241 human active and 13 inactive phosphatases in total;
194 phosphatases have substrate data;
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336 protein substrates;
83 non-protein substrates;
1215 dephosphorylation interactions;
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299 KEGG pathways;
876 Reactome pathways;
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last scientific update: 11 Mar, 2019
last maintenance update: 01 Sep, 2023
Cyclin-dependent kinase 5 activator 1, p35:Cell membrane Note=In the primary corticalneurons, p35 is present in the peripheries and nerve terminals Cyclin-dependent kinase 5 activator 1, p25:Nucleus Cytoplasm, perinuclear region Note=The conversion of p35to p25 relocalizes the protein from the cell periphery to thecytoplasm, in nuclear and perinuclear regions In the primarycortical neurons, p25 is primarily concentrated in the cell somaand is largely absent from neurites
Function (UniProt annotation)
p35 is a neuron specific activator of CDK5 The complexp35/CDK5 is required for neurite outgrowth and corticallamination Involved in dendritic spine morphogenesis by mediatingthe EFNA1-EPHA4 signaling Activator of TPKII The complexp35/CDK5 participates in the regulation of the circadian clock bymodulating the function of CLOCK protein: phosphorylates CLOCK at'Thr-451' and 'Thr-461' and regulates the transcriptional activityof the CLOCK-ARNTL/BMAL1 heterodimer in association with alteredstability and subcellular distribution
Alzheimer disease (AD) is a chronic disorder that slowly destroys neurons and causes serious cognitive disability. AD is associated with senile plaques and neurofibrillary tangles (NFTs). Amyloid-beta (Abeta), a major component of senile plaques, has various pathological effects on cell and organelle function. The extracellular Abeta oligomers may activate caspases through activation of cell surface death receptors. Alternatively, intracellular Abeta may contribute to pathology by facilitating tau hyper-phosphorylation, disrupting mitochondria function, and triggering calcium dysfunction. To date genetic studies have revealed four genes that may be linked to autosomal dominant or familial early onset AD (FAD). These four genes include: amyloid precursor protein (APP), presenilin 1 (PS1), presenilin 2 (PS2) and apolipoprotein E (ApoE). All mutations associated with APP and PS proteins can lead to an increase in the production of Abeta peptides, specfically the more amyloidogenic form, Abeta42. FAD-linked PS1 mutation downregulates the unfolded protein response and leads to vulnerability to ER stress.
Drug addiction is a chronic, relapsing disorder in which compulsive drug-seeking and drug-taking behavior persists despite serious negative consequences.There is strong evidence that the dopaminergic system that projects from the ventral tegmental area (VTA) of the midbrain to the nucleus accumbens (NAc), and to other forebrain sites, is the major substrate of reward and reinforcement for both natural rewards and addictive drugs. Cocaine binds strongly to the dopamine-reuptake transporter, preventing the reuptake of dopamine into the nerve terminal. Because of this blocking effect, dopamine remains at high concentrations in the synapse and continues to affect adjacent neurons, producing the characteristic cocaine high.Activated D1 receptor activates the PKA signaling pathway, and this pathway plays a critical role in mediating the behavioral responses to cocaine administration. Cocaine-induced neuroadaptations, including dopamine depletion, may underlie craving and hedonic dysregulation.
CRMPs are a small family of plexinA-interacting cytosolic phosphoproteins identified as mediators of Sema3A signaling and neuronal differentiation. After Sema3A activation Plexin-A bound CRMP's undergo phosphorylation by Cdk5, GSK3beta and Fes kinases. Phosphorylation of CRMPs by these kinases blocks the ability of CRMP to bind to tubulin dimers, subsequently induces depolymerization of F-actin, and ultimately leads to growth cone collapse
Phosphorylation of TP53 (p53) at the N-terminal serine residues S15 and S20 plays a critical role in protein stabilization as phosphorylation at these sites interferes with binding of the ubiquitin ligase MDM2 to TP53. Several different kinases can phosphorylate TP53 at S15 and S20. In response to double strand DNA breaks, S15 is phosphorylated by ATM (Banin et al. 1998, Canman et al. 1998, Khanna et al. 1998), and S20 by CHEK2 (Chehab et al. 1999, Chehab et al. 2000, Hirao et al. 2000). DNA damage or other types of genotoxic stress, such as stalled replication forks, can trigger ATR-mediated phosphorylation of TP53 at S15 (Lakin et al. 1999, Tibbetts et al. 1999) and CHEK1-mediated phosphorylation of TP53 at S20 (Shieh et al. 2000). In response to various types of cell stress, NUAK1 (Hou et al. 2011), CDK5 (Zhang et al. 2002, Lee et al. 2007, Lee et al. 2008), AMPK (Jones et al. 2005) and TP53RK (Abe et al. 2001, Facchin et al. 2003) can phosphorylate TP53 at S15, while PLK3 (Xie, Wang et al. 2001, Xie, Wu et al. 2001) can phosphorylate TP53 at S20.
Phosphorylation of TP53 at serine residue S46 promotes transcription of TP53-regulated apoptotic genes rather than cell cycle arrest genes. Several kinases can phosphorylate S46 of TP53, including ATM-activated DYRK2, which, like TP53, is targeted for degradation by MDM2 (Taira et al. 2007, Taira et al. 2010). TP53 is also phosphorylated at S46 by HIPK2 in the presence of the TP53 transcriptional target TP53INP1 (D'Orazi et al. 2002, Hofmann et al. 2002, Tomasini et al. 2003). CDK5, in addition to phosphorylating TP53 at S15, also phosphorylates it at S33 and S46, which promotes neuronal cell death (Lee et al. 2007).
