p38 MAPK Family
p38α : Crk1; Csbp1; CSBP2; Mapk14; Mitogen activated protein kinase 14; Mxi2; p38; p38 alpha Map kinase; p38 alpha MAP kinase; p38 alpha MAPK; p38-alpha; p38a; p38alpha; p38alpha MAPK; PRKM14; PRKM15
p38β : Mapk11; Mitogen-activated protein kinase 11; p38 beta MAP kinase; p38 beta Map kinase; p38 beta MAPK; p38-2; p38B; p38beta; p38beta MAPK; P38BETA2; Prkm11; Protein kinase, mitogen activated kinase, 11; SAPK2; SAPK2B
p38δ : Mapk13; MAPK13; Mitogen-activated protein kinase 13; p38 delta Map kinase; p38 delta MAP kinase; p38 delta MAPK; p38d; p38delta; p38delta MAPK; PRKM13; SAPK4; Serk4
p38γ : ERK6; Mapk12; Mitogen-activated protein kinase 12; p38 gamma MAP kinase; p38 gamma Map kinase; p38 gamma MAPK; p38g; p38gamma; p38gamma MAPK; Prkm12; SAPK-3; SAPK3; Stress-activated protein kinase 3
Historical Background: The p38 MAPK Family of Stress Response Signaling
The proteins of the p38 MAPK family comprise a cascade of multiple serine-threonine, threonine-tyrosine kinases, and phosphatases; the signals are transduced by phosphorylations that enhance specific serine-threonine kinase activities and dephosphorylation of their catalytic sites by specific phosphatases that attenuate the signaling activities (Cuadrado and Nebreda 2010; Ono and Han 2000; Zer et al. 2007). In this review, we focus on the serine/threonine and threonine/tyrosine kinase components of the p38 MAPK stress response signaling pathway, its regulation, and its relevance to tissue responses to extrinsic and intrinsic stress factors.
The p38 MAPK Family of Stress Signaling Pathways: Tissue Specificities
The p38 MAPK family of signaling proteins regulate the transcription of stress response genes (nuclear) or chaperones (cytoplasmic) via upstream cytoplasmic activator proteins (tyrosine kinases; Fig. 1). The p38 MAPK isoforms are, therefore, major nucleocytoplasmic trafficking proteins and are major crossroads for the delivery of biological responses to environmental challenges (Fig. 1). The protein-protein interactions of the MAPK pathways are, therefore, major mechanisms that control the activation of transcription factors and their targeted genes in response to intrinsic (biological) and extrinsic (environmental) factors.
The p38 MAPK family can be divided into two subsets based on sequence homology, substrate specificity, and sensitivity to inhibitors, with p38α and p38β in one group and p38γ and p38δ in the other. The p38α and p38β MAPK are 60% identical to p38γ and p38δ, indicating that they represent related but distinct MAPK subgroups (Cuadrado and Nebreda 2010; Ono and Han 2000; Zer et al. 2007). The four isoforms are ubiquitously expressed but at significantly different levels in each tissue. Both p38α and p38β are the predominant isoforms in the liver whereas p38γ is predominant in skeletal muscle (Lechner et al. 1996; Li et al. 2005), and δ is enriched in the lung, kidney, testis, pancreas, and small intestine (Jiang et al. 1996). The isoforms have distinct biological functions due, in part, to their ability to selectively phosphorylate and activate specific transcription factors as well cytoplasmic proteins such as chaperones and heat shock proteins. Importantly, the p38 MAPKs serve as a distribution center for the receipt and dissemination of biological signals within the cytoplasm as well as to their nuclear gene targets. The pathway consists, therefore, of a cascade of three serine/threonine kinase families, i.e., MAP kinase kinase kinases (MKKK), MAP kinase kinases (MKK), and MAP kinases, i.e., the p38 MAPK proteins (Fig. 1). These proteins are activated in series such that the MKKKs phosphorylate the MKK activation loop serines, which then activate the p38 MAPKs by phosphorylation of threonine-180 (Thr180) and tyrosine-182 (Tyr182). Furthermore, the sequence of phosphorylation of Thr180 and Tyr182 residues is precise in that the tyrosine residue is phosphorylated first followed by the threonine residue. (This is discussed in detail below).
