BioPAX pathway converted from "RHO GTPases Activate Formins" in the Reactome database. RHO GTPases Activate Formins RHO GTPases Activate Formins 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).<p>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).<p>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). Authored: Orlic-Milacic, Marija, 2014-10-24 Authored: Rivero Crespo, Francisco, 2014-12-26 Edited: Orlic-Milacic, Marija, 2015-02-02 FMNL1 binds RAC1:GTP FMNL1 binds RAC1:GTP FMNL1 (formin-like protein 1) binds the active, GTP-bound, form of RAC1 (Yayoshi-Yamamoto et al. 2000). Based on the sequence similarity with mouse formin Dia1, binding of RAC1:GTP relieves the autoinhibition of FMNL1 by displacing the C-terminal autoregulatory DAD domain of FMNL1 from the N-terminal FH3 domain (Rose et al. 2005, Lammers et al. 2005). As formins dimerize through their FH2 domains, it is not clear whether the autoinhibitory interaction between FH3 and DAD domains is intramolecular or intermolecular (Xu et al. 2004, Kuhn and Geyer 2014). Endogenous human FMNL1 interacts with endogenous human RAC1 in some leukemia-derived cell lines and promotes their migration (Favaro et al. 2013). FMNL1 gamma, a transcriptional isoform of FMNL1 with a DAD domain that significantly differs in sequence from DAD domains of FMNL1 transcription isoforms alpha and beta, localizes to the membrane and is active in the absence of RHO GTPase signaling. The membrane localization of FMNL1 gamma is regulated by the myristoylation of the N-terminal glycine which is triggered by an unknown mechanism (Han et al. 2009). Authored: Orlic-Milacic, Marija, 2014-10-24 Authored: Rivero Crespo, Francisco, 2014-12-26 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 442641 1 plasma membrane GO 0005886 RAC1:GTP [plasma membrane] RAC1:GTP Reactome DB_ID: 29438 1 cytosol GO 0005829 GTP(4-) [ChEBI:37565] GTP(4-) GTP gtp guanosine 5'-triphosphate(4-) Reactome http://www.reactome.org ChEBI 37565 Reactome DB_ID: 351141 1 UniProt:P63000 RAC1 RAC1 TC25 RAC1 MIG5 FUNCTION Plasma membrane-associated small GTPase which cycles between active GTP-bound and inactive GDP-bound states. In its active state, binds to a variety of effector proteins to regulate cellular responses such as secretory processes, phagocytosis of apoptotic cells, epithelial cell polarization, neurons adhesion, migration and differentiation, and growth-factor induced formation of membrane ruffles (PubMed:1643658, PubMed:28886345). Rac1 p21/rho GDI heterodimer is the active component of the cytosolic factor sigma 1, which is involved in stimulation of the NADPH oxidase activity in macrophages. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. Stimulates PKN2 kinase activity (PubMed:9121475). In concert with RAB7A, plays a role in regulating the formation of RBs (ruffled borders) in osteoclasts (PubMed:1643658). In podocytes, promotes nuclear shuttling of NR3C2; this modulation is required for a proper kidney functioning. Required for atypical chemokine receptor ACKR2-induced LIMK1-PAK1-dependent phosphorylation of cofilin (CFL1) and for up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. In neurons, is involved in dendritic spine formation and synaptic plasticity (By similarity). In hippocampal neurons, involved in spine morphogenesis and synapse formation, through local activation at synapses by guanine nucleotide exchange factors (GEFs), such as ARHGEF6/ARHGEF7/PIX (PubMed:12695502). In synapses, seems to mediate the regulation of F-actin cluster formation performed by SHANK3. In neurons, plays a crucial role in regulating GABA(A) receptor synaptic stability and hence GABAergic inhibitory synaptic transmission through its role in PAK1 activation and eventually F-actin stabilization (By similarity).FUNCTION Isoform B has an accelerated GEF-independent GDP/GTP exchange and an impaired GTP hydrolysis, which is restored partially by GTPase-activating proteins. It is able to bind to the GTPase-binding domain of PAK but not full-length PAK in a GTP-dependent manner, suggesting that the insertion does not completely abolish effector interaction.ACTIVITY REGULATION Regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP, GTPase activating proteins (GAPs) which increase the GTP hydrolysis activity, and GDP dissociation inhibitors which inhibit the dissociation of the nucleotide from the GTPase. GTP hydrolysis is stimulated by ARHGAP30.SUBUNIT Interacts with NISCH. Interacts with PIP5K1A. Interacts with the GTP-bound form of RAB7A. Interacts with SRGAP2. Interacts with CYFIP1/SRA-1. Interacts with PLXNB3. Interacts with ARHGDIA; the interaction is induced by SEMA5A, mediated through PLXNB3 and inactivates and stabilizes RAC1. Interacts (GTP-bound form preferentially) with PKN2 (via the REM repeats); the interaction stimulates autophosphorylation and phosphorylation of PKN2. Interacts with the GEF proteins PREX1, RASGRF2, FARP1, FARP2, DOCK1, DOCK2 and DOCK7, which promote the exchange between GDP and GTP, and therefore activate it. Interacts with PARD6A, PARD6B and PARD6G in a GTP-dependent manner. Part of a quaternary complex containing PARD3, some PARD6 protein (PARD6A, PARD6B or PARD6G) and some atypical PKC protein (PRKCI or PRKCZ), which plays a central role in epithelial cell polarization. Found in a trimeric complex composed of DOCK1 and ELMO1, which plays a central role in phagocytosis of apoptotic cells. Interacts with RALBP1 via its effector domain. Interacts with PLXNB1. Probably found in a ternary complex composed of DSCAM, PAK1 