Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Protein Phosphatase 1 (PP1)

  • Filipa Martins
  • Joana B. Serrano
  • Ana M. Marafona
  • Odete A. B. da Cruz e Silva
  • Sandra Rebelo
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101767

Synonyms

Historical Background

Protein phosphatase 1 (PP1), also known as phosphorylase phosphatase, was first studied in 1943 by Cori and Green in the context of glycogen metabolism, as the enzyme responsible for the conversion of phosphorylase a to phosphorylase b (Cori and Green 1943). A decade later, the discovery that this enzyme is in fact a phosphatase, together with the discovery of phosphorylase kinase by Fischer and Krebs in 1955, marked the beginning of the study of protein phosphorylation/dephosphorylation as a ubiquitous regulatory mechanism (Fischer and Krebs 1955). Research on PP1 further focused on the understanding of its enzymology and its role in glycogen metabolism. In fact, in the 1970s, PP1 catalytic subunits (PP1c) were isolated from both the liver and muscle (Brandt et al. 1975; Gratecos et al. 1977). Subsequent studies led to the discovery of PP1 inhibitors and targeting subunits, which are crucial aspects of PP1 biology, namely, the role of the inhibitor proteins in regulating protein phosphatase activity, the role of targeting subunits that specifically target the PP1 catalytic subunit (PP1c) to specific subcellular locations, and the current view that PP1c exists in many holoenzyme forms (Cohen 1989). The concept of PP1 holoenzyme emerged and is comprised by the catalytic subunit with regulatory subunits. This concept was further supported by the finding that PP1 activity is generally associated with high molecular weight complexes (Killilea et al. 1979; Mellgren et al. 1979). However, the study of PP1 enzymology is still incomplete today. Over the last decade, PP1 has been implicated in many cellular processes, including, but not limited to, cell cycle control, apoptosis, transcription, adhesion, motility, metabolism, memory, and HIV-1 viral transcription (reviewed in Cohen 2002).

Protein Phosphorylation and Protein Phosphatases

Reversible protein phosphorylation is one of the most common posttranslational modifications in eukaryotic organisms and a key mechanism regulating the biological activity of several proteins. It involves either the addition of phosphate groups via the transfer of the terminal phosphate from ATP to the target residue of the protein by protein kinases (protein phosphorylation) or its removal by protein phosphatases (dephosphorylation) (Fig. 1). More than 70% of all eukaryotic proteins are regulated by protein phosphorylation occurring mainly at serine (Ser), threonine (Thr), and tyrosine (Tyr) residues (Barford et al. 1998).
Protein Phosphatase 1 (PP1), Fig. 1

Schematic representation of reversible protein phosphorylation. Protein kinases transfer a phosphate group from ATP to the target protein (protein phosphorylation), while protein phosphatases catalyze the hydrolysis of the phosphate group from the target protein (protein dephosphorylation)

Based on structural conservation and mechanism of action of their catalytic subunit, protein phosphatases can be classified in four distinct superfamilies. The protein tyrosine phosphatase (PTP) superfamily comprises the classical and nonclassical protein tyrosine phosphatases. In addition, the dual-specificity protein phosphatases that dephosphorylate both Tyr and Ser/Thr residues are also included in this superfamily. Beyond protein substrates, some PTPs can also dephosphorylate non-protein substrates namely phospholipids, RNA, and glycogen. The HAD superfamily of hydrolases comprises some protein serine/threonine/tyrosine phosphatases. Metal-dependent protein phosphatase (PPM) superfamily is mainly composed by monomeric protein Ser/Thr phosphatases that are activated by divalent cations. Finally, the phosphoprotein phosphatase (PPP) superfamily also exclusively dephosphorylates Ser and Thr residues (Boens et al. 2013).

Phosphoprotein Phosphatase (PPP) Superfamily

PPP family includes PP1, PP2A, PP3 (also known as calcineurin or PP2B), PP4, PP5, PP6, and PP7. PPPs comprise a structurally related catalytic core domain that is conserved among species and an identical catalytic mechanism (Barford et al. 1998; Shi 2009). The remarkable degree of evolutionary conservation of these enzymes is associated with their essential role in the regulation of important cellular processes (Honkanen and Golden 2002). Several biochemical studies have indicated that PPPs catalyze more than 90% of all dephosphorylation events in eukaryotic cells, mainly performed by PP1 and PP2A. Moreover, the functional diversity achieved by PPP family is achieved by the existence of several isoforms for each catalytic subunit of each protein phosphatase. Of note, there are two genes coding for the PP2A isoforms, PP2Aα and PP2Aβ (PPP2CA and PPP2CB, respectively), that share 97% identity and are highly conserved (Honkanen and Golden 2002). PP3 comprises three isoforms (PP3α, PP3β, and PP3γ) that share more than 80% identity in their primary amino acid sequence and are coded by three distinct genes (PPP3CA, PPP3CB, and PPP3CC, respectively). Each gene, in turn, undergoes alternative splicing to each give rise to three alternatively spliced isoforms (reviewed in Korrodi-Gregório et al. 2014). Concerning PP4 and PP6, they are structurally related to PP2A and are predicted to share around 65% and 57% identity, respectively, at the amino acid sequence level when compared to PP2A. PP6 has three different isoforms derived by alternative splicing of the PPP6C gene. Of note, PP5 and PP7 belong to this family since they contain the catalytic subunit common to the other family members. However, they have different N- and C-termini that are implicated in the targeting and regulation of enzymatic activity. PP5 is coded by one single gene (PPP5C) resulting in two isoforms, while PP7, also named protein phosphatase with EF-hand calcium-binding domain (PPEF), is coded by two genes (PPEF1 and PPEF2) resulting in four isoforms (reviewed in Korrodi-Gregório et al. 2014). PP1 has four isoforms: PP1α, PP1β/δ, PP1γ1, and PP1γ2 that are discussed in detail in the next section. Overall, several functions have been ascribed to PPP family members and those should not be exclusively attributed to the different catalytic subunits; their binding to regulatory proteins should also be considered (reviewed in da Cruz e Silva et al. 2004).

Protein Phosphatase 1 (PP1)

PP1 is a major protein phosphatase present in eukaryotic organisms and is expected to catalyze the majority of protein dephosphorylation events (Bollen et al. 2010; Heroes et al. 2013). Interestingly, eukaryotic genomes contain multiple genes encoding PP1 isoforms with an exception for Saccharomyces cerevisiae that only contains one gene coding for PP1. PP1 isoforms are about 70% identical in the central region being mainly different at the N- and C-terminal sequences. Interestingly, PP1 has been indicated as one of the most conserved eukaryotic proteins. PP1 sequences are highly conserved among species, as is the case of Giardia lamblia which expresses a PP1 isoform very similar to the mammalian form. Altogether, these results suggest that PP1 might have similar functions in different organisms (Ceulemans and Bollen 2004; Lin et al. 1999). In mammals, PP1c is encoded by three separate genes PPP1CA, PPP1CB, and PPP1CC, which originate PP1α, PP1β/δ, and PP1γ, respectively (Fig. 2). Of note, alternative splicing events on each of the transcripts give rise to three PP1α isoforms, two PP1β/δ isoforms (both with the same coding sequence), and two PP1γ isoforms (Fig. 2). Particularly interesting is the case of PPP1CC gene that suffers tissue-specific splicing, giving rise to PP1γ1 isoform that is ubiquitously expressed and a testis-enriched and sperm-specific isoform, PP1γ2 (Fig. 2C). The main difference between these two PP1γ isoforms resides in the C-terminus (reviewed in Fardilha et al. 2010).
Protein Phosphatase 1 (PP1), Fig. 2