Tissue-Specific Distribution, Substrate Specificity, and Mechanism of Transduction of Stress Signals by p38 MAPK
The importance of the tissue-specific expression of the individual p38 MAPK isoforms is indicated by the observation that sustained p38α activity is associated with (a) progression of the expression of protein markers of the aging phenotype (Freund et al. 2011; Haq et al. 2002; Hsieh and Papaconstantinou 2002; Iwasa et al. 2003; Papaconstantinou and Hsieh 2010; Wong et al. 2009); (b) the development of diseases of inflammation and oxidative stress (Bendotti et al. 2005; Munoz et al. 2007) that include neurodegenerative, e.g., Alzheimer’s (Munoz and Ammit 2010), ALS (Bendotti et al. 2005), and Parkinson’s (Brobey et al. 2015); cardiovascular (Kompa et al. 2008; Sy et al. 2008); musculoskeletal and diabetes (Jeong et al. 2016); rheumatoid arthritis (Wang et al. 2015); toxin-induced preterm birth, (Bredeson et al. 2014; Guo et al. 2001); (c) ischemia-induced lethality in cultured rat neonatal cardiomyocytes (Saurin et al. 2000). Attenuation of p38α activity delays the progression of aging in multiple tissues (Papaconstantinou et al. 2015) and is protective against inflammatory insults. There is also evidence that activation of p38β correlates with cell viability (Guo et al. 2001). Furthermore, inhibition (ablation) of p38 MAPK is embryonic lethal (Allen et al. 2000) while its overexpression promotes premature aging. On the other hand, maintenance of p38β (protective) result in increased cell viability (Conrad et al. 1999). This is consistent with the differences in targets of p38α and p38β in cardiomyocyte ischemia and is further evidence for specific biological consequences of differential isoform activation.
The specificities of p38 MAPK isoform activities, i.e., differentiation, proliferation, lethality, apoptosis, survival, etc., indicates the importance of the balance (homeostasis) of these isoforms in multiple tissues and their responses to external challenges. For example, the lung epithelial cells express p38β and p38δ where the pool levels of p38β ≫ p38δ. However, the numbers of macrophages and neutrophils are elevated in inflamed, injured lungs, and the pool level of p38α is threefold higher than that of p38δ in macrophages and ninefold higher than p38δ in neutrophils. In view of the differentially elevated levels of p38 MAPK isoforms in various cell types of the diseased/inflamed lung tissues, the higher levels of p38α in the inflammatory cell lineages may overpower those of the lung tissue epithelium and favor pathological consequences associated with p38α, such as inflammation, apoptosis, and ultimately lethality which may then enhance fibrosis.
The specificities of p38 biological functions are also supported by the observation that activation of p38α (phosphorylation of its catalytic site) by overexpression of MKK6EE, a constitutively active version of MKK6 in 3 T3 fibroblasts, enhances their entry into replicative senescence (Haq et al. 2002). Thus, the overproduction of p38α in the p38γ predominant skeletal muscle, or p38β and p38δ dominant lung tissue, may play a role in the development of senescence and aging characteristics in response to environmental factors. This also applies to other respiratory tissues such as vascular cells and/or inflammatory cells that may exhibit accelerated senescence and overall respiratory disease of the lung. Importantly, since p38α regulates stem cell/progenitor cell proliferation, its overexpression in multiple tissues may dominate the activities of the other p38 MAPKs.
