell cycle. They show localization of CDK5 changes from nuclear to cytoplasmic compartment. Loss of nuclear CDK5 is also observed in cycling cells (NIH 3T3), when cells reenter a cell cycle after serum starvation (Zhang et al. 2008). Blocking nuclear export abolishes cell cycle reentry (Zhang et al. 2008). The interaction between CDK5 and p27 contributes to nuclear localization. Moreover, p27 tightly regulates mitogenic signals to the cell cycle at the restriction point and is essential for G0 arrest (Coats et al. 1996). Transcription factor E2F1, a major factor regulating the G0/G1- to S-phase transition (Trimarchi and Lees 2002), also interacts with CDK5. The assembling of E2F1-CDK5-p35 complex in neuronal nucleus excludes the E2F1 cofactor, DP1, thus inhibiting E2F1 binding to cell cycle gene promoter and driving the cycle (Zhang et al. 2010b). The p27 can affect assembling of E2F1-CDK5-p35 trimer because the N-terminal truncation of CDK5 which lacks the binding domain with p27 loses its interaction with E2F1 (Zhang and Herrup 2011). In turn, CDK5/p35 directly phosphorylates and stabilizes p27, maintaining the amount of p27 in postmitotic neurons (Kawauchi et al. 2006).

Neuronal Survival, Migration, and Synaptic Plasticity

CDK5 activity is essential for a variety of neuronal functions such as neuronal survival, neuronal migration, and synaptic plasticity (Hisanaga and Endo 2010). CDK5-null mice exhibit perinatal lethality associated with unique lesions in brain development, including neuronal loss, neuronal migration defects, disrupted forebrain layering, as well as loss of cortical laminar structure (Ohshima et al. 1996) (Takahashi et al. 2010). CDK5 phosphorylates neuregulin receptors (ErbB), supporting neuregulin-mediated neuronal survival via PI3K/Akt activation (Li et al. 2003). CDK5 associates with and phosphorylates Bcl-2 to maintain its survival function (Cheung et al. 2008). By comparison, phosphorylation of JNK3 by CDK5 inhibits JNK3 activity and subsequent c-Jun phosphorylation, reducing neuronal apoptosis (Li et al. 2002). CDK5 phosphorylates and inhibits MEK1, repressing ERK induced apoptosis in cortical neurons (Zheng et al. 2007). CDK5 can protect neurons against oxidative damage via phosphorylating nuclear factor-erythroid 2-related factor-2 (Nrf2). Phosphorylated Nrf2 induces antioxidant gene expression and boosts glutathione metabolism (Jimenez-Blasco et al. 2015). Besides that, CDK5 regulates locomotion mode which covers most of neuronal migration routes in the developing cerebral cortex (Nishimura et al. 2010). CDK5 also contributes to proper position of the cortical neurons (Ohshima et al. 2001), facial branchiomotor, and inferior olive neurons (Ohshima et al. 2002) in the developing mouse brain. These biological functions mainly rely on CDK5-mediated phosphorylation of a number of substrates, including PAK1 (Rashid et al. 2001), focal adhesion kinase (Fak) (Xie et al. 2003), doublecortin (DCX) (Tanaka et al. 2004), microtubule-associated protein (MAP1B) (Kawauchi et al. 2005), G protein regulated inducer of neurite outgrowth 1 (Grin1) (Contreras-Vallejos et al. 2014), and drebrin (Tanabe et al. 2014). Ras-related protein/guanine nucleotide-exchange factor (RapGEF) signaling is critically involved in neuronal migration (Bos et al. 2001). By phosphorylation of RapGEF1(Utreras et al. 2013) or RapGEF2 (Ye et al. 2014), CDK5 facilitates proper neuronal migration in the cerebral cortex.

The induction of synaptic plasticity as well as spatial learning is affected in CDK5 or p35-null mice (Ohshima et al. 2005; Takahashi et al. 2010; Mishiba et al. 2014). By phosphorylation of numerous substrates, CDK5 is involves in regulating every aspect of synaptic function, from neurotransmitter release, vesicle cycling, and ion channel modulation to protein clustering and synaptic structural change along with spine formation (Lai and Ip 2009). CDK5 functions as an integral element in synaptic homeostatic scaling by influencing the number (Kim and Ryan 2010) and size (Marra et al. 2012) of synaptic vesicles when driving neurotransmitter release. CDK5-dependent phosphorylation of dephosphin protein contributes to maintaining synaptic vesicle endocytosis in nerve terminals (Tan et al. 2003). CDK5 can regulate polarity of neuropeptide-containing dense-core vesicles (DCVs) by promoting DCV trafficking in axons (Goodwin et al. 2012). NR2B, the subunit of N-methyl-D-aspartate receptor (NMDAR), improves synaptic plasticity and memory. CDK5 helps NR2B-containing NMDAR to localize in synaptic membrane, thereby modulating NMDAR-mediated synaptic currents (Plattner et al. 2014). CDK5 dynamically regulates Ca2+ channel. Phosphorylation of N-type Ca2+ channel by CDK5 enhances (Su et al. 2012), whereas phosphorylation of P/Q-type voltage-dependent Ca2+ channel reduces Ca2+ influx and neurotransmitter release (Tomizawa et al. 2002). Postsynaptic density 95 (PSD-95), a postsynaptic scaffolding protein, is implicated in synaptic maturation, strength, and plasticity. CDK5 phosphorylates PSD-95 and regulates the clustering of PSD-95/NMDA receptors at synapse (Morabito et al. 2004). CDK5 inhibits protein interaction between PSD-95 and Mdm2 (ubiquitin E3 ligase) and reduces PSD-95 ubiquitination, thereby repressing its subsequent interaction with clathrin adaptor protein complex AP-2 (Bianchetta et al. 2011). Through phosphorylation of TrkB, a receptor of neurotrophin brain-derived neurotrophic factor (BDNF), CDK5 activates Rac1 during dendritic spine remodeling, which is crucial for spatial memory formation (Lai et al. 2012). Both Cyclic AMP and CDK5 participate in phosphorylation of Wiskott–Aldrich syndrome protein family verprolin homologous protein 1(WAVE1) in neurons, which plays an essential role in the formation of the filamentous actin cytoskeleton, and thus in the regulation of dendritic spine morphology (Kim et al. 2006).

β-Cell and Insulin Secretion

CDK5 promotes pancreatic β-cell survival and proliferation via phosphorylating Fak (Daval et al. 2011) and retinoblastoma (Rb) (Draney et al. 2016). CDK5 is also involved in regulating gene transcription and protein secretion of insulin, a key glucose-lowering hormone. But this regulation is complex, depending on culture conditions (high vs. low glucose and duration). Glucose (20 mM, 24 h) upregulates CDK5/p35 activity through increasing p35 mRNA and protein expression in INS-1 cell. The active CDK5/p35 further activates insulin promoter (Ubeda et al. 2004). Munc18-1, an essential regulator in membrane fusion, is a substrate of CDK5. CDK5-dependent phosphorylation promotes Ca2+-dependent insulin exocytosis in primary β-cell treated with 10 mM glucose (Lilja et al. 2004). Phosphorylation of phospholipase D2 (PLD2) by CDK5 is an important process in the generation of phosphatidic acid and subsequent fusion event, which controls insulin secretion (Lee et al. 2008). Moreover, CDK5-mediated phosphorylation of β2-syntrophin can enhance insulin secretion by promoting the mobilization of cortical granules in β-cell (Schubert et al. 2010).

Endothelial Cell and Adipocyte

CDK5 expression is low in quiescent whereas high in proliferating endothelial cells. The highest CDK5 expression is detected when cells prepare for division (Sharma et al. 2004). CDK5 is required for endothelial cell motility and angiogenesis via regulating the activity of small GTPase Rac1 (Liebl et al. 2010). By phosphorylation of the forkhead transcription factor 2 (Foxc2), CDK5 is essential for lymphatic vessel development and lymphatic vascular remodeling (Liebl et al. 2015). CDK5-dependent phosphorylation of endothelial nitric oxide synthase (eNOS) at serine 113 (Chang et al. 2010) or serine 116 (Cho et al. 2010) reduces nitric oxide production. In 3T3-L1 adipocyte, CDK5/p35 interacts with glucose transporter type 4(GLUT4). The activity of CDK5 is stimulated by insulin which is dependent on PI3K pathway. The active CDK5 phosphorylates synaptotagmin homolog E-Syt1 and contributes to protein interaction between E-Syt1 and GLUT4, which leads to enhanced glucose uptake in adipocytes (Lalioti et al. 2009). However, a contradictory statement is proposed that CDK5-dependent phosphorylation of Rho family GTP-binding protein TC10α is responsible for its inhibitory function on insulin-stimulated GLUT4 translocation in 3T3-L1 adipocyte (Okada et al. 2008).

Pathological Functions

Neuronal Disease

Aberrant activation of CDK5 triggers pathological events in the central nervous system, leading to neurodegenerative disorders such as Alzheimer’s (AD) and Parkinson’s diseases (PD). AD is the most common form of dementia in elderly population, featured by progressive impairment of cognitive functions. The predominant hallmarks of AD pathology include extracellular deposition of β-amyloid peptide in senile plaques, intracellular accumulation of hyperphosphorylated tau protein in neurofibrillary tangles (NFTs), neuronal loss, and synaptic dysfunction (Liu et al. 2016). In human AD postmortem brain, a significant elevation of CDK5 activity is detected, accompanied by accumulation of p25 and active calpain (Grynspan et al. 1997; Lee et al. 1999; Tseng et al. 2002). Animal studies confirm the contribution of CDK5 deregulation to neuronal loss in AD (Cruz and Tsai 2004). PD is a common movement disorder, which is characterized by the early selective dopaminergic neuron loss in the substantia nigra and formation of Lewy bodies. Elevated calpain levels as well as increased CDK5/p35 are also observed in postmortem PD brains (Mouatt-Prigent et al. 1996; Nakamura et al. 1997). Calpain-mediated cleavage of p35 into p25 has been regarded as the predominant culprit of hyperactivation of CDK5 activities, leading to this pathological event (Cruz et al. 2003).