Structure of the humanPPP1Cgenes and respective mRNAs and proteins. (a) The human PPP1CA, located at chromosome position 11q13, contains seven exons. Human PPP1CA transcript variants differ only by an alternative splicing of exon 2 in transcript variant 2 or by an alternative in-frame splice site at the 5′ end of exon 2 in transcript variant 3. Human PP1α isoforms 2 and 3 have the same N- and C-termini as isoform 1; however isoform 2 lacks an internal region, and isoform 3 is longer compared to isoform 1. (b) The human PPP1CB, located at chromosome position 2p23, contains eight exons. (c) The human PPP1CC, located at chromosome position 12q24.1–q24.2, contains eight exons. Human PPP1CC transcript variant 2 is generated by alternative splicing of exon 7, which results in a longer testis-enriched and sperm-specific PP1γ2 isoform with a distinct C-terminus compared to isoform 1. Coding exons are represented by a white line running across the boxes, while noncoding sequences in exons are represented by opaque boxes. The in-frame ATG codons are indicated by arrows

PP1 holoenzymes are essentially composed of a highly conserved PP1 catalytic subunit (PP1c) that is associated with one or two variable regulatory subunits (also known as PP1 regulatory subunit, PP1R or PP1-interacting protein, PIP). The PIPs interact with PP1c through well-characterized PP1-docking motifs. So far, about ten distinct PP1-docking motifs were described, but certainly, more will be identified in a near future. These include RVxF, SILK, MyPhoNe, SpiDoC, RNYF, IDoHA, BiSTriP, AnkCap, NiHiP, and the apoptotic signature (Boens et al. 2013; Ayllón et al. 2000) (Table 1). Of note is that some of the binding motifs are often found in only one of the known PIPs, while others have been identified in several PIPs. For example, IDoHA motif only exists in inhibitor-2, while the RVxF motif is found in about 90% of all identified PIPs. Additionally, some PP1-binding motifs are isoform specific, and thereby specific holoenzymes are formed with only one PP1 isoform. The AnkCap motif consists of ankyrin repeats that bind especially to PP1β/δ (Terrak et al. 2004). Moreover, most PIPs contain several PP1-docking motifs in order to form a unique and stable complex with PP1 (Boens et al. 2013).

To date, more than 200 PIPs are known, and many more will be certainly identified in the future. PIPs confer specificity to PP1c by targeting it to a specific subcellular compartment, modulating its specificity, inhibiting its catalytic activity, or serving as substrates. According to this, PIPs can be categorized as targeting subunits, substrate-specifier subunits (s-s subunits), inhibitory subunits, and substrates (Fig. 3) (reviewed in Bollen et al. 2009; in Bollen et al. 2010; and in Rebelo et al. 2015). However, for most PIPs, the physiological relevance of their binding to PP1 is not known.
Protein Phosphatase 1 (PP1), Fig. 3

Schematic representation of the PP1 holoenzyme structure. The protein phosphatase 1 catalytic subunit (PP1c) interacts with regulatory subunits that can be targeting proteins (a), substrate specifiers (b), inhibitors of the catalytic activity (c), or substrates (d)

Some specific PP1-binding proteins target PP1 to either a specific subcellular compartment or to a protein complex. For example, spinophilin directs PP1 to dendritic spines in the brain, near to potential substrates, mediating the regulation of PP1 synaptic function (Allen et al. 1997). Additionally, other PP1 complexes have been identified, as is the case of APP:Fe65:PP1, where Fe65 is the scaffolding protein responsible for the bridging between PP1 and the Alzheimer’s amyloid precursor protein (APP), being the latter dephosphorylated, apparently by PP1 (Rebelo et al. 2013). Phosphatase 1 nuclear targeting subunit (PNUTS) is a PP1-targeting subunit, and recently the C-terminal domain (CTD) of RNAPII was described as the first substrate of the PNUTS:PP1 complex. Many substrates that directly associate with PP1c are enzymes that are activated by dephosphorylation, as is the case for focal adhesion kinase, E3 ubiquitin ligase, and caspase 2 (reviewed in Bollen et al. 2010). Some substrates are dephosphorylated specifically on a single residue, whereas others are dephosphorylated on multiple residues. Recently, lamina-associated protein 1 (LAP1), BRI2, and BRI3 were added to the list of PP1 substrates (Santos et al. 2013; Martins et al. 2016a). Some PIPS are substrate specifiers since they enhance PP1 activity towards PP1 substrates, as is the case of myosin phosphatase targeting subunit 1 (MYPT1). Interaction of the later protein with PP1 not only promotes the dephosphorylation of the myosin regulatory light chain but also decreases PP1 activity towards other substrates. PP1 inhibitors are capable of blocking the PP1 active site and inhibit the dephosphorylation of all substrates. Inhibitor-1, DARPP-32 (dopamine and cAMP-regulated phosphoprotein), inhibitor-2, and inhibitor-3 are potent PP1c inhibitors (reviewed in Bollen et al. 2010; and in Ceulemans and Bollen 2004a).

PP1 Isoform Expression

All three PP1 isoforms (PP1α, PP1β, and PP1γ1) are ubiquitously expressed in mammalian tissues; PP1α is particularly enriched in the brain and heart, PP1β in the brain, small intestine, muscle, and lung, and PP1γ1 in the brain, heart, and skeletal muscle. Regarding PP1γ2, it is now well accepted that it is highly enriched in the testis, presenting only low expression in the brain (Aoyama et al. 2011; da Cruz e Silva et al. 1995; Lüss et al. 2000; Ouimet et al. 1995; Strack et al. 1999) (Table 2). All PP1 isoforms are differentially distributed in the brain, and PP1α and PP1γ1 isoforms present the highest expression levels. From all brain tissues, PP1α and PP1γ1 were found to be greatly expressed in the striatum (da Cruz e Silva et al. 1995). PP1γ2 is homogeneously expressed in most forebrain regions but particularly enriched in the striatum. However, lower levels were observed in the hindbrain and cerebellum. PP1β levels were quite similar in all forebrain regions analyzed and lower in the hindbrain and cerebellum (Strack et al. 1999). Using in situ hybridization, it was established that PP1α, PP1β, and PP1γ1 genes were widely expressed throughout the rat brain. Broad cortical distribution was observed, but their mRNAs were particularly abundant in the hippocampus and cerebellum. All three PP1 isoforms were found in the striatum; however, a lower signal was observed for PP1β compared to PP1α and PP1γ. From the three PP1 isoforms, only PP1β and PP1γ1 presented significant expression levels in the midbrain (da Cruz e Silva et al. 1995). Further, using RT-PCR and Northern blot techniques, it was shown that all three PP1 isoforms are expressed in human muscular tissues (heart and skeletal muscle). The expression levels of PP1α, PP1β, and PP1γ were higher in right ventricles than in right atria (Lüss et al. 2000). Additional microarray studies using failing human hearts revealed that PP1α and PP1γ mRNAs were downregulated, while the mRNA for PP1β was upregulated in end stage of dilated cardiomyopathy (Paul and Jozef 2004).