Substrate Specificity of p38 MAPK Isoforms
In general the specificities of the p38 isoforms have been demonstrated by genetic KO and by the use of inhibitors. The genetic ablation of specific p38 MAPK family members has been a major approach in demonstrating their functional redundancies (Sabio et al. 2005). The use of p38 KO mouse models has shown specific functions. For example, the ablation of p38α is an embryonic lethality; overexpression of p38α results in acceleration of development of the aging phenotype, and the dominant negative p38α(+/−) results in a beneficial healthspan in which the development of many of the physiological dysfunctions of aging are attenuated or delayed (Papaconstantinou et al. 2015; Wong et al. 2009). The results of these studies with the DN-p38α(+/−) model clearly show the importance of the homeostasis of p38α. Similarly the use of p38 KO mouse models of p38γ and p38δ and double p38γ/p38δ KOs are viable and fertile (Sabio et al. 2005). Furthermore, it has been shown that the p38γ KO attenuates the fusion of skeletal muscle satellite cells to form myofibers, but there is no effect on progenitor cell proliferation. (Perdiguero et al. 2007).
Formation of p38 MAPK-transcription factor complexes is a critical determinant of kinase specificity. For example, p38α and p38β phosphorylate and activate the muscle-specific transcription factors, MEF2A and MEF2C (Yang et al. 1999). These isoforms target transcription factors by a docking domain distinct from the phosphoacceptor motifs that confer responsiveness to p38α and p38β but not p38γ or p38δ (Engel et al. 1995; Jiang et al. 1996).
The diverse functions of the four MAPK isoforms are seen in their role in the Fas-mediated apoptosis of endothelial cells of the murine liver sinusoids (Cardier and Erickson-Miller 2002) versus their role as the MAPK required for pathogen defense against Pseudomonas infection in C. elegans (Kim et al. 2002). Further diversity is indicated by the fact that the B. anthracis lethal factor selectively induces apoptosis by cleaving the amino-terminal domain of map kinase kinases (MKKs) thereby eliminating the docking domain that is required for the activation of p38 MAPK (Park et al. 2002). This dismantling of the p38 MAPK-MKK interaction is the mechanism by which B. anthracis paralyzes the host innate immunity. Similarly, in HeLa cells, p38α induces apoptosis while p38β promotes cell survival suggesting both overlapping and distinct physiological roles of these isoforms but clearly demonstrating their roles in establishing a biochemical phenotype.
The p38 MAPKs also exhibit differential responses to specific drugs and inflammatory agents (Lee et al. 1999; Peifer et al. 2009). One subgroup (p38α and p38β) is inhibited by pyridinyl imidazole derivatives, drugs which inhibit the production of proinflammatory cytokines, while the others (p38γ and p38δ) are insensitive to these drugs (Lee et al. 1999). Thus, the four p38 MAPK isoforms can target genes in response to specific drugs and inflammatory agents (Cuadrado and Nebreda 2010; Lee et al. 1999; Peifer et al. 2009). p38 MAPK signaling is mediated by interaction with upstream serine/threonine MAPK kinases, MKK3 and MKK6 (Fig. 1). While MKK6 is a common activator of p38α, β, γ, and δ, MKK3 activates only p38α, γ, and δ (Yang et al. 1998). This exclusive inability of MKK6 to activate p38β contributes to this pathway’s signaling specificity. Targeted disruption of the mkk3 and mkk6 genes has shown their nonredundant functions (Enslen et al. 1998; Lee et al. 1999). For example, co-expression of MKK3 with p38β enhances hypertrophy, whereas co-expression with p38α enhances apoptosis (Enslen et al. 1998; Wang et al. 1998; Wei et al. 1998). This signaling specificity exemplifies the importance of how specific complexing of pathway proteins target and affect specific biological processes.
There are two core regulatory mechanisms, dual loop phosphorylation (catalytic sites) and docking (protein-protein interactions) that are used by the MAPKs. These interactions involve the activation of substrate kinases (MKKs) and their inactivation by phosphatases. Their mechanisms involve a variety of interactions that require docking sites that are remote from the catalytic sites. (Goldsmith 2011; Tanoue et al. 2001). Furthermore, the docking interactions confer pathway specificity that is required for the diverse steric demands of substrate protein-protein interactions with both kinases and phosphatases. These specificities are conferred by short sequential kinase interacting motifs (KIMS), e.g., D-motifs which confer specificity (Zhou et al. 2001) have been described as follows: the D-motifs are usually found in unstructured tail regions in the substrate (or enzyme). The docking sites of the MAPKs, e.g., p38α (CD) are located in the C-terminus of the MAPKs (Tanoue et al. 2001); the MAPK sites are bipartite with a negatively charged CD site and a hydrophobic grove (Chang et al. 2002; Goldsmith et al. 2007). The CD site is highly conserved and located at the C-terminus (Zhou et al. 2006).