In AD pathology, CDK5/p25 forms a vicious cycle with Aβ. Aβ is derived from β-secretase (BACE1)-mediated cleavage of glycoprotein APP. CDK5/p25 can promote Aβ generation and accumulation by direct and indirect regulations of APP. Direct phosphorylation of APP by CDK5/p25 at threonine688 is found to not only increase Aβ formation but also transform GSK-3β activity for APP to modulate Aβ generation (Wilkaniec et al. 2016). Enhanced BACE1 transcription by CDK5-mediated phosphorylation of STAT3 (Wen et al. 2008) as well as elevated presenilin level via phosphorylation of PS1 by CDK5 (Lau et al. 2002) can lead to increased production of Aβ from APP. CDK5-mediated phosphorylation of Foxo3 initially rescues cells from oxidative stress by upregulating Mn-superoxide dismutase (MnSOD) but eventually promotes neuronal death and aberrant Aβ processing via activating genes of Bim and FasL (Shi et al. 2016). In turn, Aβ generation triggers Ca2+ influx, thereby further activating calpain-dependent cleavage of p35 to p25 (Kawahara 2010). Aβ-stimulated CDK5 activation can induce p38 activation via generation of reactive oxygen species (ROS) in neuronal cells, thus increasing expression of c-Jun, which is overexpressed in AD and significantly contributes to neurodegenerative diseases (Chang et al. 2010). Aβ can increase S-nitrosylation of CDK5 and activates CDK5 activity by evoking calcium imbalance (Qu et al. 2012). The increased S-nitrosylation induces nitrosylation of dynamin-related protein 1 (Drp1), contributing to excessive mitochondrial fragmentation, with subsequent bioenergetics compromise and dendritic spine loss (Qu et al. 2011). This positive feedback loop results in accumulation of Aβ in the postmitotic neuron, which induces neurotoxicity associated with amyloid cascade and finally leads to neuronal loss. CDK5/p25 has been shown potent capability to phosphorylate tau at various sites directly or indirectly. The direct phosphorylation of tau leads to NFT formation in AD. This modification of tau impairs its capability to assemble tubulin into microtubules, thereby inducing dysfunctions of cytoskeleton and axonal transport. Phosphorylation by CDK5 also causes tau oligomerization and then aggregation into intraneuronal tangles of paired helical filaments (PHF), the main components of NFTs. GSK-3β is another important kinase involved in tau phosphorylation and proved to be activated by binding of p25 (Chow et al. 2014). CDK5-mediated phosphorylation of protein phosphates 1 contributes to increased tau phosphorylation. PI3K/Akt pathway can be activated by CDK5, leading to increased tau accumulation (Dickey et al. 2008). In AD transgenic mice, c-Abl can further promote CDK5 activity by phosphorylation of tyrosine15 and promote tau hyperphosphorylation (Zukerberg et al. 2000).

In AD progression, hyperactivation of CDK5/p25 is involved in neuron apoptosis as well as neuron death via multiple mechanisms. For example, CDK5/p25 is proved to induce the expression and activity of the p53 tumor suppressor by phosphorylation, thus promoting expression of its downstream proapoptotic target Bax (Lee et al. 2007). Phosphorylation of lamin A and B1 in neurons by CDK5 results in robust nuclear fragmentation and high neurotoxicity, which is an early and irreversible trigger for apoptosis (Chang et al. 2011). CDK5 is also responsible for neurotoxicity-induced apoptosis through phosphorylation of transcription factor MEF2 (Ke et al. 2015). Reduced activity of apurinic/apyrimidinic endonuclease 1 via phosphorylation by CDK5 leads to dysfunction of base excision repair following DNA damage and further neuronal death (Huang et al. 2010). Cell cycle reentry indicates the stress-induced conversion of mature neurons from the steady G0 state to reenter the cell cycle, which has been revealed in human AD brains (Lopes et al. 2009). Neuron cells encountering cell cycle reentry cannot go through G2/M checkpoint and then initiates apoptotic cell death pathways. CDK5 deregulation triggers reentry of cell cycle, which acts as a novel mechanism related with neuronal apoptosis and death (Folch et al. 2012). CDK5 deregulation triggered by Aβ or other stimuli can translocate CDK5 from nucleus to cytoplasm and impair assembling of E2F1-CDK5-p35-p27 in neuronal nucleus. Thus, CDK5 loses capability to control cell cycle arrest (Trimarchi and Lees 2002) (Zhang and Herrup 2011). CDK5 improves the CDK1/2/4 kinase activities via phosphorylation of cell division cycle proteins, Cdc 25A/B/C phosphatases, thus leading to cell cycle-driven death (Chang et al. 2012).

In PD pathology, α-synuclein (ASN) is the major protein linked to PD neuronal pathology. In vitro studies show that ASN can activate CDK5 activity by phosphorylating CDK5 at tyrosine15 and induce calpain-dependent formation of p25 (Czapski et al. 2013). Dysfunction of parkin, a ubiquitin-protein ligase, is another key cause of PD. Parkin phosphorylation by CDK5 results in aggregation and impairment of parkin enzymatic activity, with subsequent accumulation of toxic misfolded proteins (Avraham et al. 2007). CDK5/p35 is critical for mitochondrial toxin-induced dopaminergic death. CDK5-mediated phosphorylation of Prx2, an antioxidant enzyme, reduces its peroxidase activity (Qu et al. 2007). CDK5-mediated phosphorylation of EndoB1 at tyrosine145 is also required in autophagy and neuronal loss in PD (Wong et al. 2011) (Fig. 1).
CDK5, Fig. 1

Pathological roles of CDK5 in neuronal diseases. Calpain-mediated cleavage of p35 to p25 prolongs activation of CDK5. β-amyloid peptide (Aβ), oxidative stress, DNA damage, and toxic stimuli can induce calcium influx, thus activating calpain. CDK5/p25 can facilitate Aβ generation and accumulation through STAT3, BACE1, PS1, etc. CDK5/p25 can phosphorylate p53 to trigger apoptotic pathways, leading to neuron apoptosis and death. CDK5/p25 not only hyperphosphorylates tau protein by itself but also regulate kinase GSK-3β-mediated phosphorylation of tau protein, promoting Alzheimer’s diseases. Aβ also facilitates S-nitrosylation of CDK5. CDK5 induces transnitrosylation of Drp1and results in mitochondrial dysfunction and spine loss. MPP+ treatment can activate CDK5 activity. The a-synuclein (ASN) can also increase CDK5 activation by phosphorylation. CDK5/p25 can phosphorylate parkin, leading to aborative ubiquitination and misfolded protein accumulation. CDK5/p25 elevated autophagy via phosphorylation of EndoB1. CDK5/p25 also causes excessive oxidative stress by phosphorylating Prx2. All these regulations eventually result in neuron loss and progressive Parkinson’s diseases

Cardiometabolic Diseases

In type 2 diabetes, sustained high glucose impairs pancreatic β-cell survival and function, termed as glucotoxicity (Butler et al. 2003). β-cells under glucotoxicity conditions (30 mM Glucose, 48 h) exhibit pronounced activation of CDK5/p35 but reduced insulin gene transcription. PDX-1, a pancreas specific transcription factor, enhances insulin gene expression by binding to insulin promoter (Harmon et al. 1998). CDK5-dependent phosphorylation of PDX-1 depletes its nuclear localization and insulin promoter binding (Ubeda et al. 2006). CDK5 phosphorylates loop II-III of the α1C subunit of L-type voltage-dependent Ca2+ channel (L-VDCC), leading to decreased L-VDCC activity. Inhibition of CDK5 specifically enhances inward Ca2+ current and Ca2+ influx across L-VDCC upon stimulation with high glucose, concurrent with increased insulin secretion. However, no effects are observed in the presence of low-glucose stimuli (Wei et al. 2005). Compared with wild-type mice, p35-null mice challenged with glucose show higher insulin secretion but lower blood glucose level (Wei et al. 2005). These evidences suggest that CDK5-dependent insulin secretion is a stimulation-dependent event under pathophysiological regulation. CDK5 also plays a role in regulating insulin sensitivity. Phosphorylation of PPARγ by CDK5 suppresses gene expressions of insulin-sensitizing adipokines such as adiponectin and adipsin (Choi et al. 2010). Mice challenged with high-fat/high-sugar diet for 13 weeks show hyperinsulinaemia, increased p25, and enhanced CDK5 activity in line with increased phosphorylation of PPARγ at serine 273. CDK5-mediated phosphorylation occurs in both inguinal fat and epididymal fat, with greater intensity in epididymal depots (Choi et al. 2010). Administration with pharmacological compounds that bind to the ligand-binding domain of PPARγ (Thiazolidinedione, TZD) competitively blocks CDK5-dependent phosphorylation and restores the target gene expressions. As a result, mice subjected to the treatment exhibit improved glucose tolerance and reduced fasting insulin levels (Choi et al. 2010) (Amato et al. 2012) (Fig. 2).
CDK5, Fig. 2