PP1 Isoform Cellular and Subcellular Localization

Interestingly, all PP1 isoforms are present in all mammalian cells analyzed, but their localization within those cells is surprisingly different and specific. During interphase, all PP1 isoforms are present both in the cytoplasm and nucleus (Table 2). Within the nucleus, PP1α is found associated with the nuclear matrix, PP1β localizes to non-nucleolar whole chromatin, and PP1γ1 concentrates in nucleoli in association with RNA. Further, using the transient expression of PP1 fused with fluorescent proteins (FP), it was established that FP-PP1α is mainly found in a diffuse nucleoplasmic pool and largely excluded from the nucleolus. PP1γ accumulates predominantly in the nucleolus, and PP1β is found in both the nucleoplasm and nucleolus, but its accumulation in the nucleolus is different to that observed for PP1γ (Trinkle-Mulcahy et al., 2003). Furthermore, it is known that PP1 plays a key role in mitosis where PP1 isoforms are differentially targeted to specific subcellular structures (Table 2). Essentially during mitosis, PP1α and PP1γ are distributed throughout the cell excluding the chromosomal area and are also in the mitotic spindle and midbody. PP1α is also localized to the centrosome, and PP1β strongly associates with chromosomes (Santos et al. 2012; Andreassen et al. 1998; Trinkle-Mulcahy et al. 2003). Given that PP1α and PP1γ1 isoforms were found particularly enriched in medium-sized spiny neurons of the striatum (da Cruz e Silva et al. 1995), the subcellular localization of those isoforms in neuronal cells is of particular interest (see Table 2). Furthermore, the PP1γ2 isoform is highly enriched in the testis where it is localized at the cytoplasm and nucleus of secondary spermatocytes, round spermatids, as well as elongating spermatids, and testicular and epididymal spermatozoa (Table 2). However, all PP1 isoforms are expressed in mammalian testis where PP1γ1 is mainly observed in the cytoplasm of interstitial cells, spermatogonia, and preleptotene spermatocytes and PP1α in the cytoplasm of Leydig and peritubular cells, spermatogonia, and preleptotene spermatocytes (Table 2). In spermatozoa, only PP1α, PP1β, and PP1γ2 were present, being the latter more abundant and present in sperm head and more predominantly at the tail (Fardilha et al. 2011; Korrodi-Gregório et al. 2014) (Table 2).
Protein Phosphatase 1 (PP1), Table 1

PP1-docking motifs. PP1-docking motifs are presented, as well as the specific sequence, the function, and other known characteristics

PP1-docking motif

Consensus sequence

Function

Other characteristics

References

RVxF

[RK]-X(0,1)-[VI]-{P}-[FW]

PP1 anchoring

Binds to a hydrophobic groove of the PP1c, which is opposite to the catalytic site

Egloff et al. (1997) and Wakula et al. (2003)

X (0,1) is any aa, present or absent; {P} represents any aa except P

Binding through this motif does not affect PP1 conformation and activity

SILK

[GS-I-L-[RK]

PP1 anchoring

Binds to a hydrophobic groove of the PP1c, which is opposite to the catalytic site

Reviewed in Hendrickx et al. (2009) and Bollen et al. (2010)

N-terminally positioned to RVxF motif

Binding through this motif does not affect PP1 conformation

MyPhone

R-X-X-Q-[VIL]-[KR] – X-[YW]

Substrate selection

Binds to a shallow hydrophobic cleft of PP1

Reviewed in Bollen et al. (2010)

X is any aa

N-terminally positioned to RVxF motif

SpiDoC

8-residue motif

Substrate selection

Binds to the C-terminal groove of PP1

Reviewed in Heroes et al. (2013) and Boens et al. (2013)

RNYF

R-N-Y-F

The binding sequence of the motif on PP1c is ND

Llanos et al. (2011)

IDoHA

α-helix structure

Inhibition

Prevents access to the active site of PP1 by binding the hydrophobic and acidic grooves of PP1

Reviewed in Heroes et al. (2013)

BiSTriP

Leucine-rich repeats

Binds to the triangular region of PP1 delineated by helices α4–6

Reviewed in Ceulemans and Bollen (2004a)

AnkCap

8 ankyrin repeats

Substrate selection

Enclose the C-terminus of PP1β

Reviewed in Heroes et al. (2013)

NiHip

α-helix structure

Binds to the PP1 bottom surface

Reviewed in Boens et al. (2013)

Apoptotic signature

F-X-X-[KR]-X-[KR]

The binding sequence of the motif on PP1c is ND

Godet et al. (2010)

X is any aa

The motif is found in several proteins involved in the control of cell survival pathways

MyPhone myosin phosphatase N-terminal element, SpiDoC spinophilin docking site for the C-terminal groove, IDoHA inhibitor-2 docking site for the hydrophobic and acidic grooves, BiSTriP bipartide docking site of the leucine-rich repeat protein SDS22 interacting with a triangular region that is delineated by helices α4–6 of PP1, AnkCap ankyrin repeat Cap, NiHip NIPP1 helix that interacts with PP1, aa amino acid, ND not determined

Protein Phosphatase 1 (PP1), Table 2

Tissue expression and subcellular distribution of the PP1 isoforms’ tissue expression, as well as subcellular localization, are presented

Gene name

PP1 catalytic isoform

Tissue expression

Subcellular localization

References

PPP1CA

PP1α

Ubiquitous; enriched in the brain and heart

Cytoplasm (centrosomes) and nucleus (nuclear matrix and nucleoplasm)

da Cruz e Silva et al. (1995), Aoyama et al. (2011), Lüss et al. (2000), Ouimet et al. (1995) Strack et al. (1999), Korrodi-Gregório et al. (2014), Trinkle-Mulcahy et al. (2003), and Santos et al. (2012)

During mitosis, it is in the centrosomes and kinetochores

In neurons, it is localized at dendritic spines, perikaryal cytoplasm, and nucleus

Present in spermatozoa

PPP1CB

PP1β

Ubiquitous; enriched in the brain, small intestine, muscle, and lung

Cytoplasm and nucleus (nucleoplasm and nucleolus)

da Cruz e Silva et al. (1995), Aoyama et al. (2011), Korrodi-Gregório et al. (2014),Strack et al. (1999), and Trinkle-Mulcahy et al. (2003)

During mitosis, it is associated with chromosomes

In neurons, it is localized in cell soma and associated with microtubules

In spermatozoa, it is in sperm head and tail

PPP1CC

PP1γ1

Ubiquitous; enriched in brain, heart and skeletal muscle

Cytoplasm and nucleus (nucleolus)

da Cruz e Silva et al. (1995) Ouimet et al. (1995), Trinkle-Mulcahy et al. (2003), Santos et al. (2012), and Strack et al. (1999)

During mitosis, it is in the kinetochores and associated with chromatin

In neurons, it is localized in dendritic spines and presynaptic terminals and associated with actin cytoskeleton

PP1γ2

Highly enriched in testis; low levels of expression in the brain

In spermatozoa, it is present in the posterior region and equatorial segment of sperm head and more predominantly at the tail

da Cruz e Silva et al. (1995), Fardilha et al. (2011), and Korrodi-Gregório et al. (2014)

PP1 Function

PP1 has been associated with a variety of cellular functions including glycogen metabolism, transcription, protein synthesis, cell cycle, meiosis, and apoptosis. It is known that when nutrients are abundant, PP1 stimulates glycogen synthesis and also enables the return to the basal state of protein synthesis, recycling the transcription factors. PP1 is also important for regulating nuclear events, particularly transcription and mRNA processing and cell cycle (interphase and mitosis) through association with specific nuclear regulatory proteins (Fig. 4) (reviewed in Rebelo et al. 2015). Additionally, PP1 can promote apoptosis when cells are subjected to DNA damage. PP1 has also been involved in additional cellular processes, namely, neurotransmission, neurite outgrowth, synapse formation (reviewed in Ceulemans and Bollen 2004; and in Cohen 2002), spermatogenesis, and sperm motility (reviewed in Han et al. 2007; in Fardilha et al. 2011; and in Silva et al. 2014) (Fig. 4).
Protein Phosphatase 1 (PP1), Fig. 4

