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
Cytoplasm, cytoskeleton, microtubuleorganizing center, centrosome, centriole Nucleus Note=Centrosome of S-phase, interphase and mitotic cells
Function (UniProt annotation)
Plays a fundamental role in microtubule organizingcenter structure and function Required for centriole duplicationand correct spindle formation Has a role in regulatingcytokinesis and genome stability via cooperation with CALM1 andCCP110 Involved in global genome nucleotide excision repair(GG-NER) by acting as component of the XPC complex Cooperativelywith RAD23B appears to stabilize XPC In vitro, stimulates DNAbinding of the XPC:RAD23B dimer The XPC complex is proposed to represent the firstfactor bound at the sites of DNA damage and together with othercore recognition factors, XPA, RPA and the TFIIH complex, is partof the pre-incision (or initial recognition) complex The XPCcomplex recognizes a wide spectrum of damaged DNA characterized bydistortions of the DNA helix such as single-stranded loops,mismatched bubbles or single-stranded overhangs The orientationof XPC complex binding appears to be crucial for inducing aproductive NER XPC complex is proposed to recognize and tointeract with unpaired bases on the undamaged DNA strand which isfollowed by recruitment of the TFIIH complex and subsequentscanning for lesions in the opposite strand in a 5'-to-3'direction by the NER machinery Cyclobutane pyrimidine dimers(CPDs) which are formed upon UV-induced DNA damage esacpedetection by the XPC complex due to a low degree of structuralperurbation Instead they are detected by the UV-DDB complex whichin turn recruits and cooperates with the XPC complex in therespective DNA repair Component of the TREX-2 complex (transcription andexport complex 2), composed of at least ENY2, GANP, PCID2, SEM1,and either centrin CETN2 or CETN3 (PubMed:22307388) The TREX-2complex functions in docking export-competent ribonucleoproteinparticles (mRNPs) to the nuclear entrance of the nuclear porecomplex (nuclear basket) TREX-2 participates in mRNA export andaccurate chromatin positioning in the nucleus by tethering genesto the nuclear periphery (PubMed:22307388)
Nucleotide excision repair (NER) is a mechanism to recognize and repair bulky DNA damage caused by compounds, environmental carcinogens, and exposure to UV-light. In humans hereditary defects in the NER pathway are linked to at least three diseases: xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD). The repair of damaged DNA involves at least 30 polypeptides within two different sub-pathways of NER known as transcription-coupled repair (TCR-NER) and global genome repair (GGR-NER). TCR refers to the expedited repair of lesions located in the actively transcribed strand of genes by RNA polymerase II (RNAP II). In GGR-NER the first step of damage recognition involves XPC-hHR23B complex together with XPE complex (in prokaryotes, uvrAB complex). The following steps of GGR-NER and TCR-NER are similar.
The kinase activity of PLK1 is required for cell cycle progression as PLK1 phosphorylates and regulates a number of cellular proteins during mitosis. Centrosomic AURKA (Aurora A kinase), catalytically activated through AJUBA facilitated autophosphorylation on threonine residue T288 at G2/M transition (Hirota et al. 2003), activates PLK1 on centrosomes by phosphorylating threonine residue T210 of PLK1, critical for PLK1 activity (Jang et al. 2002), in the presence of BORA (Macurek et al. 2008, Seki et al. 2008). Once activated, PLK1 phosphorylates BORA and targets it for ubiquitination mediated degradation by SCF-beta-TrCP ubiquitin ligases. Degradation of BORA is thought to allow PLK1 to interact with other substrates (Seki, Coppinger, Du et al. 2008, Seki et al. 2008).The interaction of PLK1 with OPTN (optineurin) provides a negative-feedback mechanism for regulation of PLK1 activity. Phosphorylated PLK1 binds and phosphorylates OPTN associated with the Golgi membrane GTPase RAB8, promoting dissociation of OPTN from Golgi and translocation of OPTN to the nucleus. Phosphorylated OPTN facilitates the mitotic phosphorylation of the myosin phosphatase subunit PPP1R12A (MYPT1) and myosin phosphatase activation (Kachaner et al. 2012). The myosin phosphatase complex dephosphorylates threonine residue T210 of PLK1 and inactivates PLK1 (Yamashiro et al. 2008)
Several factors that participate in DNA damage response and repair are SUMOylated (reviewed in Dou et al. 2011, Bekker-Jensen and Mailand 2011, Ulrich 2012, Psakhye and Jentsch 2012, Bologna and Ferrari 2013, Flotho and Melchior 2013, Jackson and Durocher 2013). SUMOylation can alter enzymatic activity and protein stability or it can serve to recruit additional factors. For example, SUMOylation of Thymine DNA glycosylase (TDG) causes TDG to lose affinity for its product, an abasic site opposite a G residue, and thus increases turnover of the enzyme. During repair of double-strand breaks SUMO1, SUMO2, SUMO3, and the SUMO E3 ligases PIAS1 and PIAS4 accumulate at double-strand breaks where BRCA1, HERC1, RNF168, MDC1, and TP53BP1 are SUMOylated. SUMOylation of BRCA1 may increase its ubiquitin ligase activity while SUMOylation of MDC1 and HERC2 appears to play a role in recruitment of proteins such as RNF4 and RNF8 to double strand breaks. Similarly SUMOylation of RPA1 (RPA70) recruits RAD51 in the homologous recombination pathway