The pathological roles of CDK5 in diabetes mellitus. High glucose increases CDK5/p35 activity in pancreatic β-cell. Over-activated CDK5/p35 impairs nuclear PDX-1 binding to insulin promoter, thereby suppressing insulin gene expression. CDK5/p35 also phosphorylates L-type voltage-dependent Ca2+ channel (L-VDCC), which reduces L-VDCC activity and decreases insulin secretion (left). In adipocytes, increased phosphorylation of PPARγ (peroxisome proliferator-activated receptor γ) under obese state is driven by CDK5. This phosphorylation suppresses a number of PPARγ controlled-gene expressions of insulin-sensitizing adipokines. Thiazolidinedione (TZD) can block CDK5-dependent phosphorylation

Vascular aging is a major risk factor for development of atherosclerosis and, therefore, for coronary artery diseases. This pathology is associated with a reduction in the regenerative capacity of the endothelium but increased endothelial senescence (Brandes et al. 2005). Senescent endothelial cells undergoing morphological alternations and growth arrest are proinflammatory, proatherosclerotic, and prothrombotic (Erusalimsky 2009). CDK5 activity is increased in senescent endothelial cells, aged or atherosclerotic mouse artery tissues, in line with elevated p25 level (Bai et al. 2012, 2014). In addition, activated CDK5 and increased p25 are also detected in endothelial cells exposed to hypoxia (Kim et al. 2015) or in human brain microvessels following acute ischemic injury (Mitsios et al. 2007). CDK5 acts as an upstream kinase to phosphorylate the serine 47 residue of SIRT1, a key longevity regulator with potent antivascular ageing activity (Zu et al. 2010; Wang et al. 2011; Bai and Wang 2013). CDK5-dependent phosphorylation of SIRT1 prevents its intracellular translocation from nuclear to the cytosol compartment, where it exerts antisenescence effects by promoting the degradation of LKB1. In addition, this modification also abolishes interaction between SIRT1 with telomeric repeat-binding factor 2-interacting protein 1 (TERF2IP) in nuclei, in turn contributing to proinflammatory response mediated by TERF2IP/NFκB cascade. Consistently, senescent endothelial cells or aged mouse vessels exhibit significantly elevated inflammatory gene expression (Bai et al. 2012, 2014) (Fig. 3).
CDK5, Fig. 3

The pathological roles of CDK5 in endothelial dysfunction. CDK5 acts as an upstream kinase to phosphorylate serine 47 of SIRT1, thereby preventing its intracellular translocalization from nuclei to the cytosol compartment where it exerts antisenescence effects by promoting degradation of LKB1. In addition, this modification also abolishes interaction between SIRT1 with telomeric repeat-binding factor 2-interacting protein 1 (TERF2IP) in nuclei, in turn contributing to proinflammatory response mediated by TERF2IP/NFκB cascade. Phosphorylation of eNOS at serine 113/116 impairs this enzyme activity and decreases nitric oxide production

Cancer

CDK5 has been implicated in the development of various types of cancers. Gene copy number of CDK5 is increased in human gastric cancer genome (Yang 2007). CDK5 promoter polymorphisms contribute to the genetic susceptibility to human lung cancer (Choi et al. 2009). Moreover, increased CDK5/p35 expression is detected in human hepatocellular carcinoma (HCC) (Ehrlich et al. 2015), non–small cell lung cancer (Liu et al. 2011), and nasopharyngeal carcinoma (NPC) (Zhang et al. 2015). Elevated p35 alone is found in invasive prolactin pituitary adenomas (Xie et al. 2016). The positive correlation between high level of CDK5 and lymph node metastasis is observed in NPC patients (Zhang et al. 2015) or patients with lung cancer (Liu et al. 2011). CDK5 regulates STAT3 activation by phosphorylation at serine 727, which promotes androgen receptor activity and supports prostate cancer growth (Hsu et al. 2013). CDK5 also modulates phosphorylation of Rb and activates downstream effectors, CDK2/cyclin A, thereby inducing medullary thyroid carcinoma (Pozo et al. 2013). Isoform A of phosphatidylinositol 3-kinase enhancer (PIKE-A), a prooncogenic factor, is phosphorylated by CDK5. This phosphorylation stimulates activity of PIKE-A GTPase and downstream Akt, thereby benefitting migration and invasion of human glioblastoma cells (Liu et al. 2008). CDK5-dependent phosphorylation can downregulate protein stability of caldesmon, in turn rescues motility and invasion/migration of melanoma cell (Bisht et al. 2015). Talin is a β-integrin tail-binding protein required for integrin activation. CDK5-dependent phosphorylation at head domain inhibits its ubiquitination and degradation. Thus, CDK5 controls talin head turnover, adhesion stability, and ultimately pheochromocytoma cell migration (Huang et al. 2009). Phosphorylation of FAK by CDK5 is found to be involved in TGFβ1 induced epithelial-mesenchymal transition in breast cancer (Liang et al. 2013). Despite information above, the impacts of CDK5 on tumor cell survival and migration have not been addressed in details yet.

Pharmacological Inhibitors

Nowadays, inhibition of CDK5 is pharmacologically achievable. Acitvity of CDK5 can be blocked upon occupation of its ATP-binding pockets by specific compounds. Roscovitine ([2-(1-ethyl-2- hydroxyethylamino)-6-benzylamino-9-isopropylpurine, also CYC202, (R)-Roscovitine, Seliciclib]) is a chemically synthesized purine analogue displaying high efficiency and selectivity towards CDKs. Due to the lowest IC50 value (0.16 μM) of CDK5 compared with other CDKs (Meijer et al. 1997), roscovitine is widely used as CDK5 inhibitor in basic research or clinical trials. With rat model of traumatic brain injury, roscovitine reduces neuronal loss, glial activation, and neurologic defects (Hilton et al. 2008). Roscovitine downregulates p38-induced c-Jun expression upon Aβ stimulation, thereby decreasing neuron death in primary neuron cells (Chang et al. 2010). Roscovitine can exert protective effect for β-cell against glucotoxicity (Ubeda et al. 2006). It also restores antisenescence functions of SIRT1 and exhibits therapeutic potential for combating vascular senescence and atherosclerosis in vivo (Bai et al. 2012, 2014). Roscovitine has been tested in several clinical trials in patients with non–small cell lung cancer, hepatocellular carcinoma, and undifferentiated nasopharyngeal carcinoma. But only partial tumor response is observed in some patients (Benson et al. 2007; Le Tourneau et al. 2010; Hsieh et al. 2009). A truncated form of p35 consisting of residues 154–279 demonstrated high affinity to CDK5 and is termed as CDK5 inhibitory peptide (CIP) (Kesavapany et al. 2004, 2007). CIP is found to selectively inhibit CDK5/p25 complex activity without affecting CDK5/p35 or mitotic CDK activities both in vitro and in vivo. Tau hyperphosphorylation and apoptosis is reduced in primary neurons by CIP (Zheng et al. 2005; Kesavapany et al. 2007). Overexpression of CIP in mice can reduce neuroinflammation by antagonizing deleterious effects of tau and amyloid pathologies (Sundaram et al. 2013). CIP can protect β-cell against glucotoxicity induced by high glucose and recover insulin secretion (Zheng et al. 2013). A 24-residue peptide, p5 fragment, spanning CIP residues Lys245-Ala277 is determined as a more effective peptide that selectively inhibit CDK5/p25 activities, demonstrating reduced Aβ-neuronal loss in cortical neurons (Binukumar et al. 2015). Calpain inhibitors also have potential to inhibit aberrant CDK5/p25 hyperactivities. Calpain activation by abnormal Ca2+ influx is closely related NMDAR activities. An NMDAR antagonist, D-2-amino-5-phosphonovalerate, and a non-NMDAR antagonist, 6-cyano-7-nitroquinoxaline-2, are utilized to reduce activation of calpain, however fail in clinical trials due to unacceptable side effects. A transactivating regulatory protein-metabotropic glutmate receptor 1 is later developed as an alternative to general receptor antagonist and shows neuroprotective effects (Xu et al. 2009). Inhibition of calpain activity or its downstream targets also exhibits neuroprotection. Apart from the intrinsic inhibitor of calpain, calpastatin, a number of reversible or irreversible exogenous caplain inhibitors are developed including AJK275, MDL-28170, PD150606, SJA6017, A-705253, SNJ-1945, and Calpeptin (Yildiz-Unal et al. 2015).

Summary

In summary, it is certain that CDK5 is of great importance in the development of CNS. It is also functionally important in various types of cells and physiological contexts. However, aberrant expression or activation of CDK5 turns it into an active participant of multiple pathogenic events. Inhibition of CDK5 is pharmacologically accessible. Although preclinical studies have shown therapeutic potentials of CDK5 inhibitors against neurodegeneration, high glucose induced glucotoxicity, endothelial senescence as well as tumorigenesis and metastasis, its translational values have not been supported by sufficient clinical evidence. The limited clinical trials only show partial antitumor response of CDK5 inhibition in tumor patients. Evaluations in other pathologies are still lacking. What is more, mechanistic roles of CDK5 in different pathogenesis deserve intensive investigations because of the versatility of this kinase in different cell types and tissues. How does CDK5 complex switch from physiological to pathological events precisely? Are there any other mechanisms contributing to AD apart from cleavage of p35 to p25? Does CDK5 signaling participate in innate and acquired immune response in neurodegeneration? In nonneuronal cells, does CDK5 still suppress cell cycle reentry? Is this mechanism also involved in endothelial senescence or tumor cell growth? Why is CDK5 expression increased in many cancer cases but maintained stable under other pathological conditions? Which mechanism is responsible for different transcriptional/translational regulation of CDK5 in different cell types? Future studies will be of great significance to clarify the detailed CDK5-related mechanisms in different pathological pathways, which will supply more cues for therapeutic approach development.