Diagram of PP1 functions. Examples of PIPs, which together with PP1c, have been associated with a variety of cellular functions. PIP PP1-interacting protein, NrbI neurabin-I, NrbII neurabin-II

PP1 Function in the Nucleus

Protein phosphorylation is a crucial regulatory mechanism involved in key nuclear events, namely, gene transcription, mRNA processing, cell survival, and cell cycle (reviewed in Rebelo et al. 2015). PP1 is enriched in the nucleus, and its localization is highly dynamic and changes throughout mitosis. The nuclear PP1-binding proteins associated with transcription include PNUTS, RNAPII CTD, HDAC1, CREB, Hox11, HCF1, MEF2, SARP1, SARP2, PITK, and hnRNP K. From these, the transcription factor CREB mediates the expression of cAMP-induced genes. Moreover, when it is dephosphorylated at Ser133 by PP1, the cAMP gene transcription is attenuated (reviewed in Rebelo et al. 2015).

Several reports have already suggested that PP1 activity is required for pre-mRNA splicing. Indeed, PNUTS and nuclear inhibitor of protein phosphatase 1 (NIPP1), the most abundant nuclear PIPs, bind to RNA and are involved in the regulation of pre-mRNA splicing. For example, PNUTS was shown to inhibit the phosphatase activity of PP1γ and PP1α in vitro and anchors PP1 to specific RNA-associated complexes. Moreover, PNUTS interacts with RNA polymerase II (RNAPII) at active sites of transcription. PNUTS:PP1 holoenzyme is capable of enhancing the dephosphorylation of RNAPII C-terminal domain which suggests that this complex is also important for gene transcription regulation (reviewed in Rebelo et al. 2015).

The following list of nuclear PIPS are the ones involved in mRNA processing, specifically NIPP1, CDC5L, SAP155, P54nrb, PSF, Tra2-beta1, and SIPP1. From these proteins, NIPP1 has a nucleoplasmic distribution and also accumulates in nuclear speckles where it binds to pre-mRNA splicing factors. Further, NIPP mediates the interaction between PP1 and CDC5L (a regulator of pre-RNA splicing). It has been suggested that CDC5L and PP1:NIPP1 complex may be involved in the splice reaction and in the spliceosome disassembly (reviewed in Rebelo et al. 2015).

A role for PP1 in controlling cell cycle progression is supported by the existence of multiple substrates for PP1 in all phases of the cell cycle and by the evidence supporting that PP1 is targeted to some mitotic structures such as chromosomes, centrosomes, and spindle apparatus. In fact, some PP1 complexes are involved in the regulation of numerous cellular architecture changes, namely, chromosome condensation, nuclear envelope disassembly, spindle formation, and chromosome segregation (reviewed in Rebelo et al. 2015). PP1 is also suggested to be involved in centrosome maturation (G2 phase), a process characterized by recruitment of γ-tubulin and other proteins that function as nucleation sites for microtubules, by dephosphorylating and activating BRCA1 protein. PP1 controls the entry into mitosis by regulating the activity of mitotic kinases. Indeed, activation of Cdk1, by Cdc25B and Cdc25C dephosphorylation, in association with the cyclins, is a key molecular indicator for entry into mitosis. Interestingly, Cdc25 activation is achieved by dephosphorylation mediated by PP1, further resulting in the activation of Cdk1 and consequently in the transition between G2/M phase (reviewed in Rebelo et al. 2015).

PP1 may prevent premature splitting of centrosomes, by inactivating some kinases involved in this process, namely, Aurora A and Nek2A (reviewed in Rebelo et al. 2015). Moreover, after the proper separation of centrosomes, they should be correctly positioned near the outer nuclear membrane. Nuclear envelope (NE) proteins, namely, LAP1 and emerin are crucial in this process. However, LAP1 is not only crucial for centrosome positioning near the NE but also its depletion results in a decrease of mitotic cells and in the levels of acetylated α-tubulin and lamin B1. In addition, LAP1 activity is regulated by PP1 dephosphorylation at residues Ser306 and Ser310 (Santos et al. 2014a, b).

Additionally, PP1 activity is involved in the maintenance of microtubule-kinetochore attachment and spindle assembly checkpoint (SAC) which are crucial for accurate chromosome separation. For example, PP1 stabilizes correct microtubule-kinetochore attachment during metaphase by reversing the activity of Aurora B, a kinase that phosphorylates numerous proteins involved in the destabilization of microtubule-kinetochore binding. Protein phosphatases, namely, PP1, are required for the mitotic exit which is characterized by mitotic spindle breakdown, chromosome decondensation, and reassembly of interphase structures such as the NE. For example, PP1 and its regulatory subunit, Repo-man (recruits PP1 to chromatin at anaphase), are required for chromosome decondensation. At the end of mitosis, PP1/Repo-man complex is responsible for histone H3 dephosphorylation that seems to be correlated with chromosome decondensation. Furthermore, PP1 is involved in nuclear envelope reassembly by dephosphorylating lamin-B, a component of the nuclear lamina that is phosphorylated at the onset of mitosis leading to nuclear lamina disassembly. At the end of mitosis, PP1 is targeted to lamin-B by AKAP149 resulting in reassembly of the nuclear lamina (reviewed in Rebelo et al. 2015). Given the presence of PP1γ in the cleavage furrow and spindle zone at the end of mitosis and in the center of the midbody during cytokinesis, it has been suggested that PP1 may have a role in cytokinesis regulation; however, the precise mode of action remains elusive (reviewed in Rebelo et al. 2015).

PP1 Regulation of Neuronal Functions

Protein phosphorylation plays an important and critical role in many aspects of neuronal function, namely, in neurotransmission, synaptic plasticity, and neurite outgrowth. In fact, dopamine-regulated signaling pathways involving the DARPP-32 and PP1 in the brain are well documented (reviewed in Greengard et al. 1999). Briefly, the neurotransmitter dopamine has an excitatory effect on striatonigral neurons expressing D1 receptors and causes activation of PKA and phosphorylation of DARPP-32 on Thr34, leading to PP1 inhibition. In a sharp contrast, striatopallidal neurons expressing D2 receptors are inhibited by dopamine, restoring PP1 activity by inhibiting PKA or by mediating the dephosphorylation of DARPP-32 by the Ca2+/calmodulin-dependent PP2B. Other neurotransmitters could also affect the DARP-32/PP1 pathway. For instance, glutamate binding to N-methyl-D-aspartate (NMDA) receptors stimulates DARPP-32 dephosphorylation by PP2B due to Ca2+ influx. In contrast, the activation of adenosine A2 receptors activates PKA leading to DARPP-32 phosphorylation and inhibition of PP1c (reviewed in Greengard et al. 1999).

