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
Chromosome, centromere, kinetochoreCytoplasm, cytoskeleton, spindle Chromosome, centromere Note=Associates with kinetochores during congression (as early asprometaphase), relocates to the spindle midzone at anaphase, andis quantitatively discarded at the end of the cell division (Bysimilarity) Recruited to the kinetochore in a SEPT7, CENPQ andTRAPPC12-dependent manner (PubMed:18460473, PubMed:25918224,PubMed:25395579) Recruited to the pericentromeric/centromericregions of the chromosome in a CTCF-dependent manner(PubMed:26321640)
Function (UniProt annotation)
Microtubule plus-end-directed kinetochore motor whichplays an important role in chromosome congression, microtubule-kinetochore conjugation and spindle assembly checkpointactivation Drives chromosome congression (alignment ofchromosomes at the spindle equator resulting in the formation ofthe metaphase plate) by mediating the lateral sliding of polarchromosomes along spindle microtubules towards the spindle equatorand by aiding the establishment and maintenance of connectionsbetween kinetochores and spindle microtubules (PubMed:7889940,PubMed:23891108, PubMed:25395579) The transport of pole-proximalchromosomes towards the spindle equator is favored by microtubuletracks that are detyrosinated (PubMed:25908662) Acts as aprocessive bi-directional tracker of dynamic microtubule tips;after chromosomes have congressed, continues to play an activerole at kinetochores, enhancing their links with dynamicmicrotubule ends (PubMed:23955301) Suppresses chromosomecongression in NDC80-depleted cells and contributes positively tocongression only when microtubules are stabilized(PubMed:25743205) Plays an important role in the formation ofstable attachments between kinetochores and spindle microtubules(PubMed:17535814) The stabilization of kinetochore-microtubuleattachment also requires CENPE-dependent localization of otherproteins to the kinetochore including BUB1B, MAD1 and MAD2 Playsa role in spindle assembly checkpoint activation (SAC) via itsinteraction with BUB1B resulting in the activation of its kinaseactivity, which is important for activating SAC Necessary for themitotic checkpoint signal at individual kinetochores to preventaneuploidy due to single chromosome loss (By similarity)
The signal from unattached kinetochores is amplified through a Mad2 inhibitory signal that is propagated by the binding of Mad1 to the kinetochore, the association of Mad2 with Mad1, the conversion of Mad2 conformation to an inhibitory form through its association with Mad1 and finally the release of the inhibitory form of Mad2 from the kinetochore
Antigen presenting cells (APCs) such as B cells, dendritic cells (DCs) and monocytes/macrophages express major histocompatibility complex class II molecules (MHC II) at their surface and present exogenous antigenic peptides to CD4+ T helper cells. CD4+ T cells play a central role in immune protection. On their activation they stimulate differentiation of B cells into antibody-producing B-cell blasts and initiate adaptive immune responses. MHC class II molecules are transmembrane glycoprotein heterodimers of alpha and beta subunits. Newly synthesized MHC II molecules present in the endoplasmic reticulum bind to a chaperone protein called invariant (Ii) chain. The binding of Ii prevents the premature binding of self antigens to the nascent MHC molecules in the ER and also guides MHC molecules to endocytic compartments. In the acidic endosomal environment, Ii is degraded in a stepwise manner, ultimately to free the class II peptide-binding groove for loading of antigenic peptides. Exogenous antigens are internalized by the APC by receptor mediated endocytosis, phagocytosis or pinocytosis into endocytic compartments of MHC class II positive cells, where engulfed antigens are degraded in a low pH environment by multiple acidic proteases, generating MHC class II epitopes. Antigenic peptides are then loaded into the class II ligand-binding groove. The resulting class II peptide complexes then move to the cell surface, where they are scanned by CD4+ T cells for specific recognition (Berger & Roche 2009, Zhou & Blum 2004, Watts 2004, Landsverk et al. 2009)
While sister chromatids resolve in prometaphase, separating along chromosomal arms, the cohesion of sister centromeres persists until anaphase. At the anaphase onset, the anaphase promoting complex/cyclosome (APC/C) ubiquitinates PTTG1 (securin), targeting it for degradation (Hagting et al. 2002). PTTG1 acts as an inhibitor of ESPL1 (known as separin i.e. separase). Hence, PTTG1 removal initiated by APC/C, enables ESPL1 to become catalytically active (Zou et al. 1999, Waizenegger et al. 2002). ESPL1 undergoes autoleavage (Waizenegger et al. 2002) and also cleaves RAD21 subunit of centromeric cohesin (Hauf et al. 2001). RAD21 cleavage promotes dissociation of cohesin complexes from sister centromeres, leading to separation of sister chromatids. Subsequent movement of sister chromatids to opposite poles of the mitotic spindle segregates replicated chromosomes to two daughter cells (Waizenegger et al. 2000, Hauf et al. 2001, Waizenegger et al. 2002)
The resolution of sister chromatids in mitotic prometaphase involves removal of cohesin complexes from chromosomal arms, with preservation of cohesion at centromeres (Losada et al. 1998, Hauf et al. 2001, Hauf et al. 2005). CDK1-mediated phosphorylation of cohesin-bound CDCA5 (Sororin) at threonine T159 provides a docking site for PLK1, enabling PLK1-mediated phosphorylation of cohesin subunits STAG2 (SA2) and RAD21 (Hauf et al. 2005, Dreier et al. 2011, Zhang et al. 2011). Further phosphorylation of CDCA5 by CDK1 results in dissociation of CDCA5 from cohesin complex, which restores the activity of WAPAL in removing STAG2-phosphorylated cohesin from chromosomal arms (Hauf et al. 2005, Gandhi et al. 2006, Kueng et al. 2006, Shintomi and Hirano 2006, Nishiyama et al. 2010, Zhang et al. 2011). At centromeres, kinetochore proteins shugoshins (SGOL1 and SGOL2) enable PP2A-B56 (also a kinetochore constituent) to dephosphorylate the STAG2 subunit of centromeric cohesin. Dephosphorylation of STAG2 enables maintenance of centromeric cohesion, thus preventing separation of sister chromatids until anaphase (Salic et al. 2004, Kitajima et al. 2004, Kitajima et al. 2005, Kitajima et al. 2006)
Formins are a family of proteins with 15 members in mammals, organized into 8 subfamilies. Formins are involved in the regulation of actin cytoskeleton. Many but not all formin family members are activated by RHO GTPases. Formins that serve as effectors of RHO GTPases belong to different formin subfamilies but they all share a structural similarity to Drosophila protein diaphanous and are hence named diaphanous-related formins (DRFs).