References

  1. Alvarez A, Toro R, Cáceres A, Maccioni RB. Inhibition of tau phosphorylating protein kinase cdk5 prevents β-amyloid-induced neuronal death. FEBS Lett. 1999;459:421–6.CrossRefPubMedGoogle Scholar
  2. Amato AA, Rajagopalan S, Lin JZ, Carvalho BM, Figueira ACM, Lu J, et al. GQ-16, a novel peroxisome proliferator-activated receptor gamma (PPAR gamma) ligand, promotes insulin sensitization without weight gain. J Biol Chem. 2012;287:28169–79. doi: 10.1074/jbc.M111.332106.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Asada A, Yamamoto N, Gohda M, Saito T, Hayashi N, Hisanaga S. Myristoylation of p39 and p35 is a determinant of cytoplasmic or nuclear localization of active cycline-dependent kinase 5 complexes. J Neurochem. 2008;106:1325–36. doi: 10.1111/j.1471-4159.2008.05500.x.CrossRefPubMedGoogle Scholar
  4. Asada A, Saito T, Hisanaga S. Phosphorylation of p35 and p39 by Cdk5 determines the subcellular location of the holokinase in a phosphorylation-site-specific manner. J Cell Sci. 2012;125:3421–9. doi: 10.1242/jcs.100503.CrossRefPubMedGoogle Scholar
  5. Avraham E, Rott R, Liani E, Szargel R, Engelender S. Phosphorylation of Parkin by the cyclin-dependent kinase 5 at the linker region modulates its ubiquitin-ligase activity and aggregation. J Biol Chem. 2007;282:12842–50.CrossRefPubMedGoogle Scholar
  6. Bai B, Wang Y. Methods to investigate the role of SIRT1 in endothelial senescence. Methods Mol Biol. 2013;965:327–39. doi: 10.1007/978-1-62703-239-1_22.CrossRefPubMedGoogle Scholar
  7. Bai B, Liang Y, Xu C, Lee MY, Xu A, Wu D, et al. Cyclin-dependent kinase 5-mediated hyperphosphorylation of sirtuin-1 contributes to the development of endothelial senescence and atherosclerosis. Circulation. 2012;126:729–40. doi: 10.1161/CIRCULATIONAHA.112.118778.CrossRefPubMedGoogle Scholar
  8. Bai B, Vanhoutte PM, Wang Y. Loss-of-SIRT1 function during vascular ageing: hyperphosphorylation mediated by cyclin-dependent kinase 5. Trends Cardiovasc Med. 2014;24:81–4. doi: 10.1016/j.tcm.2013.07.001.CrossRefPubMedGoogle Scholar
  9. Baumann K, Mandelkow E-M, Biernat J, Piwnica-Worms H, Mandelkow E. Abnormal Alzheimer-like phosphorylation of tau-protein by cyclin-dependent kinases cdk2 and cdk5. FEBS Lett. 1993;336:417–24.CrossRefPubMedGoogle Scholar
  10. Benson C, White J, De Bono J, O’Donnell A, Raynaud F, Cruickshank C, et al. A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days. Br J Cancer. 2007;96:29–37. doi: 10.1038/sj.bjc.6603509.CrossRefPubMedGoogle Scholar
  11. Bianchetta MJ, Lam TT, Jones SN, Morabito MA. Cyclin-dependent kinase 5 regulates PSD-95 ubiquitination in neurons. J Neurosci. 2011;31:12029–35. doi: 10.1523/Jneurosci.2388-11.2011.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Bibb JA, Snyder GL, Nishi A, Yan Z, Meijer L, Fienberg AA, et al. Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. Nature. 1999;402:669–71.CrossRefPubMedGoogle Scholar
  13. Bibb JA, Chen J, Taylor JR, Svenningsson P, Nishi A, Snyder GL, et al. Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5. Nature. 2001;410:376–80.CrossRefPubMedGoogle Scholar
  14. Binukumar BK, Shukla V, Amin ND, Bhaskar M, Skuntz S, Steiner J, et al. Analysis of the inhibitory elements in the p5 peptide fragment of the CDK5 activator, p35, CDKR1 protein. J Alzheimers Dis. 2015;48:1009–17. doi: 10.3233/Jad-150412.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Bisht S, Nolting J, Schutte U, Haarmann J, Jain P, Shah D, et al. Cyclin-dependent kinase 5 (CDK5) controls melanoma cell motility, invasiveness, and metastatic spread-identification of a promising novel therapeutic target. Transl Oncol. 2015;8:295–307. doi: 10.1016/j.tranon.2015.06.002.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Bos JL, de Rooij J, Reedquist KA. Rap1 signalling: adhering to new models. Nat Rev Mol Cell Biol. 2001;2:369–77. doi: 10.1038/35073073.CrossRefPubMedGoogle Scholar
  17. Brandes RP, Fleming I, Busse R. Endothelial aging. Cardiovasc Res. 2005;66:286–94. doi: 10.1016/j.cardiores.2004.12.027.CrossRefPubMedGoogle Scholar
  18. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52:102–10.CrossRefPubMedGoogle Scholar
  19. Chang KH, De Pablo Y, HP L, HG L, Smith MA, Shah K. Cdk5 is a major regulator of p38 cascade: relevance to neurotoxicity in Alzheimer’s disease. J Neurochem. 2010;113:1221–9.PubMedGoogle Scholar
  20. Chang KH, Multani PS, Sun KH, Vincent F, de Pablo Y, Ghosh S, et al. Nuclear envelope dispersion triggered by deregulated Cdk5 precedes neuronal death. Mol Biol Cell. 2011;22:1452–62. doi: 10.1091/mbc.E10-07-0654.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Chang KH, Vincent F, Shah K. Deregulated Cdk5 triggers aberrant activation of cell cycle kinases and phosphatases inducing neuronal death. J Cell Sci. 2012;125:5124–37. doi: 10.1242/jcs.108183.CrossRefPubMedGoogle Scholar
  22. Cheung ZH, Gong K, Ip NY. Cyclin-dependent kinase 5 supports neuronal survival through phosphorylation of Bcl-2. J Neurosci. 2008;28:4872–7. doi: 10.1523/Jneurosci.0689-08.2008.CrossRefPubMedGoogle Scholar
  23. Ching Y-P, Pang AS, Lam W-H, Qi RZ, Wang JH. Identification of a neuronal Cdk5 activator-binding protein as Cdk5 inhibitor. J Biol Chem. 2002;277:15237–40.CrossRefPubMedGoogle Scholar
  24. Cho DH, Seo J, Park JH, Jo C, Choi YJ, Soh JW, et al. Cyclin-dependent kinase 5 phosphorylates endothelial nitric oxide synthase at serine 116. Hypertension. 2010;55:345–52. doi: 10.1161/HYPERTENSIONAHA.109.140210.CrossRefPubMedGoogle Scholar
  25. Choi HS, Lee Y, Park KH, Sung JS, Lee JE, Shin ES, et al. Single-nucleotide polymorphisms in the promoter of the CDK5 gene and lung cancer risk in a Korean population. J Hum Genet. 2009;54:298–303. doi: 10.1038/jhg.2009.29.CrossRefPubMedGoogle Scholar
  26. Choi JH, Banks AS, Estall JL, Kajimura S, Bostrom P, Laznik D, et al. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5. Nature. 2010;466:451–6. doi: 10.1038/nature09291.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Choi JH, Banks AS, Kamenecka TM, Busby SA, Chalmers MJ, Kumar N, et al. Antidiabetic actions of a non-agonist PPAR gamma ligand blocking Cdk5-mediated phosphorylation. Nature. 2011;477:477–U131. doi: 10.1038/nature10383.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Chow HM, Guo D, Zhou JC, Zhang GY, Li HF, Herrup K, et al. CDK5 activator protein p25 preferentially binds and activates GSK3beta. Proc Natl Acad Sci U S A. 2014;111:E4887–95. doi: 10.1073/pnas.1402627111.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Cicero S, Herrup K. Cyclin-dependent kinase 5 is essential for neuronal cell cycle arrest and differentiation. J Neurosci. 2005;25:9658–68. doi: 10.1523/Jneurosci.1773-05.2005.CrossRefPubMedGoogle Scholar
  30. Coats S, Flanagan WM, Nourse J, Roberts JM. Requirement of p27Kip1 for restriction point control of the fibroblast cell cycle. Science. 1996;272:877–80.CrossRefPubMedGoogle Scholar
  31. Contreras-Vallejos E, Utreras E, Borquez DA, Prochazkova M, Terse A, Jaffe H, et al. Searching for novel Cdk5 substrates in brain by comparative phosphoproteomics of wild type and Cdk5−/− mice. PLoS One. 2014;9:e90363. doi: 10.1371/journal.pone.0090363.CrossRefPubMedPubMedCentralGoogle Scholar
  32. Cruz JC, Tsai LH. Cdk5 deregulation in the pathogenesis of Alzheimer’s disease. Trends Mol Med. 2004;10:452–8. doi: 10.1016/j.molmed.2004.07.001.CrossRefPubMedGoogle Scholar