Of particular relevance, PP1 has been identified as a key regulator of synaptic plasticity in both long-term depression (LTD) and long-term potentiation (LTP). PP1 is activated during LTD, whereas inhibition of PP1 has been suggested to take place during LTP (Blitzer et al. 1998; Mulkey et al. 1994). In fact, LTD-inducing stimuli promote the targeting of PP1 to dendritic spines, where it can dephosphorylate specific substrates, such as calcium/calmodulin-dependent protein kinase II (CaMKII), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and NMDA receptors (Mulkey et al. 1994). On the other hand, LTP-inducing stimuli lead to cAMP-dependent phosphorylation of the inhibitor-1 resulting in decreased PP1 activity. Consequently, an increase in phosphorylation level of CaMKII at Thr286 is observed and also an increase in its activity, which phosphorylates the AMPA receptor subunits and potentiates synaptic current (Soderling and Derkach 2000). PP1 also binds yotiao, a protein member of the AKAP family. Yotiao functions as a scaffold protein that attaches PP1 and PKA to NMDA receptors to regulate channel activity (Westphal et al. 1999).

Protein phosphorylation also plays a dynamic role in regulating the extension and branching of neurites in growing neurons in response to specific guidance cues. Indeed, PP1, alongside with PP2A, were reported to have a role in the neurite structure. Inhibition of PP1 and PP2A in cultured hippocampal neurons leads to decrease number and length of neurites and synapse loss (Malchiodi-Albedi et al. 1997). Additionally, another study showed that general inhibition of all PP1 isoforms in hippocampal neurons, using lower concentrations of tautomycin, reduced neuritis length and branching. Further, it was suggested that PP1 is responsible for the focal adhesion kinase (FAK) targeting, during growth cone advance and adhesion, in the earlier stages of outgrowth. Indeed, PP1 could stimulate FAK activity promoting actin polymerization and growth cone movement (Monroe and Heathcote 2013).

Recently it was demonstrated that BRI2 protein is a novel PP1 substrate. It was shown that the interaction is mediated through an RVxF motif, specifically 3RVTF6. By using BRI2 PP1-binding motif mutant constructs, where the BRI2:PP1 interaction is diminished (Myc-BRI2 KVTA) or abolished (Myc-BRI2 KATA), it was possible to observe a dramatic increase in BRI2 phosphorylation levels. Moreover, when BRI2:PP1 interaction was abolished, a phenotype consistent with neurite outgrowth and neuronal differentiation was observed (Martins et al. 2016a, b).

PP1 in Cytoskeletal Regulation

Cytoskeleton organization and dynamics are controlled by signaling pathways that clearly involve protein phosphorylation, namely, PP1 and some of its regulatory subunits. Two families of PP1 regulatory subunits, neurabins and MYPTs, are involved in actin and actomyosin reorganization.

Neurabin-I and spinophilin (also called neurabin-II) in response to physiological signals are able to target signaling proteins, such as PP1, to the actin cytoskeleton in order to control cell morphology. Neurabin-I is a neural-specific actin-binding protein highly enriched in both dendritic spines and growth cones, and its expression is important to support neurite formation (McAvoy et al. 1999; Oliver et al. 2002). In fact, neurabin-I targets PP1 to actin-rich structures, such as postsynaptic density, to promote the formation of filopodia as well as the maturation of dendritic spines, suggesting a significant role in spine morphogenesis. Additionally, PP1/neurabin-I complex regulates the trafficking of AMPA receptors to the synaptic membrane and therefore modulates synaptic transmission (Hu et al. 2006). Neurabin-I is phosphorylated near the PP1-binding motif at Ser461 by PKA which results in a dramatic reduction of PP1 affinity (Oliver et al. 2002). Spinophilin is a ubiquitously expressed actin-binding protein that targets PP1 to the dendritic spine compartment, where it associates with the actin-rich cytoskeletal structure known as the postsynaptic density (PSD) (Ragusa et al. 2011). In the PSD, the complex PP1:spinophilin regulates actin cytoskeleton organization and spine density by targeting PP1 to several substrates in dendritic spines (such as AMPA and NMDA receptors), controlling their phosphorylation (Feng et al. 2000; Ragusa et al. 2011). Blocking the spinophilin:PP1 complex formation prevents PP1-mediated dephosphorylation of the AMPA receptors, decreasing the rundown of AMPA currents and increasing the latter’s activity (Yan et al. 1999). Spinophilin-knockout mice exhibited a marked increase in spine density during development and altered filopodia formation, suggesting it functions as a negative regulator of spine morphogenesis. PKA also phosphorylates spinophilin but at Ser94 residue reducing its interaction with F-actin, displacing spinophilin from the PSD to the cytosol, which may ultimately serve to control PP1-mediated changes in the actin cytoskeleton or PP1 anchoring to receptors (Hsieh-Wilson et al. 2003).

Protein phosphorylation of myosin II regulatory light chain subunit (myosin II LC) regulates the contraction of actomyosin fibers which are responsible for several cellular functions, namely, smooth muscle contraction, cell shape change, and cell motility. Phosphorylation of myosin II LC relieves their inhibitory action on the contraction of actomyosin fibers, whereas its dephosphorylation favors the relaxation of those fibers (Ceulemans and Bollen 2004). Briefly, the phosphorylation of myosin II LC enables the interaction of myosin II with actin filaments converting the chemical energy of ATP into mechanical force or movement. Several kinases are responsible for myosin II LC phosphorylation; nonetheless, the most predominant is the Ca2+/calmodulin myosin light chain kinase (MLCK). On the other hand, dephosphorylation of myosin II LC is catalyzed by a myosin light chain phosphatases (MLCP) that is composed by PP1β in complex with a myosin phosphatase-targeting (MYPT) subunit. Therefore, MYPTs are PIPs that confer substrate specificity and subcellular localization to PP1β. MYPT subunit family consists of five different members, MYPT1, MYPT2, protein phosphatase 1 myosin-binding subunit of 85 kDa (MBS85), MYPT3, and the TGF-β1-inhibited, membrane-associated protein (TIMAP) (Grassie ME et al. 2011), which possess different expression patterns. MYPT1 is ubiquitously expressed but highly enriched in smooth muscle cells where it is involved in contraction. Briefly, smooth muscle contraction is activated by a raise of the cytosolic Ca2+ concentration which results in the activation of MLCK mediated by calmodulin. Further, MLCK phosphorylates myosin II LC at Ser19 promoting the interaction of myosin II with actin resulting in the generation of a contractile force. Once this stimulus has stopped, cytosolic Ca2+ concentration returns to its basal levels, and the myosin II LC is dephosphorylated by the MLCP. Therefore, actin and myosin II dissociate allowing for the relaxation of the muscle (Grassie et al. 2011; reviewed in Ceulemans and Bollen 2004). In addition, the phosphorylation of myosin II LC is responsible for the formation of stress fibers that connect focal adhesions thus regulating cell shape, migration, and adhesion (Xia et al. 2005). MYPT2 is expressed in striated muscles and in the brain, and both cardiac and skeletal muscle MLCPs consist of MYPT2 in complex with PP1β. However, in the striated muscle contraction, the phosphorylation of myosin II LC is not a requirement but affects the speed and force of contraction (Grassie et al. 2011; reviewed in Ceulemans and Bollen 2004). At the postsynaptic density, PP1 also binds to NF-L, a major component of the intermediate filament network in neurons. NF-L targets PP1 to neuronal membranes and cytoskeleton. Additionally, NF-L:PP1 complex seems to control NF-L phosphorylation levels as well as other neurofilament proteins, thus regulating the neurofilament assembly (Terry-Lorenzo et al. 2000). Moreover, PP1 is associated with microtubule network organization and dynamics, namely, by association with tau protein, a neuronal microtubule-associated protein (MAP). In fact, Tau is a PP1 substrate, and its dephosphorylation enhances its association with microtubules promoting their stability (Gong et al. 1994; Liao et al. 1998).