The activation (phosphorylation) of all four p38 MAPK isoforms requires the interaction of the MKKs with a p38 docking domain which is located in the N-terminal region of the MKKs (Enslen et al. 1998). Synthetic peptides of the MKK6 docking sites inhibit activation of p38β indicating that MKK binding is necessary for the activation. On the other hand, MKK3, which lacks this docking site, can activate p38α, p38γ, and p38δ but not p38β; this accounts for the selective activation of p38α but not p38β by MKK3. Differences in the primary sequences of the T-loop of the p38 MAPK isoforms also contribute to signaling specificity. Thus, the specificity of p38 MAPK activation by MKKs requires multiple intramolecular domains present in both kinases, i.e., p38 MAPK and MKKs.
The Precisely Ordered Phosphorylation of the Catalytic Site Amino Acid Residues of the Serine/Threonine and Threonine/Tyrosine MAPKs
The order of phosphorylation, i.e., random versus sequential, of the catalytic site amino acid residues has been shown to proceed through a rigorous sequential order (Humphreys et al. 2013; Piala et al. 2014). Thus, a preferential phosphorylation of the proteins of the serine/threonine* pathway (ASK1) (Tao1) → MKK6 and a preferential phosphorylation of the tyrosine in the Thr/Tyr* activity of the p38α suggests an overall design of the cascade as “an excursion from Ser/Thr chemistry to Tyr chemistry (Humphreys et al. 2013; Piala et al. 2014), a mechanism that is sequential and precise.” The sequence of phosphorylation of ASK1 → p38 pathway proceeds through ASK1/Thr* → MKK6/ST* → p38α/TY* → ATF2/Thr*. In fact, the phosphorylation of p38α goes through a dominant intermediate p38α/Tyr* (Humphreys et al. 2013).
Although there is no structural/model information to explain why the Tyr182 is phosphorylated first, the progression curves and model fitting show that MKK6 binding to p38α at Tyr185 leads to a more rapid catalysis in comparison to the p38αThr183 binding (Humphreys et al. 2013).
Other important p38 MAPK protein-protein interactions involve the nuclear localization of the MAP-kinase-activated protein kinases (MAPKAPKs; 2pk, 3pk Fig. 2b). The formation of 2pk- or 3pk-p38 MAPK functional signaling complexes occurs at a conserved docking motif at the C-terminal region. This domain is used for binding to MKKs, nuclear localized 2pk, 3pk, and MAPK phosphatases (MPKs) (Fig. 2). The p38α CD domain is located outside of the active center (Fig. 2). Conceptually, therefore, recognition between p38 MAPKs and interacting proteins involves both the docking interaction domains and the transient enzyme-substrate interaction at the T-loop (Thr180-Tyr182), both of which regulate the efficiency and specificity of the enzymatic (kinase) reactions (Gavin and Nebreda 1999; Jiang et al. 1997; Muda et al. 1998; Wang et al. 1998; Yang et al. 1998).
The ED site determines docking specificity toward the nuclear localized 2pk and 3pk, which associate with p38 MAPK and transcription factors (Fig. 2a, b; Gavin and Nebreda 1999; Tanoue et al. 2001). This site which is located at p38 MAPK Glu160 and Asp161would explain the ability to serve as a common docking groove (Tanoue et al. 2001). This 3D molecular model shows the proximity of the CD and the ED domains. Thus every MAPK-interacting molecule may bind to this docking groove, and each residue therein is differentially involved in each docking interaction (Ben-Levy et al. 1998).