MAPKAPK5 (PRAK) phosphorylates TP53 at serine residue S37, promoting cell cycle arrest and cellular senescence in response to oncogenic RAS signaling (Sun et al. 2007).
NUAK1 phosphorylates TP53 at S15 and S392, and phosphorylation at S392 may contribute to TP53-mediated transcriptional activation of cell cycle arrest genes (Hou et al. 2011). S392 of TP53 is also phosphorylated by the complex of casein kinase II (CK2) bound to the FACT complex, enhancing transcriptional activity of TP53 in response to UV irradiation (Keller et al. 2001, Keller and Lu 2002).
The activity of TP53 is inhibited by phosphorylation at serine residue S315, which enhances MDM2 binding and degradation of TP53. S315 of TP53 is phosphorylated by Aurora kinase A (AURKA) (Katayama et al. 2004) and CDK2 (Luciani et al. 2000). Interaction with MDM2 and the consequent TP53 degradation is also increased by phosphorylation of TP53 threonine residue T55 by the transcription initiation factor complex TFIID (Li et al. 2004).
Aurora kinase B (AURKB) has been shown to phosphorylate TP53 at serine residue S269 and threonine residue T284, which is possibly facilitated by the binding of the NIR co-repressor. AURKB-mediated phosphorylation was reported to inhibit TP53 transcriptional activity through an unknown mechanism (Wu et al. 2011). A putative direct interaction between TP53 and AURKB has also been described and linked to TP53 phosphorylation and S183, T211 and S215 and TP53 degradation (Gully et al. 2012)
Post-mitotic neurons do not have an active cell cycle. However, deregulation of Cyclin Dependent Kinase-5 (CDK5) activity in these neurons can aberrantly activate various components of cell cycle leading to neuronal death (Chang et al. 2012). Random activation of cell cycle proteins has been shown to play a key role in the pathogenesis of several neurodegenerative disorders (Yang et al. 2003, Lopes et al. 2009). CDK5 is not activated by the canonical cyclins, but binds to its own specific partners, CDK5R1 and CDK5R2 (aka p35 and p39, respectively) (Tsai et al. 1994, Tang et al. 1995). Expression of p35 is nearly ubiquitous, whereas p39 is largely expressed in the central nervous system. A variety of neurotoxic insults such as beta-amyloid (A-beta), ischemia, excitotoxicity and oxidative stress disrupt the intracellular calcium homeostasis in neurons, thereby leading to the activation of calpain, which cleaves p35 into p25 and p10 (Lee et al. 2000). p25 has a six-fold longer half-life compared to p35 and lacks the membrane anchoring signal, which results in its constitutive activation and mislocalization of the CDK5:p25 complex to the cytoplasm and the nucleus. There, CDK5:p25 is able to access and phosphorylate a variety of atypical targets, triggering a cascade of neurotoxic pathways that culminate in neuronal death. One such neurotoxic pathway involves CDK5-mediated random activation of cell cycle proteins which culminate in neuronal death. Exposure of primary cortical neurons to oligomeric beta-amyloid (1-42) hyper-activates CDK5 due to p25 formation, which in turn phosphorylates CDC25A, CDC25B and CDC25C. CDK5 phosphorylates CDC25A at S40, S116 and S261; CDC25B at S50, T69, S160, S321 and S470; and CDC25C at T48, T67, S122, T130, S168 and S214. CDK5-mediated phosphorylation of CDC25A, CDC25B and CDC25C not only increases their phosphatase activities but also facilitates their release from 14-3-3 inhibitory binding. CDC25A, CDC25B and CDC25C in turn activate CDK1, CDK2 and CDK4 kinases causing neuronal death. Consistent with this mechanism, higher CDC25A, CDC25B and CDC25C activities were observed in human Alzheimer's disease (AD) clinical samples, as compared to age-matched controls
CDK5, in complex with its activator CDK5R1 (p35), binds to BDNF-activated NTRK2 (TRKB). NTRK2 promotes CDK5 catalytic activity by phosphorylating CDK5 at tyrosine residue Y15 (Cheung et al. 2007), although CDK5 can also be phosphorylated at Y15 independently of NTRK2 (Zhao et al. 2009). CDK5 phosphorylates serine residue S479 of NTRK2 (corresponds to S478 in mouse and rat) (Cheung et al. 2007, Zhao et al. 2009). Phosphorylation of NTRK2 at S479 is needed for BDNF-triggered dendritic growth (Cheung et al. 2007), hippocampal long-term potentiation (LTP) and spatial memory (Lai et al. 2012). These processes involve NTRK2-mediated activation of RHO GTPases RAC1 (Lai et al. 2012) and possibly CDC42 (Cheung et al. 2007). In cultured isolated neurons, phosphorylation at S479 affects localization of NTRK2 (Zhao et al. 2009), but this does not appear to be the case in vivo (Lai et al. 2012).
CDK5-mediated phosphorylation of NTRK2 was suggested to influence the level of AKT activity, downstream mTOR signaling and DLG4 (PSD-95) expression, but further elucidation is needed (Lai et al. 2012).
Signaling by TRKB and CDK5 plays a role in inflammation induced hypersensitivity to heat-triggered pain in rats (Zhang et al. 2014)
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