PP1 in Spermatogenesis and Sperm Motility

PP1 has been shown to be expressed in the testis and/or in spermatozoa, suggesting an important role in spermatogenesis and spermatozoa physiology (reviewed in Han et al. 2007; in Fardilha et al. 2011; and in Silva et al. 2014). Indeed, Ppp1CC-null male mice were shown to be infertile due to defective spermatogenesis and increased apoptosis of germ cells, leading to the absence of epididymal spermatozoa (reviewed in Han et al. 2007). Remarkably, some PIPs, namely, testis/sperm-specific PIPs, have been identified. These include, for instance, the spermatogenic zip protein 1 (Spz1), a member of the basic helix-loop-helix family of transcription factors that specifically interact with PP1γ2. Remarkably, Spz1 overexpression and PP1γ loss in the testis show similar phenotypes, namely, increased apoptosis and spermatogenic cycle arrest, suggesting a functional association for both proteins (reviewed in Han et al. 2007). Recently, LAP1 was, for the first time, associated with the spermatogenesis. LAP1 was found expressed during nuclear elongation in spermiogenesis and was located at the centriolar pole of spermatids. In addition, PP1γ2 staining shares an extraordinary similar pattern to that observed for LAP1, due to their homogenous distribution in the cytoplasm at the posterior pole. Given that LAP1 and PP1 interact and also that both proteins have important roles in mitosis, regulating MT dynamics, there is an additional putative significance for this complex in the spermatid elongation process (Serrano et al. 2016).

As mentioned before, in sperm, PP1γ2 is present along the entire flagellum including the midpiece, consistent with a role in sperm motility, but it is also found in the posterior and equatorial regions of the head, suggesting a role in the acrosome reaction. Several proteins have been implicated in the regulation of PP1γ2 activity during sperm maturation: inhibitor-2, sds22, inhibitor-3, 14-3-3, and AKAPs (Fardilha et al. 2011). Inhibitor-2 forms a stable complex with PP1, where PP1 is inactive. However, when inhibitor-2 is phosphorylated by GSK3, its inhibitory effect is relieved, and PP1 becomes active. Thus, it is proposed that in the first segments of the epididymis, the sperm is immotile because the PP1γ2:inhibitor-2 complex is activated by GSK3. In the last segment of the epididymis, the complex is inactive triggering sperm motility (Silva et al. 2014). AKAP4 is a major fibrous sheath protein located in the principal piece of spermatozoa that recruits PKA and facilitates local phosphorylation to regulate flagellum function (Han et al. 2007). In Akap4-knockout mice, spermatozoa lack motility and are infertile. Remarkably, the activity and phosphorylation of PP1γ2 are significantly altered, suggesting a functional relationship between PP1 and AKAP4 in sperm motility (Han et al. 2007; Silva et al. 2014)

Summary

The major posttranslational modification in eukaryotes is reversible protein phosphorylation, a key mechanism for signal transduction. Protein phosphatase 1 (PP1) is a ubiquitous serine/threonine phosphatase that belongs to the phosphoprotein phosphatase (PPP) superfamily and is responsible for about one-third of all dephosphorylations that occur in the eukaryotic cell. In mammals, three PP1 isoforms (PP1α, PP1β/δ, and PP1γ) exist that are coded by three different genes (PPP1CA, PPP1CB, and PPP1CC, respectively). The PPP1CC gene undergoes tissue-specific splicing, giving rise to a ubiquitously expressed isoform, PP1γ1, and a testis-enriched and sperm-specific isoform, PP1γ2. The PP1 isoforms are expressed in virtually all tissues but exhibit different tissue expression and subcellular localization. Since its discovery, several roles have been attributed to PP1 in the regulation of several cellular functions, such as glycogen metabolism. In the nucleus, PP1 is involved in gene transcription, mRNA processing, cell survival, and cell cycle regulation. Moreover, PP1 is important in cytoskeleton organization and regulates many aspects associated with neurotransmission, synaptic plasticity, neurite outgrowth, spermatogenesis, and sperm motility. This versatility of PP1 is determined by the binding of its catalytic subunit (PP1c) to different regulatory subunits, also known as PP1-interacting proteins (PIPs). PIPs are essential regulators that modulate PP1 cellular localization and substrate specificity and also activity. The binding of PIPs to PP1 is mediated by conserved PP1-binding motifs, and about ten have already been described. To date, more than 200 PIPs were identified, and in the near future, several more will certainly be found, increasing the number of cellular processes involving PP1.