  33. Cruz JC, Tseng H-C, Goldman JA, Shih H, Tsai L-H. Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron. 2003;40:471–83.CrossRefPubMedGoogle Scholar
  34. Czapski GA, Gąssowska M, Wilkaniec A, Cieślik M, Adamczyk A. Extracellular alpha-synuclein induces calpain-dependent overactivation of cyclin-dependent kinase 5 in vitro. FEBS Lett. 2013;587:3135–41.CrossRefPubMedGoogle Scholar
  35. Daval M, Gurlo T, Costes S, Huang CJ, Butler PC. Cyclin-dependent kinase 5 promotes pancreatic beta-cell survival via Fak-Akt signaling pathways. Diabetes. 2011;60:1186–97. doi: 10.2337/db10-1048.CrossRefPubMedPubMedCentralGoogle Scholar
  36. Dickey CA, Koren J, Zhang YJ, Xu YF, Jinwal UK, Birnbaum MJ, et al. Akt and CHIP coregulate tau degradation through coordinated interactions. Proc Natl Acad Sci USA. 2008;105:3622–7. doi: 10.1073/pnas.0709180105.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Draney C, Hobson AE, Grover SG, Jack BO, Tessem JS. Cdk5r1 overexpression induces primary beta-cell proliferation. J Diabetes Res. 2016;2016:6375804. doi: 10.1155/2016/6375804.CrossRefPubMedGoogle Scholar
  38. Ehrlich SM, Liebl J, Ardelt MA, Lehr T, De Toni EN, Mayr D, et al. Targeting cyclin dependent kinase 5 in hepatocellular carcinoma – a novel therapeutic approach. J Hepatol. 2015;63:102–13. doi: 10.1016/j.jhep.2015.01.031.CrossRefPubMedGoogle Scholar
  39. Erusalimsky JD. Vascular endothelial senescence: from mechanisms to pathophysiology. J Appl Physiol. 2009;106:326–32. doi: 10.1152/japplphysiol.91353.2008.CrossRefPubMedGoogle Scholar
  40. Folch J, Junyent F, Verdaguer E, Auladell C, Pizarro JG, Beas-Zarate C, et al. Role of cell cycle re-entry in neurons: a common apoptotic mechanism of neuronal cell death. Neurotox Res. 2012;22:195–207.CrossRefPubMedGoogle Scholar
  41. Goodwin PR, Sasaki JM, Juo P. Cyclin-dependent kinase 5 regulates the polarized trafficking of neuropeptide-containing dense-core vesicles in Caenorhabditis elegans motor neurons. J Neurosci. 2012;32:8158–72. doi: 10.1523/Jneurosci.0251-12.2012.CrossRefPubMedPubMedCentralGoogle Scholar
  42. Goodyear S, Sharma MC. Roscovitine regulates invasive breast cancer cell (MDA-MB231) proliferation and survival through cell cycle regulatory protein cdk5. Exp Mol Pathol. 2007;82:25–32.CrossRefPubMedGoogle Scholar
  43. Grynspan F, Griffin WR, Cataldo A, Katayama S, Nixon RA. Active site-directed antibodies identify calpain II as an early-appearing and pervasive component of neurofibrillary pathology in Alzheimer’s disease. Brain Res. 1997;763:145–58. doi: 10.1016/S0006-8993(97)00384-3.CrossRefPubMedGoogle Scholar
  44. Harmon JS, Tanaka Y, Olson LK, Robertson RP. Reconstitution of glucotoxic HIT-T15 cells with somatostatin transcription factor-1 partially restores insulin promoter activity. Diabetes. 1998;47:900–4.CrossRefPubMedGoogle Scholar
  45. Hellmich MR, Pant HC, Wada E, Battey JF. Neuronal cdc2-like kinase: a cdc2-related protein kinase with predominantly neuronal expression. Proc Natl Acad Sci U S A. 1992;89:10867–71.CrossRefPubMedPubMedCentralGoogle Scholar
  46. Herrup K, Yang Y. Cell cycle regulation in the postmitotic neuron: oxymoron or new biology? Nat Rev Neurosci. 2007;8:368–78. doi: 10.1038/nrn2124.CrossRefPubMedGoogle Scholar
  47. Hilton GD, Stoica BA, Byrnes KR, Faden AI. Roscovitine reduces neuronal loss, glial activation, and neurologic deficits after brain trauma. J Cereb Blood Flow Metab. 2008;28:1845–59.CrossRefPubMedPubMedCentralGoogle Scholar
  48. Hisanaga S, Endo R. Regulation and role of cyclin-dependent kinase activity in neuronal survival and death. J Neurochem. 2010;115:1309–21. doi: 10.1111/j.1471-4159.2010.07050.x.CrossRefPubMedGoogle Scholar
  49. Hsieh WS, Soo R, Peh BK, Loh T, Dong D, Soh D, et al. Pharmacodynamic effects of seliciclib, an orally administered cell cycle modulator, in undifferentiated nasopharyngeal cancer. Clin Cancer Res. 2009;15:1435–42. doi: 10.1158/1078-0432.CCR-08-1748.CrossRefPubMedGoogle Scholar
  50. Hsu FN, Chen MC, Lin KC, Peng YT, Li PC, Lin E, et al. Cyclin-dependent kinase 5 modulates STAT3 and androgen receptor activation through phosphorylation of Ser(7)(2)(7) on STAT3 in prostate cancer cells. Am J Physiol Endocrinol Metab. 2013;305:E975–86. doi: 10.1152/ajpendo.00615.2012.CrossRefPubMedGoogle Scholar
  51. Huang C, Rajfur Z, Yousefi N, Chen Z, Jacobson K, Ginsberg MH. Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration. Nat Cell Biol. 2009;11:624–30. doi: 10.1038/ncb1868.CrossRefPubMedPubMedCentralGoogle Scholar
  52. Huang E, Qu D, Zhang Y, Venderova K, Haque ME, Rousseaux MW, et al. The role of Cdk5-mediated apurinic/apyrimidinic endonuclease 1 phosphorylation in neuronal death. Nat Cell Biol. 2010;12:563–71.CrossRefPubMedGoogle Scholar
  53. Jimenez-Blasco D, Santofimia-Castano P, Gonzalez A, Almeida A, Bolanos JP. Astrocyte NMDA receptors’ activity sustains neuronal survival through a Cdk5-Nrf2 pathway. Cell Death Differ. 2015;22:1877–89. doi: 10.1038/cdd.2015.49.CrossRefPubMedPubMedCentralGoogle Scholar
  54. Kamei H, Saito T, Ozawa M, Fujita Y, Asada A, Bibb JA, et al. Suppression of calpain-dependent cleavage of the CDK5 activator p35 to p25 by site-specific phosphorylation. J Biol Chem. 2007;282:1687–94. doi: 10.1074/jbc.M610541200.CrossRefPubMedGoogle Scholar
  55. Kawahara M. Neurotoxicity of β-amyloid protein: oligomerization, channel formation and calcium dyshomeostasis. Curr Pharm Des. 2010;16:2779–89.CrossRefPubMedGoogle Scholar
  56. Kawauchi T, Chihama K, Nishimura YV, Nabeshima Y, Hoshino M. MAP1B phosphorylation is differentially regulated by Cdk5/p35, Cdk5/p25, and JNK. Biochem Biophys Res Commun. 2005;331:50–5. doi: 10.1016/j.bbrc.2005.03.132.CrossRefPubMedGoogle Scholar
  57. Kawauchi T, Chihama K, Nabeshima Y-i, Hoshino M. Cdk5 phosphorylates and stabilizes p27kip1 contributing to actin organization and cortical neuronal migration. Nat Cell Biol. 2006;8:17–26.CrossRefPubMedGoogle Scholar
  58. Ke K, Shen J, Song Y, Cao M, Lu H, Liu C, et al. CDK5 contributes to neuronal apoptosis via promoting MEF2D phosphorylation in rat model of intracerebral hemorrhage. J Mol Neurosci. 2015;56:48–59. doi: 10.1007/s12031-014-0466-5.CrossRefPubMedGoogle Scholar
  59. Kesavapany S, Li BS, Amin N, Zheng YL, Grant P, Pant HC. Neuronal cyclin-dependent kinase 5: role in nervous system function and its specific inhibition by the Cdk5 inhibitory peptide. Biochim Biophys Acta. 2004;1697:143–53. doi: 10.1016/j.bbapap.2003.11.020.CrossRefPubMedGoogle Scholar
  60. Kesavapany S, Zheng YL, Amin N, Pant HC. Peptides derived from Cdk5 activator p35, specifically inhibit deregulated activity of Cdk5. Biotechnol J. 2007;2:978–87. doi: 10.1002/biot.200700057.CrossRefPubMedGoogle Scholar
  61. Kim SH, Ryan TA. CDK5 serves as a major control point in neurotransmitter release. Neuron. 2010;67:797–809. doi: 10.1016/j.neuron.2010.08.003.CrossRefPubMedPubMedCentralGoogle Scholar
  62. Kim Y, Sung JY, Ceglia I, Lee KW, Ahn JH, Halford JM, et al. Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology. Nature. 2006;442:814–7. doi: 10.1038/nature04976.CrossRefPubMedGoogle Scholar