Activation of the p38 MAPK Catalytic Site
Activation of the p38 MAPKs occurs by sequential phosphorylation of Thr180 and Tyr182 in the T-loop (Fig. 2). While p38α is phosphorylated preferentially on Tyr182 by MKK3 due to its lack of a MAPK docking site, those with a MAPK docking site (MKK6) phosphorylate both Thr180 and Tyr182 residues of p38α MAPK. Thus, this differential phosphorylation by MKK3 versus MKK6 participates in the specificity of signaling of these upstream activators.
Subcellular Localization and Nucleocytoplasmic Transport of the p38 MAPK Signal
Subcellular localization is an integral part of the diverse functions of the p38 MAPK signaling pathway (Figs. 3 and 4). The mechanism of complex formation involves the nucleocytoplasmic trafficking of 2pk or 3pk which are p38 MAPK nuclear substrates. Both 2pk and 3pk contain a nuclear localization signal domain (NLS) and nuclear export signal domain (NES) as an integral part of their structure that enables their nucleocytoplasmic trafficking. These proteins are localized in the nucleus in unstimulated cells. Upon stimulation, they dock with and are phosphorylated by p38 MAPK (Gavin and Nebreda 1999). Although this complex phosphorylates (activates) specific transcription factors, it is also exported to the cytoplasm where it mediates the phosphorylation/activation of its substrates (Fig. 3). Furthermore, phosphorylation of 2pk and 3pk by p38 MAPK not only activates the kinase so that it can phosphorylate its transcription factor substrates, but it has also been postulated to expose the NES that results in cytoplasmic localization of both proteins (Fig. 4; Ben-Levy et al. 1998; Engel et al. 1995; Enslen et al. 1998).
The NES and nuclear localization sequence (NLS) of 2pk and 3pk are located at their C-terminal end (Fig. 2, Engel et al. 1995; Gavin and Nebreda 1999). In addition, 3pk is localized in the nucleus before osmotic stress and in the cytoplasm upon recovery. The docking of p38 MAPK with 2pk or 3pk is essential for their phosphorylation and nucleocytoplasmic export of the complex. Thus, the docking interaction between p38 MAPK and 3pk is achieved via direct interaction of the CD domain and the ED site of p38 MAPK with the C-terminal portion of 3pk. (Figs. 2 and 4). The model in Fig. 4 suggests, therefore, that a p38–2pk/3pk complex may be formed in the cytoplasm of unstimulated cells and translocated to the nucleus where it may be activated.
The fact that there are cytoplasmic substrates, e.g., the p38 regulated/activated kinase (PRAK) and heat shock protein 27 (Hsp27), which are phosphorylated by p38 MAPK in the cytoplasm points to the diversity of its activity for downstream targets. Interestingly, the activation of p38 MAPK by DNA-damaging agents supports the idea that the p38 MAPK cascade might be initiated in the nucleus (Suh 2001). Activation of p38 MAPK in the nucleus, on the other hand, would indicate that MKK3 and MKK6 must be localized there. It has been shown that both MKK3 and MKK6 are localized in both the cytoplasm and nucleus. It has been shown that both MKK3 and MKK6 are localized in both the cytoplasm and nucleus (Ben-Levy et al. 1998) Thus, 2pk and 3pk may serve a dual function, both as effectors of p38 MAPK by phosphorylating substrates such as Hsp27 (cytoplasmic) and the nuclear cAMP responsive element-binding protein (CREB) and as determinants of p38 MAPK localization (Figs. 3 and 4).
Feedback Control of MAPK-Regulated Transcription
Inactivation of the MAPKs is achieved by the dual-specificity MAP kinase phosphatases (MKPs) which target the two regulatory phosphorylation sites of the catalytic domain (Keyse 2000). There are ∼9 mammalian MKPs, divided into two groups according to their patterns of transcriptional regulation and subcellular localization (Keyse 2000). The nuclear MKPs are rapidly and highly inducible by many of the stimuli that activate the MAPKs. It is postulated, therefore, that these MKPs play an important role in the feedback control of MAPK signaling in the nucleus. Hutter et al. (2002) showed that activation of MKP-1 involves its interaction with the C-terminal end of nuclear p38 MAPK to activate MKP-1 catalytically. This raises the question of whether a 2pk/3pk-p38-MKP complex forms in the nucleus and is exported into the cytoplasm (Fig. 3) and whether this complex is targeted in the process of inactivation of p38 MAPK.