References

  1. Allen PB, Ouimet CC, Greengard P. Spinophilin, a novel protein phosphatase 1 binding protein localized to dendritic spines. Proc Natl Acad Sci U S A. 1997;94:9956–61.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Andreassen PR, Lacroix FB, Villa-Moruzzi E, Margolis RL. Differential subcellular localization of protein phosphatase-1 alpha, gamma1, and delta isoforms during both interphase and mitosis in mammalian cells. J Cell Biol. 1998;141:1207–15.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Aoyama H, Ikeda Y, Miyazaki Y, Yoshimura K, Nishino S, Yamamoto T, Yano M, Inui M, Aoki H, Matsuzaki M. Isoform-specific roles of protein phosphatase 1 catalytic subunits in sarcoplasmic reticulum-mediated Ca(2+) cycling. Cardiovasc Res. 2011;89:79–88.PubMedCrossRefGoogle Scholar
  4. Ayllón V, Martínez-A C, García A, Cayla X, Rebollo A. Protein phosphatase 1alpha is a Ras-activated Bad phosphatase that regulates interleukin-2 deprivation-induced apoptosis. EMBO J. 2000;19:2237–46.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Barford D, Das AK, Egloff MP. The structure and mechanism of protein phosphatases: insights into catalysis and regulation. Annu Rev Biophys Biomol Struct. 1998;27:133–64.PubMedCrossRefGoogle Scholar
  6. Blitzer RD, Connor JH, Brown GP, Wong T, Shenolikar S, Iyengar R, Landau EM. Gating of CaMKII by cAMP-regulated protein phosphatase activity during LTP. Science. 1998;280:1940–2.PubMedCrossRefGoogle Scholar
  7. Boens S, Szekér K, Van EA, Bollen M. Interactor-guided dephosphorylation by protein phosphatase-1. Methods Mol Biol. 2013;1053:271–81.PubMedCrossRefGoogle Scholar
  8. Bollen M, Gerlich DW, Lesage B. Mitotic phosphatases: from entry guards to exit guides. Trends Cell Biol. 2009;19:531–41.PubMedCrossRefGoogle Scholar
  9. Bollen M, Peti W, Ragusa MJ, Beullens M. The extended PP1 toolkit: designed to create specificity. Trends Biochem Sci. 2010;35:450–8.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Brandt H, Capulong ZL, Lee EY. Purification and properties of rabbit liver phosphorylase phosphatase. J Biol Chem. 1975;250:8038–44.PubMedGoogle Scholar
  11. Ceulemans H, Bollen M. Functional diversity of protein phosphatase-1, a cellular economizer and reset button. Physiol Rev. 2004;84:1–39.PubMedCrossRefGoogle Scholar
  12. Cohen P. The structure and regulation of protein phosphatases. Annu Rev Biochem. 1989;58:453–508.PubMedCrossRefGoogle Scholar
  13. Cohen PTW. Protein phosphatase 1 – targeted in many directions. J Cell Sci. 2002;115:241–56.PubMedPubMedCentralGoogle Scholar
  14. Cori G, Green A. Crystalline muscle phosphorylase II. prosthetic group. J Biol Chem. 1943;151:31–8.Google Scholar
  15. da Cruz e Silva EF, Fox CA, Ouimet CC, Gustafson E, Watson SJ, Greengard P. Differential expression of protein phosphatase 1 isoforms in mammalian brain. J Neurosci. 1995;15:3375–89.PubMedPubMedCentralGoogle Scholar
  16. da Cruz e Silva OAB, Fardilha M, Henriques AG, Rebelo S, Vieira S, da Cruz e Silva EF. Signal transduction therapeutics: relevance for Alzheimer’s disease. J Mol Neurosci. 2004;23:123–42.PubMedCrossRefGoogle Scholar
  17. Egloff MP, Johnson DF, Moorhead G, Cohen PT, Cohen P, Barford D. Structural basis for the recognition of regulatory subunits by the catalytic subunit of protein phosphatase 1. EMBO J. 1997;16:1876–87.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Fardilha M, Esteves SLC, Korrodi-Gregório L, da Cruz e Silva OAB, da Cruz e Silva FF. The physiological relevance of protein phosphatase 1 and its interacting proteins to health and disease. Curr Med Chem. 2010;17:3996–4017.PubMedCrossRefGoogle Scholar
  19. Fardilha M, Esteves SLC, Korrodi-Gregório L, Pelech S, Cruz E, Silva OAB d, Cruz E, Silva E d. Protein phosphatase 1 complexes modulate sperm motility and present novel targets for male infertility. Mol Hum Reprod. 2011;17:466–77.PubMedCrossRefGoogle Scholar
  20. Feng J, Yan Z, Ferreira A, Tomizawa K, Liauw JA, Zhuo M, Allen PB, Ouimet CC, Greengard P. Spinophilin regulates the formation and function of dendritic spines. Proc Natl Acad Sci U S A. 2000;97:9287–92.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Fischer E, Krebs E. Conversion of phosphorylase b to phosphorylase a in muscle extracts. J Biol Chem. 1955;216:121–32.PubMedPubMedCentralGoogle Scholar
  22. Godet AN, Guergnon J, Maire V, Croset A, Garcia A. The combinatorial PP1-binding consensus Motif (R/K)x( (0,1))V/IxFxx(R/K)x(R/K) is a new apoptotic signature. PLoS ONE. 2010;5:e9981.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Gong C-X, Grundke-Iqbal I, Damuni Z, Iqbal K. Dephosphorylation of microtubule-associated protein tau by protein phosphatase-1 and -2C and its implication in Alzheimer disease. No longer published by Elsevier; 1994;341:94–8.Google Scholar
  24. Grassie ME, Moffat LD, Walsh MP, MacDonald JA. The myosin phosphatase targeting protein (MYPT) family: a regulated mechanism for achieving substrate specificity of the catalytic subunit of protein phosphatase type 1δ. Arch Biochem Biophys. 2011;510:147–59.PubMedCrossRefGoogle Scholar
  25. Gratecos D, Detwiler TC, Hurd S, Fischer EH. Rabbit muscle phosphorylase phosphatase. 1. purification and chemical properties. Biochemistry. 1977;16:4812–7.PubMedCrossRefGoogle Scholar
  26. Greengard P, Allen PB, Nairn AC. Beyond the dopamine receptor: the DARPP-32/protein phosphatase-1 cascade. Neuron. 1999;23:435–47.PubMedCrossRefGoogle Scholar
  27. Han Y, Haines CJ, Feng HL. Role(s) of the serine/threonine protein phosphatase 1 on mammalian sperm motility. Arch Androl. 2007;53:169–77.PubMedCrossRefGoogle Scholar
  28. Hendrickx A, Beullens M, Ceulemans H, Den AT, Van EA, Nicolaescu E, Lesage B, Bollen M. Docking motif-guided mapping of the interactome of protein phosphatase-1. Chem Biol. 2009;16(4):365–71.PubMedCrossRefGoogle Scholar
  29. Heroes E, Lesage B, Görnemann J, Beullens M, Van Meervelt L, Bollen M. The PP1 binding code: a molecular-lego strategy that governs specificity. FEBS J. 2013;280:584–95.PubMedCrossRefGoogle Scholar
  30. Honkanen RE, Golden T. Regulators of serine/threonine protein phosphatases at the dawn of a clinical era? Curr Med Chem. 2002;9:2055–75.PubMedCrossRefGoogle Scholar
  31. Hsieh-Wilson LC, Benfenati F, Snyder GL, Allen PB, Nairn AC, Greengard P. Phosphorylation of spinophilin modulates its interaction with actin filaments. J Biol Chem. 2003;278:1186–94.PubMedCrossRefGoogle Scholar
  32. Hu XD, Huang Q, Roadcap DW, Shenolikar SS, Xia H. Actin-associated neurabin-protein phosphatase-1 complex regulates hippocampal plasticity. J Neurochem. 2006;98:1841–51.PubMedCrossRefGoogle Scholar
  33. Killilea SD, Mellgren RL, Aylward JH, Metieh ME, Lee EY. Liver protein phosphatases: studies of the presumptive native forms of phosphorylase phosphatase activity in liver extracts and their dissociation to a catalytic subunit of Mr 35,000. Arch Biochem Biophys. 1979;193:130–9.PubMedCrossRefGoogle Scholar
  34. Korrodi-Gregório L, Esteves SLC, Fardilha M. Protein phosphatase 1 catalytic isoforms: specificity toward interacting proteins. Transl Res. 2014;164:366–91.PubMedCrossRefGoogle Scholar
  35. Liao H, Li Y, Brautigan DL, Gundersen GG. Protein phosphatase 1 is targeted to microtubules by the microtubule-associated protein Tau. J Biol Chem. 1998;273:21901–8.PubMedCrossRefGoogle Scholar