  63. Kim BS, Serebreni L, Fallica J, Hamdan O, Wang L, Johnston L, et al. Cyclin-dependent kinase five mediates activation of lung xanthine oxidoreductase in response to hypoxia. PLoS One. 2015;10:e0124189. doi: 10.1371/journal.pone.0124189.CrossRefPubMedPubMedCentralGoogle Scholar
  64. Lai KO, Ip NY. Recent advances in understanding the roles of Cdk5 in synaptic plasticity. Biochim Biophys Acta. 2009;1792:741–5. doi: 10.1016/j.bbadis.2009.05.001.CrossRefPubMedGoogle Scholar
  65. Lai KO, Wong ASL, Cheung MC, Xu P, Liang ZY, Lok KC, et al. TrkB phosphorylation by Cdk5 is required for activity-dependent structural plasticity and spatial memory. Nat Neurosci. 2012;15:1506–15. doi: 10.1038/nn.3237.CrossRefPubMedGoogle Scholar
  66. Lalioti V, Muruais G, Dinarina A, van Damme J, Vandekerckhove J, Sandoval IV. The atypical kinase Cdk5 is activated by insulin, regulates the association between GLUT4 and E-Syt1, and modulates glucose transport in 3T3-L1 adipocytes. Proc Natl Acad Sci USA. 2009;106:4249–53. doi: 10.1073/pnas.0900218106.CrossRefPubMedPubMedCentralGoogle Scholar
  67. Lau K-F, Howlett DR, Kesavapany S, Standen CL, Dingwall C, McLoughlin DM, et al. Cyclin-dependent kinase-5/p35 phosphorylates Presenilin 1 to regulate carboxy-terminal fragment stability. Mol Cell Neurosci. 2002;20:13–20.CrossRefPubMedGoogle Scholar
  68. Le Tourneau C, Faivre S, Laurence V, Delbaldo C, Vera K, Girre V, et al. Phase I evaluation of seliciclib (R-roscovitine), a novel oral cyclin-dependent kinase inhibitor, in patients with advanced malignancies. Eur J Cancer. 2010;46:3243–50. doi: 10.1016/j.ejca.2010.08.001.CrossRefPubMedGoogle Scholar
  69. Lee KY, Clark AW, Rosales JL, Chapman K, Fung T, Johnston RN. Elevated neuronal Cdc2-like kinase activity in the Alzheimer disease brain. Neurosci Res. 1999;34:21–9.CrossRefPubMedGoogle Scholar
  70. Lee J-H, Kim H-S, Lee S-J, Kim K-T. Stabilization and activation of p53 induced by Cdk5 contributes to neuronal cell death. J Cell Sci. 2007;120:2259–71.CrossRefPubMedGoogle Scholar
  71. Lee HY, Jung H, Jang IH, Suh P-G, Ryu SH. Cdk5 phosphorylates PLD2 to mediate EGF-dependent insulin secretion. Cell Signal. 2008;20:1787–94. doi: 10.1016/j.cellsig.2008.06.009.CrossRefPubMedGoogle Scholar
  72. Lew J, Huang Q-Q, Qi Z, Winkfein RJ, Aebersold R, Hunt T, et al. A brain-specific activator of cyclin-dependent kinase 5. Nature. 1994;371(6496):423–6.CrossRefPubMedGoogle Scholar
  73. Li BS, Zhang L, Takahashi S, Ma W, Jaffe H, Kulkarni AB, et al. Cyclin-dependent kinase 5 prevents neuronal apoptosis by negative regulation of c-Jun N-terminal kinase 3. EMBO J. 2002;21:324–33. doi: 10.1093/emboj/21.3.324.CrossRefPubMedPubMedCentralGoogle Scholar
  74. Li BS, Ma W, Jaffe H, Zheng YL, Takahashi S, Zhang L, et al. Cyclin-dependent kinase-5 is involved in neuregulin-dependent activation of phosphatidylinositol 3-kinase and Akt activity mediating neuronal survival. J Biol Chem. 2003;278:35702–9. doi: 10.1074/jbc.M302004200.CrossRefPubMedGoogle Scholar
  75. Liang Q, Li L, Zhang J, Lei Y, Wang L, Liu DX, et al. CDK5 is essential for TGF-beta1-induced epithelial-mesenchymal transition and breast cancer progression. Sci Report. 2013;3:2932. doi: 10.1038/srep02932.CrossRefGoogle Scholar
  76. Liebl J, Weitensteiner SB, Vereb G, Takacs L, Furst R, Vollmar AM, et al. Cyclin-dependent kinase 5 regulates endothelial cell migration and angiogenesis. J Biol Chem. 2010;285:35932–43. doi: 10.1074/jbc.M110.126177.CrossRefPubMedPubMedCentralGoogle Scholar
  77. Liebl J, Zhang S, Moser M, Agalarov Y, Demir CS, Hager B, et al. Cdk5 controls lymphatic vessel development and function by phosphorylation of Foxc2. Nat Commun. 2015;6:7274. doi: 10.1038/ncomms8274.CrossRefPubMedGoogle Scholar
  78. Lilja L, Johansson JU, Gromada J, Mandic SA, Fried G, Berggren PO, et al. Cyclin-dependent kinase 5 associated with p39 promotes Munc18-1 phosphorylation and Ca(2+)-dependent exocytosis. J Biol Chem. 2004;279:29534–41. doi: 10.1074/jbc.M312711200.CrossRefPubMedGoogle Scholar
  79. Liu R, Tian B, Gearing M, Hunter S, Ye K, Mao Z. Cdk5-mediated regulation of the PIKE-A-Akt pathway and glioblastoma cell invasion. Proc Natl Acad Sci U S A. 2008;105:7570–5. doi: 10.1073/pnas.0712306105.CrossRefPubMedPubMedCentralGoogle Scholar
  80. Liu JL, Wang XY, Huang BX, Zhu F, Zhang RG, Wu G. Expression of CDK5/p35 in resected patients with non-small cell lung cancer: relation to prognosis. Med Oncol. 2011;28:673–8. doi: 10.1007/s12032-010-9510-7.CrossRefPubMedGoogle Scholar
  81. Liu SL, Wang C, Jiang T, Tan L, Xing A, Yu JT. The role of Cdk5 in Alzheimer’s disease. Mol Neurobiol. 2016;53:4328–42. doi: 10.1007/s12035-015-9369-x.CrossRefPubMedGoogle Scholar
  82. Lopes JP, Oliveira CR, Agostinho P. Cdk5 acts as a mediator of neuronal cell cycle re-entry triggered by amyloid-β and prion peptides. Cell Cycle. 2009;8:97–104.CrossRefPubMedGoogle Scholar
  83. Malumbres M, Harlow E, Hunt T, Hunter T, Lahti JM, Manning G, et al. Cyclin-dependent kinases: a family portrait. Nat Cell Biol. 2009;11:1275–6.CrossRefPubMedPubMedCentralGoogle Scholar
  84. Marra V, Burden JJ, Thorpe JR, Smith IT, Smith SL, Hausser M, et al. A preferentially segregated recycling vesicle pool of limited size supports neurotransmission in native central synapses. Neuron. 2012;76:579–89. doi: 10.1016/j.neuron.2012.08.042.CrossRefPubMedPubMedCentralGoogle Scholar
  85. Meijer L, Borgne A, Mulner O, Chong JP, Blow JJ, Inagaki N, et al. Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur J Biochem. 1997;243:527–36.CrossRefPubMedGoogle Scholar
  86. Minegishi S, Asada A, Miyauchi S, Fuchigami T, Saito T, Hisanaga S. Membrane association facilitates degradation and cleavage of the cyclin-dependent kinase 5 activators p35 and p39. Biochemistry. 2010;49:5482–93. doi: 10.1021/bi100631f.CrossRefPubMedGoogle Scholar
  87. Mishiba T, Tanaka M, Mita N, He XJ, Sasamoto K, Itohara S, et al. Cdk5/p35 functions as a crucial regulator of spatial learning and memory. Mol Brain. 2014;7:82. doi: 10.1186/s13041-014-0082-x.CrossRefPubMedPubMedCentralGoogle Scholar
  88. Mitsios N, Pennucci R, Krupinski J, Sanfeliu C, Gaffney J, Kumar P, et al. Expression of cyclin-dependent kinase 5 mRNA and protein in the human brain following acute ischemic stroke. Brain Pathol. 2007;17:11–23. doi: 10.1111/j.1750-3639.2006.00031.x.CrossRefPubMedGoogle Scholar
  89. Miyajima M, Nornes HO, Neuman T. Cyclin-E is expressed in neurons and forms complexes with Cdk5. Neuroreport. 1995;6:1130–2. doi: 10.1097/00001756-199505300-00014.CrossRefPubMedGoogle Scholar
  90. Moorthamer M, Chaudhuri B. Identification of ribosomal protein L34 as a novel Cdk5 inhibitor. Biochem Biophys Res Commun. 1999;255:631–8.CrossRefPubMedGoogle Scholar
  91. Moorthamer M, Zumstein-Mecker S, Chaudhuri B. DNA binding protein dbpA binds Cdk5 and inhibits its activity. FEBS Lett. 1999;446:343–50.CrossRefPubMedGoogle Scholar
  92. Morabito MA, Sheng M, Tsai LH. Cyclin-dependent kinase 5 phosphorylates the N-terminal domain of the postsynaptic density protein PSD-95 in neurons. J Neurosci. 2004;24:865–76. doi: 10.1523/Jneurosci.4582-03.2004.CrossRefPubMedGoogle Scholar
  93. Mouatt-Prigent A, Karlsson J, Agid Y, Hirsch E. Increased M-calpain expression in the mesencephalon of patients with Parkinson’s disease but not in other neurodegenerative disorders involving the mesencephalon: a role in nerve cell death? Neuroscience. 1996;73:979–87.CrossRefPubMedGoogle Scholar