Several cytosolic MKPs can be triggered by direct interaction with MAPKs. MKP-3 interacts specifically with ERK; binding of ERK2 to MKP-3 dramatically enhances the latter’s catalytic activity (Tanoue et al. 2001). On the other hand, MKP-4 interacts with all members of the three major MAPK subfamilies to become catalytically activated (Keyse 2000). These novel mechanisms ensure the tight feedback control of MAPK signaling in the cytosol.
Role of p38 MAPK Signaling in Response to Stress Challenges and Aging
Elevated and sustained expression of p38 MAPK signaling activity is a major physiological characteristic of aging (Freund et al. 2011; Haq et al. 2002; Hsieh and Papaconstantinou 2002; Hsieh et al. 2003; Iwasa et al. 2003; Papaconstantinou and Hsieh 2010; Papaconstantinou et al. 2015). This age-associated state of chronic stress is attributed to such sources of ROS generation as mitochondrial ETC dysfunction and is a key factor that promotes stress-induced aging characteristics. Thus, endogenous ROS are important factors that regulate signaling pathways that control the development of senescence and aging phenotypes as well as diseases of inflammation and oxidative stress. We have demonstrated that mitochondrial generated ROS activates p38 MAPK through the ASK1-signalosome → p38 MAPK pathway (Hsieh and Papaconstantinou 2006; Papaconstantinou and Hsieh 2010). Activation of ASK1 initiates the activation of MKK3/6 which activates p38 MAPK. Thus, the mechanism of regulation of p38 MAPK in response to ROS involves activation of the ASK1-signalosome. Through this mechanism, mitochondrial generated ROS activates p38 MAPK and links the activation of senescence pathways (p16Ink4a and p19Arf) via p38 MAPK. Based on this hypothesis, it might be expected that (a) the increased and persistent level of oxidative stress may affect the activity of the p38 MAPK stress signaling pathways; (b) as aging progresses, the constitutive activity of stress-activated signal pathways would increase; and (c) this new level of activity is stabilized –becoming a basic factor in the development of chronic stress in aged tissues.
Biological signaling is a highly specific process that enables cells and tissues to regulate their responses to their environment, both intrinsic and extrinsic. This review focused on the p38 MAPK family of signaling proteins that respond to mitogenic and stress-activating signaling challenges. Although the p38 MAPK stress response pathway was first discovered in response to an inflammatory challenge by bacterial endotoxin (LPS), its diverse functions have been rapidly identified thus making it a major and critical pathway that regulates numerous biological processes. This is seen in its regulation of differentiation, apoptosis, senescence, and aging. The demonstration that the mechanism of cellular destruction by anthrax lethal factor involves blocking the p38 pathway adds to the significance of the diversity of this pathway. Most certainly, there are other equally important signaling pathways that play a key role in the response to stress factors, mitogens, hormones, etc., such as the ERK and SAPK/JNK pathways and the hormone-activated pathways such as insulin/IGF-1 and GH pathways. All of these pathways share several mechanisms of signal transduction, e.g., protein-protein interactions (docking), protein modifications (phosphorylation), and intracellular trafficking (nucleocytoplasmic, mitochondrial). Thus, in our discussion of the mechanisms of p38 MAPK pathways, our purpose was to familiarize the reader with these mechanisms which occur in most signaling processes. Furthermore, our focus on how aging affects the function of the p38 MAP kinase pathway is meant to demonstrate that in addition to environmental and intrinsic factors, signaling pathways also play a key regulatory role in biological processes during the entire life cycle, i.e., spanning the embryonic young adult and aging phases of life.
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