DRFs activated by RHO GTPases contain a GTPase binding domain (GBD) at their N-terminus, followed by formin homology domains 3, 1, and 2 (FH3, FH1, FH2) and a diaphanous autoregulatory domain (DAD) at the C-terminus. Most DRFs contain a dimerization domain (DD) and a coiled-coil region (CC) in between FH3 and FH1 domains (reviewed by Kuhn and Geyer 2014). RHO GTPase-activated DRFs are autoinhibited through the interaction between FH3 and DAD which is disrupted upon binding to an active RHO GTPase (Li and Higgs 2003, Lammers et al. 2005, Nezami et al. 2006). Since formins dimerize, it is not clear whether the FH3-DAD interaction is intra- or intermolecular. FH2 domain is responsible for binding to the F-actin and contributes to the formation of head-to-tail formin dimers (Xu et al. 2004). The proline-rich FH1 domain interacts with the actin-binding proteins profilins, thereby facilitating actin recruitment to formins and accelerating actin polymerization (Romero et al. 2004, Kovar et al. 2006).
Different formins are activated by different RHO GTPases in different cell contexts. FMNL1 (formin-like protein 1) is activated by binding to the RAC1:GTP and is involved in the formation of lamellipodia in macrophages (Yayoshi-Yamamoto et al. 2000) and is involved in the regulation of the Golgi complex structure (Colon-Franco et al. 2011). Activation of FMNL1 by CDC42:GTP contributes to the formation of the phagocytic cup (Seth et al. 2006). Activation of FMNL2 (formin-like protein 2) and FMNL3 (formin-like protein 3) by RHOC:GTP is involved in cancer cell motility and invasiveness (Kitzing et al. 2010, Vega et al. 2011). DIAPH1, activated by RHOA:GTP, promotes elongation of actin filaments and activation of SRF-mediated transcription which is inhibited by unpolymerized actin (Miralles et al. 2003). RHOF-mediated activation of DIAPH1 is implicated in formation of stress fibers (Fan et al. 2010). Activation of DIAPH1 and DIAPH3 by RHOB:GTP leads to actin coat formation around endosomes and regulates endosome motility and trafficking (Fernandez-Borja et al. 2005, Wallar et al. 2007). Endosome trafficking is also regulated by DIAPH2 transcription isoform 3 (DIAPH2-3) which, upon activation by RHOD:GTP, recruits SRC kinase to endosomes (Tominaga et al. 2000, Gasman et al. 2003). DIAPH2 transcription isoform 2 (DIAPH2-2) is involved in mitosis where, upon being activated by CDC42:GTP, it facilitates the capture of astral microtubules by kinetochores (Yasuda et al. 2004, Cheng et al. 2011). DIAPH2 is implicated in ovarian maintenance and premature ovarian failure (Bione et al. 1998). DAAM1, activated by RHOA:GTP, is involved in linking WNT signaling to cytoskeleton reorganization (Habas et al. 2001)
Retrograde traffic from the cis-Golgi to the ERGIC or the ER is mediated in part by microtubule-directed COPI-coated vesicles (Letourneur et al, 1994; Shima et al, 1999; Spang et al, 1998; reviewed in Lord et al, 2013; Spang et al, 2013). These assemble at the cis side of the Golgi in a GBF-dependent fashion and are tethered at the ER by the ER-specific SNAREs and by the conserved NRZ multisubunit tethering complex, known as DSL in yeast (reviewed in Tagaya et al, 2014; Hong and Lev, 2014). Typical cargo of these retrograde vesicles includes 'escaped' ER chaperone proteins, which are recycled back to the ER for reuse by virtue of their interaction with the Golgi localized KDEL receptors (reviewed in Capitani and Sallese, 2009; Cancino et al, 2013)
The dissolution of the nuclear membrane marks the beginning of the prometaphase. Kinetochores are created when proteins attach to the centromeres. Microtubules then attach at the kinetochores, and the chromosomes begin to move to the metaphase plate
Kinesins are a superfamily of microtubule-based motor proteins that have diverse functions in transport of vesicles, organelles and chromosomes, and regulate microtubule dynamics. There are 14 families of kinesins, all reprsented in humans. A standardized nomenclature was published in 2004 (Lawrence et al.)
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