  94. Nagano T, Hashimoto T, Nakashima A, Hisanaga S-i, Kikkawa U, Kamada S. Cyclin I is involved in the regulation of cell cycle progression. Cell Cycle. 2013;12:2617–24.CrossRefPubMedPubMedCentralGoogle Scholar
  95. Nakamura S, Kawamoto Y, Nakano S, Akiguchi I, Kimura J. p35nck5a and cyclin-dependent kinase 5 colocalize in Lewy bodies of brains with Parkinson’s disease. Acta Neuropathol. 1997;94:153–7.CrossRefPubMedGoogle Scholar
  96. Nikolic M, Dudek H, Kwon YT, Ramos Y, Tsai L-H. The cdk5/p35 kinase is essential for neurite outgrowth during neuronal differentiation. Genes Dev. 1996;10:816–25.CrossRefPubMedGoogle Scholar
  97. Nikolic M, Chou MM, Lu W, Mayer BJ, Tsai L-H. The p35/Cdk5 kinase is a neuron-specific Rac effector that inhibits Pak1 activity. Nature. 1998;395:194–8.CrossRefPubMedGoogle Scholar
  98. Nishimura YV, Sekine K, Chihama K, Nakajima K, Hoshino M, Nabeshima Y, et al. Dissecting the factors involved in the locomotion mode of neuronal migration in the developing cerebral cortex. J Biol Chem. 2010;285:5878–87. doi: 10.1074/jbc.M109.033761.CrossRefPubMedGoogle Scholar
  99. Ohshima T, Ward JM, Huh CG, Longenecker G, Veeranna, Pant HC, et al. Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc Natl Acad Sci USA. 1996;93:11173–8.CrossRefPubMedPubMedCentralGoogle Scholar
  100. Ohshima T, Ogawa M, Veeranna, Hirasawa M, Longenecker G, Ishiguro K, et al. Synergistic contributions of cyclin-dependant kinase 5/p35 and Reelin/Dab1 to the positioning of cortical neurons in the developing mouse brain. Proc Natl Acad Sci U S A. 2001;98:2764–9. doi: 10.1073/pnas.051628498.CrossRefPubMedPubMedCentralGoogle Scholar
  101. Ohshima T, Ogawa M, Takeuchi K, Takahashi S, Kulkarni AB, Mikoshiba K. Cyclin-dependent kinase 5/p35 contributes synergistically with Reelin/Dab1 to the positioning of facial branchiomotor and inferior olive neurons in the developing mouse hindbrain. J Neurosci. 2002;22:4036–44.PubMedGoogle Scholar
  102. Ohshima T, Ogura H, Tomizawa K, Hayashi K, Suzuki H, Saito T, et al. Impairment of hippocampal long-term depression and defective spatial learning and memory in p35 mice. J Neurochem. 2005;94:917–25. doi: 10.1111/j.1471-4159.2005.03233.x.CrossRefPubMedGoogle Scholar
  103. Okada S, Yamada E, Saito T, Ohshima K, Hashimoto K, Yamada M, et al. CDK5-dependent phosphorylation of the Rho family GTPase TC10(alpha) regulates insulin-stimulated GLUT4 translocation. J Biol Chem. 2008;283:35455–63. doi: 10.1074/jbc.M806531200.CrossRefPubMedGoogle Scholar
  104. Patrick GN, Zhou P, Kwon YT, Howley PM, Tsai L-H. p35, the neuronal-specific activator of cyclin-dependent kinase 5 (Cdk5) is degraded by the ubiquitin-proteasome pathway. J Biol Chem. 1998;273:24057–64.CrossRefPubMedGoogle Scholar
  105. Patrick GN, Zukerberg L, Nikolic M, de La Monte S, Dikkes P, Tsai L-H. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature. 1999;402:615–22.CrossRefPubMedGoogle Scholar
  106. Patzke H, Tsai LH. Calpain-mediated cleavage of the cyclin-dependent kinase-5 activator p39 to p29. J Biol Chem. 2002;277:8054–60. doi: 10.1074/jbc.M109645200.CrossRefPubMedGoogle Scholar
  107. Plattner F, Hernandez A, Kistler TM, Pozo K, Zhong P, Yuen EY, et al. Memory enhancement by targeting Cdk5 regulation of NR2B. Neuron. 2014;81:1070–83. doi: 10.1016/j.neuron.2014.01.022.CrossRefPubMedPubMedCentralGoogle Scholar
  108. Pozo K, Castro-Rivera E, Tan C, Plattner F, Schwach G, Siegl V, et al. The role of Cdk5 in neuroendocrine thyroid cancer. Cancer Cell. 2013;24:499–511. doi: 10.1016/j.ccr.2013.08.027.CrossRefPubMedGoogle Scholar
  109. Qu D, Li Q, Lim H-Y, Cheung NS, Li R, Wang JH, et al. The protein SET binds the neuronal Cdk5 activator p35 nck5a and modulates Cdk5/p35 nck5a activity. J Biol Chem. 2002;277:7324–32.CrossRefPubMedGoogle Scholar
  110. Qu D, Rashidian J, Mount MP, Aleyasin H, Parsanejad M, Lira A, et al. Role of Cdk5-mediated phosphorylation of Prx2 in MPTP toxicity and Parkinson’s disease. Neuron. 2007;55:37–52.CrossRefPubMedGoogle Scholar
  111. Qu J, Nakamura T, Cao G, Holland EA, McKercher SR, Lipton SA. S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by β-amyloid peptide. Proc Natl Acad Sci USA. 2011;108:14330–5.CrossRefPubMedPubMedCentralGoogle Scholar
  112. Qu J, Nakamura T, Holland EA, McKercher SR, Lipton SA. S-nitrosylation of Cdk5: potential implications in amyloid-β-related neurotoxicity in Alzheimer disease. Prion. 2012;6:364–70.CrossRefPubMedPubMedCentralGoogle Scholar
  113. Rashid T, Banerjee M, Nikolic M. Phosphorylation of Pak1 by the p35/Cdk5 kinase affects neuronal morphology. J Biol Chem. 2001;276:49043–52. doi: 10.1074/jbc.M105599200.CrossRefPubMedGoogle Scholar
  114. Roder H, Ingram V. Two novel kinases phosphorylate tau and the KSP site of heavy neurofilament subunits in high stoichiometric ratios. J Neurosci. 1991;11:3325–43.PubMedGoogle Scholar
  115. Schubert S, Knoch KP, Ouwendijk J, Mohammed S, Bodrov Y, Jager M, et al. beta 2-Syntrophin is a Cdk5 substrate that restrains the motility of insulin secretory granules. Plos One. 2010;5:e12929. doi: 10.1371/journal.pone.0012929.CrossRefPubMedPubMedCentralGoogle Scholar
  116. Sharma MR, Tuszynski GP, Sharma MC. Angiostatin-induced inhibition of endothelial cell proliferation/apoptosis is associated with the down-regulation of cell cycle regulatory protein cdk5. J Cell Biochem. 2004;91:398–409. doi: 10.1002/jcb.10762.CrossRefPubMedGoogle Scholar
  117. Shi C, Viccaro K, Lee H-g, Shah K. Cdk5–Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer’s disease models. J Cell Sci. 2016;129:1815–30.CrossRefPubMedPubMedCentralGoogle Scholar
  118. Smith PD, Mount MP, Shree R, Callaghan S, Slack RS, Anisman H, et al. Calpain-regulated p35/cdk5 plays a central role in dopaminergic neuron death through modulation of the transcription factor myocyte enhancer factor 2. J Neurosci. 2006;26:440–7.CrossRefPubMedGoogle Scholar
  119. Su SC, Seo J, Pan JQ, Samuels BA, Rudenko A, Ericsson M, et al. Regulation of N-type voltage-gated calcium channels and presynaptic function by cyclin-dependent kinase 5. Neuron. 2012;75:675–87. doi: 10.1016/j.neuron.2012.06.023.CrossRefPubMedPubMedCentralGoogle Scholar
  120. Sundaram JR, Poore CP, Bin Sulaimee NH, Pareek T, Asad ABMA, Rajkumar R, et al. Specific inhibition of p25/Cdk5 activity by the Cdk5 inhibitory peptide reduces neurodegeneration in vivo. J Neurosci. 2013;33:334–43. doi: 10.1523/Jneurosci.3593-12.2013.CrossRefPubMedGoogle Scholar
  121. Takahashi S, Ohshima T, Hirasawa M, Pareek TK, Bugge TH, Morozov A, et al. Conditional deletion of neuronal cyclin-dependent kinase 5 in developing forebrain results in microglial activation and neurodegeneration. Am J Pathol. 2010;176:320–9. doi: 10.2353/ajpath.2010.081158.CrossRefPubMedPubMedCentralGoogle Scholar
  122. Tan TC, Valova VA, Malladi CS, Graham ME, Berven LA, Jupp OJ, et al. Cdk5 is essential for synaptic vesicle endocytosis. Nat Cell Biol. 2003;5:701–10. doi: 10.1038/ncb1020.CrossRefPubMedGoogle Scholar
  123. Tanabe K, Yamazaki H, Inaguma Y, Asada A, Kimura T, Takahashi J, et al. Phosphorylation of drebrin by cyclin-dependent kinase 5 and its role in neuronal migration. PLoS One. 2014;9:e92291. doi: 10.1371/journal.pone.0092291.CrossRefPubMedPubMedCentralGoogle Scholar