  36. Lin Q, Buckler ES, Muse SV, Walker JC. Molecular evolution of type 1 serine/threonine protein phosphatases. Mol Phylogenet Evol. 1999;12:57–66.PubMedCrossRefGoogle Scholar
  37. Llanos S, Royer C, Lu M, Bergamaschi D, Lee WH, Lu X. Inhibitory member of the apoptosis-stimulating proteins of the p53 family (iASPP) interacts with protein phosphatase 1 via a noncanonical binding motif. J Biol Chem. 2011;286:43039–44.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Lüss H, Klein-Wiele O, Bokník P, Herzig S, Knapp J, Linck B, Müller FU, et al. Regional expression of protein phosphatase type 1 and 2A catalytic subunit isoforms in the human heart. J Mol Cell Cardiol. 2000;32:2349–59.PubMedCrossRefGoogle Scholar
  39. Malchiodi-Albedi F, Petrucci TC, Picconi B, Iosi F, Falchi M. Protein phosphatase inhibitors induce modification of synapse structure and tau hyperphosphorylation in cultured rat hippocampal neurons. J Neurosci Res. 1997;48:425–38.PubMedCrossRefGoogle Scholar
  40. Martins F, Rebelo S, Santos M, Cotrim CZ, Cruz E, Silva EF d, Cruz E, Silva OAB d. BRI2 and BRI3 are functionally distinct phosphoproteins. Cell Signal. 2016a;28:130–44.PubMedCrossRefGoogle Scholar
  41. Martins F, Serrano J, Muller T, da Cruz e Silva O, Rebelo S. BRI2 processing and neuritogenic role is modulated by complexing with protein phosphatase 1. Cell Signal. 2016b. (submitted).Google Scholar
  42. McAvoy T, Allen PB, Obaishi H, Nakanishi H, Takai Y, Greengard P, Nairn AC, Hemmings HC. Regulation of neurabin I interaction with protein phosphatase 1 by phosphorylation. Biochemistry. 1999;38:12943–9.PubMedCrossRefGoogle Scholar
  43. Mellgren RL, Aylward JH, Killilea SD, Lee EY. The activation and dissociation of a native high molecular weight form of rabbit skeletal muscle phosphorylase phosphatase by endogenous CA2+-dependent proteases. J Biol Chem. 1979;254:648–52.PubMedPubMedCentralGoogle Scholar
  44. Monroe JD, Heathcote RD. Protein phosphatases regulate the growth of developing neurites. Int J Dev Neurosci. 2013;31:250–7.PubMedCrossRefGoogle Scholar
  45. Mulkey RM, Endo S, Shenolikar S, Malenka RC. Involvement of a calcineurin/inhibitor-1 phosphatase cascade in hippocampal long-term depression. Nature. 1994;369:486–8.PubMedCrossRefGoogle Scholar
  46. Oliver CJ, Terry-Lorenzo RT, Elliott E, Bloomer WAC, Li S, Brautigan DL, Colbran RJ, Shenolikar S. Targeting protein phosphatase 1 (PP1) to the actin cytoskeleton: the neurabin I/PP1 complex regulates cell morphology. Mol Cell Biol. 2002;22:4690–701.PubMedPubMedCentralCrossRefGoogle Scholar
  47. Ouimet CC, da Cruz e Silva EF, Greengard P. The alpha and gamma 1 isoforms of protein phosphatase 1 are highly and specifically concentrated in dendritic spines. Proc Natl Acad Sci U S A. 1995;92:3396–400.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Paul A, Jozef B. Human cardiac tissues, control and diseased. 2004. http://cardiogenomics.med.harvard.edu/home (2004).
  49. Ragusa MJ, Allaire M, Nairn AC, Page R, Peti W. Flexibility in the PP1:spinophilin holoenzyme. FEBS Lett. 2011;585:36–40.PubMedCrossRefGoogle Scholar
  50. Rebelo S, Domingues SC, Santos M, Fardilha M, Esteves SLC, Vieira SI, Vintém APB, Wu W, da Cruz e Silva EF, da Cruz e Silva OAB. Identification of a novel complex AβPP:Fe65:PP1 that regulates AβPP Thr668 phosphorylation levels. J Alzheimers Dis. 2013;35:761–75.PubMedPubMedCentralGoogle Scholar
  51. Rebelo S, Santos M, Martins F, da Cruz e Silva EF, da Cruz e Silva OAB. Protein phosphatase 1 is a key player in nuclear events. Cell Signal. 2015;27:2589–98.PubMedCrossRefGoogle Scholar
  52. Santos M, Rebelo S, da Cruz e Silva OAB, da Cruz e Silva EF. Immunolocalization of PPP1C isoforms in SH-SY5Y cells during the cell cycle. MicroScopy. 2012;18(S5):41–2.Google Scholar
  53. Santos M, Rebelo S, Van Kleeff PJM, Kim CE, Dauer WT, Fardilha M, da Cruz e Silva OA, da Cruz e Silva EF. The nuclear envelope protein, LAP1B, is a novel protein phosphatase 1 substrate. PLoS One. 2013;8:e76788.PubMedPubMedCentralCrossRefGoogle Scholar
  54. Santos M, Costa P, Martins F, Cruz E, da Silva EF, Cruz E, da Silva OAB, Rebelo S. LAP1 is a crucial protein for the maintenance of the nuclear envelope structure and cell cycle progression. Mol Cell Biochem. 2014a;399:143–53.PubMedCrossRefGoogle Scholar
  55. Santos M, Domingues SC, Costa P, Muller T, Galozzi S, Marcus K, Cruz E, Silva EF d, Cruz E, Silva OA d, Rebelo S. Identification of a novel human LAP1 isoform that is regulated by protein phosphorylation. PLoS ONE. 2014b;9:e113732.PubMedPubMedCentralCrossRefGoogle Scholar
  56. Serrano J, Martins F, Sousa J, VanPelt A, Rebelo S, da Cruz e Silva O. The distribution of LAP1 and associated proteins throughout spermatogenesis. Reprod Fertil Dev. 2016. (submitted).Google Scholar
  57. Shi Y. Serine/threonine phosphatases: mechanism through structure. Cell. 2009;139:468–84.PubMedCrossRefGoogle Scholar
  58. Silva JV, Freitas MJ, Fardilha M. Phosphoprotein phosphatase 1 complexes in spermatogenesis. Curr Mol Pharmacol. 2014;7:136–46.PubMedCrossRefGoogle Scholar
  59. Soderling TR, Derkach VA. Postsynaptic protein phosphorylation and LTP. Trends Neurosci. 2000;23:75–80.PubMedCrossRefGoogle Scholar
  60. Strack S, Kini S, Ebner FF, Wadzinski BE, Colbran RJ. Differential cellular and subcellular localization of protein phosphatase 1 isoforms in brain. J Comp Neurol. 1999;413:373–84.PubMedCrossRefGoogle Scholar
  61. Terrak M, Kerff F, Langsetmo K, Tao T, Dominguez R. Structural basis of protein phosphatase 1 regulation. Nature. 2004;429:780–4.PubMedCrossRefGoogle Scholar
  62. Terry-Lorenzo RT, Inoue M, Connor JH, Haystead TA, Armbruster BN, Gupta RP, Oliver CJ, Shenolikar S. Neurofilament-L is a protein phosphatase-1-binding protein associated with neuronal plasma membrane and post-synaptic density. J Biol Chem. 2000;275:2439–46.PubMedCrossRefGoogle Scholar
  63. Trinkle-Mulcahy L, Andrews PD, Wickramasinghe S, Sleeman J, Prescott A, Lam YW, Lyon C, Swedlow JR, Lamond AI. Time-lapse imaging reveals dynamic relocalization of PP1gamma throughout the mammalian cell cycle. Mol Biol Cell. 2003;14:107–17.PubMedPubMedCentralCrossRefGoogle Scholar
  64. Wakula P, Beullens M, Ceulemans H, Stalmans W, Bollen M. Degeneracy and function of the ubiquitous RVXF motif that mediates binding to protein phosphatase-1. J Biol Chem. 2003;278:18817–23.PubMedCrossRefGoogle Scholar
  65. Westphal RS, Tavalin SJ, Lin JW, Alto NM, Fraser ID, Langeberg LK, Sheng M, Scott JD. Regulation of NMDA receptors by an associated phosphatase-kinase signaling complex. Science. 1999;285:93–6.PubMedCrossRefGoogle Scholar
  66. Xia D, Stull JT, Kamm KE. Myosin phosphatase targeting subunit, affects cell migration by regulating myosin phosphorylation and action assembly. Exp Cell Res. 2005;304:506–17.Google Scholar
  67. Yan Z, Hsieh-Wilson L, Feng J, Tomizawa K, Allen PB, Fienberg AA, Nairn AC, Greengard P. Protein phosphatase 1 modulation of neostriatal AMPA channels: regulation by DARPP-32 and spinophilin. Nat Neurosci. 1999;2:13–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Filipa Martins
    • 1
  • Joana B. Serrano
    • 1
  • Ana M. Marafona
    • 1
  • Odete A. B. da Cruz e Silva
    • 1
  • Sandra Rebelo
    • 1
  1. 1.Neuroscience and Signaling Laboratory, Department of Medical SciencesInstitute of Biomedicine-iBiMED, University of AveiroAveiroPortugal