During interphase, Nlp interacts with gamma-tubulin ring complexes (gamma-TuRC), and is thought to contribute to the organization of interphase microtubules (Casenghi et al.,2003). Plk1 is activated at the onset of mitosis and phosphorylates Nlp triggering its displacement from the centrosome (Casenghi et al.,2003). Removal of Nlp appears to contribute to the establishment of a mitotic scaffold with enhanced microtubule nucleation activity
The mitotic spindle becomes established once centrosomes have\r migrated to opposite poles and the nuclear envelope has broken down. During this stage, interphase centrosomes mature into mitotic centrosomes\r recruiting additional gamma TuRC complexes and acquiring mitosis-associated centrosomal proteins including NuMA, Plk1 and CDK11p58 (reviewed in Schatten 2008; Raynaud-Messina and Merdes 2007)
In addition to recruiting proteins and complexes necessary for increased microtubule nucleation, centrosomal maturation involves the loss of proteins involved in interphase microtubule organization and centrosome cohesion (Casenghi et al., 2003; Mayor et al., 2002)
The NuMA protein, which functions as a nuclear matrix protein in interphase (Merdes and Cleveland 1998), redistributes to the cytoplasm following nuclear envelope breakdown where it plays an essential role in formation and maintenance of the spindle poles (Gaglio, et al., 1995; Gaglio, et al., 1996; Merdes et al, 1996). The mitotic activation of NuMA involves Ran-GTP-dependent dissociation from importin (Nachury et al, 2001, Wiese et al, 2001). NuMA is transported to the mitotic poles where it forms an insoluble crescent around centrosomes tethering microtubules into the bipolar configuration of the mitotic apparatus (Merdes et al., 2000; Kisurina-Evgenieva et al, 2004). Although NuMA is not a bona fide constituent of the mitotic centrosome but rather a protein associated with microtubules at the spindle pole, specific splice variants of NuMA have been identified that associate with the centrosome during interphase (Tang et al, 1994)
Cilium biogenesis is initiated by the docking of basal bodies, a centriole-derived organelle, to the plasma membrane (reviewed in Reiter et al, 2012). The centriole consists of a multiprotein core surrounded by a ring of nine microtubule triplets; the mother centriole additionally has 'distal' and 'subdistal appendages' that are critical for ciliogenesis (reviewed in Kim and Dynlacht, 2013; Firat-Karalar and Stearns, 2014; Bettencourt-Dias et al, 2011). Basal bodies initiate and anchor the extension of the axonemal microtubules and also associate with secretory vesicles which are thought to provide membrane components for the extension of the ciliary membrane (Sorokin, 1962; Sorokin, 1968; Bachmann-Gagescu et al, 2011; Tanos et al, 2013; reviewed in Ishikawa et al, 2011; Reiter et al, 2012). Basal bodies are attached to the plasma membrane through a proteinaceous network of transition fibers that form part of the 'transition zone' at the ciliary base. The transition zone acts as a selective barrier or ciliary pore, excluding vesicles and limiting the diffusion of proteins and lipids from the cytosol or plasma membrane (Deane et al, 2001; Craige et al, 2010; Garcia-Gonzalo et al, 2011; Ye et al, 2014; Joo et al, 2013; reviewed in Nachury et al, 2010; Hsiao et al, 2012; Reiter et al, 2012). In addition to the transition fibres, the transition zone also consists of the ciliary necklace (a row of protein particles at the ciliary membrane at the base of the cilium) and the Y-links (that connect the axonemal microtubules to the membrane at the ciliary necklace) (Williams et al, 2011; reviewed in Hsiao et al, 2012; Reiter et al, 2012)
In global genome nucleotide excision repair (GG-NER), the DNA damage is recognized by two protein complexes. The first complex consists of XPC, RAD23A or RAD23B, and CETN2. This complex probes the DNA helix and recognizes damage that disrupts normal Watson-Crick base pairing, which results in binding of the XPC:RAD23:CETN2 complex to the undamaged DNA strand. The second complex is a ubiquitin ligase UV-DDB that consists of DDB2, DDB1, CUL4A or CUL4B and RBX1. The UV-DDB complex is necessary for the recognition of UV-induced DNA damage and may contribute to the retention of the XPC:RAD23:CETN2 complex at the DNA damage site. The UV-DDB complex binds the damaged DNA strand (Fitch et al. 2003, Wang et al. 2004, Moser et al. 2005, Camenisch et al. 2009, Oh et al. 2011)
After the XPC complex and the UV-DDB complex bind damaged DNA, a basal transcription factor TFIIH is recruited to the nucleotide excision repair (NER) site (Volker et al. 2001, Riedl et al. 2003). DNA helicases ERCC2 (XPD) and ERCC3 (XPB) are subunits of the TFIIH complex. ERCC2 unwinds the DNA around the damage in concert with the ATPase activity of ERCC3, creating an open bubble (Coin et al. 2007). Simultaneously, the presence of the damage is verified by XPA (Camenisch et al. 2006). The recruitment of XPA is partially regulated by PARP1 and/or PARP2 (King et al. 2012).
Two DNA endonucleases, ERCC5 (XPG) and the complex of ERCC1 and ERCC4 (XPF), are recruited to the open bubble structure to form the incision complex that will excise the damaged oligonucleotide from the affected DNA strand (Dunand-Sauthier et al. 2005, Zotter et al. 2006, Riedl et al. 2003, Tsodikov et al. 2007, Orelli et al. 2010). The RPA heterotrimer coats the undamaged DNA strand, thus protecting it from the endonucleolytic attack (De Laat et al. 1998)
TPX2 binds to aurora kinase A (AURKA) at centrosomes and promotes its activation by facilitating AURKA active conformation and autophosphorylation of the AURKA threonine residue T288 (Bayliss et al. 2003, Xu et al. 2011, Giubettini et al. 2011, Dodson and Bayliss 2012)
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