  124. Tanaka T, Serneo FF, Tseng HC, Kulkarni AB, Tsai LH, Gleeson JG. Cdk5 phosphorylation of doublecortin ser297 regulates its effect on neuronal migration. Neuron. 2004;41:215–27. doi: 10.1016/S0896-6273(03)00852-3.CrossRefPubMedGoogle Scholar
  125. Tang D, Yeung J, Lee K-Y, Matsushita M, Matsui H, Tomizawa K, et al. An isoform of the neuronal cyclin-dependent kinase 5 (Cdk5) activator. J Biol Chem. 1995;270:26897–903.CrossRefPubMedGoogle Scholar
  126. Tarricone C, Dhavan R, Peng J, Areces LB, Tsai L-H, Musacchio A. Structure and regulation of the CDK5-p25 nck5a complex. Mol Cell. 2001;8:657–69.CrossRefPubMedGoogle Scholar
  127. Tomizawa K, Ohta J, Matsushita M, Moriwaki A, Li ST, Takei K, et al. Cdk5/p35 regulates neurotransmitter release through phosphorylation and downregulation of P/Q-type voltage-dependent calcium channel activity. J Neurosci. 2002;22:2590–7.PubMedGoogle Scholar
  128. Trimarchi JM, Lees JA. Sibling rivalry in the E2F family. Nat Rev Mol Cell Biol. 2002;3:11–20. doi: 10.1038/nrm714.CrossRefPubMedGoogle Scholar
  129. Tsai L-H, Delalle I, Caviness VS, Chae T, Harlow E. p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature. 1994;371:5.CrossRefGoogle Scholar
  130. Tseng HC, Zhou Y, Shen Y, Tsai LH. A survey of Cdk5 activator p35 and p25 levels in Alzheimer’s disease brains. FEBS Lett. 2002;523:58–62.CrossRefPubMedGoogle Scholar
  131. Ubeda M, Kemp DM, Habener JF. Glucose-induced expression of the cyclin-dependent protein kinase 5 activator p35 involved in Alzheimer’s disease regulates insulin gene transcription in pancreatic beta-cells. Endocrinology. 2004;145:3023–31. doi: 10.1210/en.2003-1522.CrossRefPubMedGoogle Scholar
  132. Ubeda M, Rukstalis JM, Habener JF. Inhibition of cyclin-dependent kinase 5 activity protects pancreatic beta cells from glucotoxicity. J Biol Chem. 2006;281:28858–64. doi: 10.1074/jbc.M604690200.CrossRefPubMedGoogle Scholar
  133. Utreras E, Henriquez D, Contreras-Vallejos E, Olmos C, Di Genova A, Maass A, et al. Cdk5 regulates Rap1 activity. Neurochem Int. 2013;62:848–53. doi: 10.1016/j.neuint.2013.02.011.CrossRefPubMedPubMedCentralGoogle Scholar
  134. van den Heuvel S, Harlow E. Distinct roles for cyclin-dependent kinases in cell cycle control. Science. 1993;262:2050–4.CrossRefPubMedGoogle Scholar
  135. Wang Y, Liang Y, Vanhoutte PM. SIRT1 and AMPK in regulating mammalian senescence: a critical review and a working model. FEBS Lett. 2011;585:986–94. doi: 10.1016/j.febslet.2010.11.047.CrossRefPubMedGoogle Scholar
  136. Wei FY, Nagashima K, Ohshima T, Saheki Y, Lu YF, Matsushita M, et al. Cdk5-dependent regulation of glucose-stimulated insulin secretion. Nat Med. 2005;11:1104–8. doi: 10.1038/nm1299.CrossRefPubMedGoogle Scholar
  137. Wen Y, Yu WH, Maloney B, Bailey J, Ma J, Marié I, et al. Transcriptional regulation of β-secretase by p25/cdk5 leads to enhanced amyloidogenic processing. Neuron. 2008;57:680–90.CrossRefPubMedPubMedCentralGoogle Scholar
  138. Wilkaniec A, Czapski GA, Adamczyk A. Cdk5 at crossroads of protein oligomerization in neurodegenerative diseases: facts and hypotheses. J Neurochem. 2016;136:222–33.CrossRefPubMedGoogle Scholar
  139. Wong AS, Lee RH, Cheung AY, Yeung PK, Chung SK, Cheung ZH, et al. Cdk5-mediated phosphorylation of endophilin B1 is required for induced autophagy in models of Parkinson’s disease. Nat Cell Biol. 2011;13:568–79.CrossRefPubMedGoogle Scholar
  140. Xie ZG, Sanada K, Samuels BA, Shih H, Tsai LH. Serine 732 phosphorylation of FAK by Cdk5 is important for microtubule organization, nuclear movement, and neuronal migration. Cell. 2003;114:469–82. doi: 10.1016/S0092-8674(03)00605-6.CrossRefPubMedGoogle Scholar
  141. Xie W, Liu C, Wu D, Li Z, Li C, Zhang Y. Phosphorylation of kinase insert domain receptor by cyclin-dependent kinase 5 at serine 229 is associated with invasive behavior and poor prognosis in prolactin pituitary adenomas. Oncotarget. 2016; doi: 10.18632/oncotarget.10550.Google Scholar
  142. Xu J, Kurup P, Zhang YF, Goebel-Goody SM, Wu PH, Hawasli AH, et al. Extrasynaptic NMDA receptors couple preferentially to excitotoxicity via calpain-mediated cleavage of STEP. J Neurosci. 2009;29:9330–43. doi: 10.1523/Jneurosci.2212-09.2009.CrossRefPubMedPubMedCentralGoogle Scholar
  143. Yang S. Gene amplifications at chromosome 7 of the human gastric cancer genome. Int J Mol Med. 2007;20:225–31.PubMedGoogle Scholar
  144. Ye T, Ip JP, Fu AK, Ip NY. Cdk5-mediated phosphorylation of RapGEF2 controls neuronal migration in the developing cerebral cortex. Nat Commun. 2014;5:4826. doi: 10.1038/ncomms5826.CrossRefPubMedPubMedCentralGoogle Scholar
  145. Yildiz-Unal A, Korulu S, Karabay A. Neuroprotective strategies against calpain-mediated neurodegeneration. Neuropsychiatr Dis Treat. 2015;11:297–310.CrossRefPubMedPubMedCentralGoogle Scholar
  146. Zhang J, Herrup K. Nucleocytoplasmic Cdk5 is involved in neuronal cell cycle and death in post-mitotic neurons. Cell Cycle. 2011;10:1208–14.CrossRefPubMedGoogle Scholar
  147. Zhang J, Cicero SA, Wang L, Romito-DiGiacomo RR, Yang Y, Herrup K. Nuclear localization of Cdk5 is a key determinant in the postmitotic state of neurons. Proc Natl Acad Sci USA. 2008;105:8772–7. doi: 10.1073/pnas.0711355105.CrossRefPubMedPubMedCentralGoogle Scholar
  148. Zhang J, Li H, Herrup K. Cdk5 nuclear localization is p27-dependent in nerve cells implications for cell cycle suppression and caspase-3 activation. J Biol Chem. 2010a;285:14052–61.CrossRefPubMedPubMedCentralGoogle Scholar
  149. Zhang J, Li H, Yabut O, Fitzpatrick H, D’Arcangelo G, Herrup K. Cdk5 suppresses the neuronal cell cycle by disrupting the E2F1-DP1 complex. J Neurosci. 2010b;30:5219–28. doi: 10.1523/JNEUROSCI.5628-09.2010.CrossRefPubMedPubMedCentralGoogle Scholar
  150. Zhang X, Zhong T, Dang Y, Li Z, Li P, Chen G. Aberrant expression of CDK5 infers poor outcomes for nasopharyngeal carcinoma patients. Int J Clin Exp Pathol. 2015;8:8066–74.PubMedPubMedCentralGoogle Scholar
  151. Zheng YL, Kesavapany S, Gravell M, Hamilton RS, Schubert M, Amin N, et al. A Cdk5 inhibitory peptide reduces tau hyperphosphorylation and apoptosis in neurons. EMBO J. 2005;24:209–20. doi: 10.1038/sj.emboj.7600441.CrossRefPubMedGoogle Scholar
  152. Zheng YL, Li BS, Kanungo J, Kesavapany S, Amin N, Grant P, et al. Cdk5 modulation of mitogen-activated protein kinase signaling regulates neuronal survival. Mol Biol Cell. 2007;18:404–13. doi: 10.1091/mbc.E06-09-0851.CrossRefPubMedPubMedCentralGoogle Scholar
  153. Zheng YL, Li CY, Hu YF, Cao L, Wang H, Li B, et al. Cdk5 Inhibitory Peptide (CIP) Inhibits Cdk5/p25 Activity Induced by High Glucose in Pancreatic Beta Cells and Recovers Insulin Secretion from p25 Damage. Plos One. 2013;8:e63332. doi: 10.1371/journal.pone.0063332.CrossRefPubMedPubMedCentralGoogle Scholar
  154. Zu Y, Liu L, Lee MY, Xu C, Liang Y, Man RY, et al. SIRT1 promotes proliferation and prevents senescence through targeting LKB1 in primary porcine aortic endothelial cells. Circ Res. 2010;106:1384–93. doi: 10.1161/CIRCRESAHA.109.215483.CrossRefPubMedGoogle Scholar
  155. Zukerberg LR, Patrick GN, Nikolic M, Humbert S, Wu C-L, Lanier LM, et al. Cables links Cdk5 and c-Abl and facilitates Cdk5 tyrosine phosphorylation, kinase upregulation, and neurite outgrowth. Neuron. 2000;26:633–46.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and PharmacyThe University of Hong KongHong KongChina