and RAC1. Interacts with DSCAM; the interaction requires PAK1. Part of a complex with MAP2K3, MAP3K3, CCM2 and DEF6. Interacts with BAIAP2, BAIAP2L1 and DEF6. Interacts with Y.pseudotuberculosis YPKA and PLCB2. Interacts with NOXA1. Interacts with ARHGEF2. Interacts with TBC1D2. Interacts with UNKL. Interacts with USP6. Interacts with SPATA13. Interacts with ARHGEF16; mediates activation of RAC1 by EPHA2. Interacts with ITGB4. Interacts with S100A8 and calprotectin (S100A8/9). Interacts with PACSIN2. Interacts with ITGB1BP1. Interacts (when active) with PPP5C (via TPR repeats); activates PPP5C phosphatase activity and translocates PPP5C to the cell membrane. Interacts with RAPH1 (via Ras associating and PH domains) (PubMed:18499456). Interacts with MTSS2 (via IMD domain); this interaction may be important to potentiate PDGF-induced RAC1 activation (PubMed:20875796). Interacts with PAK2 (PubMed:20696164). Interacts (GTP-bound form) with SH3RF1 and SH3RF3 (PubMed:20696164). Found in a complex with SH3RF1, MAPK8IP1/JIP1, MAP3K11/MLK3, MAP2K7/MKK7 and MAPK8/JNK1. Interacts (both active GTP- or inactive GDP-bound forms) with SH3RF2 (By similarity). Interacts (GTP-bound form preferentially) with CYRIB (PubMed:31285585, PubMed:30250061). Interacts with DOCK4 (via DOCKER domain); functions as a guanine nucleotide exchange factor (GEF) for RAC1 (PubMed:16464467). Interacts with GARRE1 (PubMed:31871319).TISSUE SPECIFICITY Isoform B is predominantly identified in skin and epithelial tissues from the intestinal tract. Its expression is elevated in colorectal tumors at various stages of neoplastic progression, as compared to their respective adjacent tissues.DOMAIN The effector region mediates interaction with DEF6.PTM (Microbial infection) AMPylation at Tyr-32 and Thr-35 are mediated by bacterial enzymes in case of infection by H.somnus and V.parahaemolyticus, respectively. AMPylation occurs in the effector region and leads to inactivation of the GTPase activity by preventing the interaction with downstream effectors, thereby inhibiting actin assembly in infected cells. It is unclear whether some human enzyme mediates AMPylation; FICD has such ability in vitro but additional experiments remain to be done to confirm results in vivo.PTM GTP-bound active form is ubiquitinated by HACE1, leading to its degradation by the proteasome.PTM (Microbial infection) Glycosylated at Tyr-32 by Photorhabdus asymbiotica toxin PAU_02230. Mono-O-GlcNAcylation by PAU_02230 inhibits downstream signaling by an impaired interaction with diverse regulator and effector proteins of Rac and leads to actin disassembly.PTM (Microbial infection) Glucosylated at Thr-35 by C.difficile toxins TcdA and TcdB in the colonic epithelium, and by P.sordellii toxin TcsL in the vascular endothelium (PubMed:7777059, PubMed:7775453, PubMed:8626575, PubMed:19744486, PubMed:24905543). Monoglucosylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption and cell death, resulting in the loss of colonic epithelial barrier function (PubMed:7777059, PubMed:7775453).PTM (Microbial infection) Glycosylated (O-GlcNAcylated) at Thr-35 by C.novyi toxin TcdA (PubMed:8810274). O-GlcNAcylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption (PubMed:8810274).SIMILARITY Belongs to the small GTPase superfamily. Rho family. Homo sapiens NCBI Taxonomy 9606 UniProt P63000 Chain Coordinates 1 EQUAL 189 EQUAL Reactome Database ID Release 81 442641 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442641 Reactome R-HSA-442641 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-442641.1 Reactome DB_ID: 5665949 1 FMNL1 [cytosol] FMNL1 FMNL1 dimer Reactome DB_ID: 5663224 2 UniProt:O95466 FMNL1 FMNL1 FRL1 FMNL1 FMNL C17orf1B C17orf1 FUNCTION May play a role in the control of cell motility and survival of macrophages (By similarity). Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the cortical actin filament dynamics and cell shape.SUBUNIT Interacts with RAC1, PFN1 and PFN2 (By similarity). Interacts (activated by RAC1) with SRGAP2 (via SH3 domain); regulates the actin filament severing activity of FMNL1.TISSUE SPECIFICITY Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.DOMAIN The DAD domain regulates activation via by an autoinhibitory interaction with the N-terminus. This autoinhibition is released upon competitive binding of an activated GTPase. The release of DAD allows the FH2 domain to then nucleate and elongate nonbranched actin filaments (By similarity).PTM Myristoylation mediates membrane localization and blebbing.SIMILARITY Belongs to the formin homology family. UniProt O95466 2 EQUAL 1100 EQUAL Reactome Database ID Release 81 5665949 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665949 Reactome R-HSA-5665949 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665949.1 Reactome DB_ID: 5663231 1 RAC1:GTP:FMNL1 [plasma membrane] RAC1:GTP:FMNL1 Reactome DB_ID: 442641 1 Reactome DB_ID: 5665949 1 Reactome Database ID Release 81 5663231 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5663231 Reactome R-HSA-5663231 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5663231.1 Reactome Database ID Release 81 5663232 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5663232 Reactome R-HSA-5663232 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5663232.2 10958683 Pubmed 2000 FRL, a novel formin-related protein, binds to Rac and regulates cell motility and survival of macrophages Yayoshi-Yamamoto, S Taniuchi, I Watanabe, T Mol. Cell. Biol. 20:6872-81 23801653 Pubmed 2013 FMNL1 promotes proliferation and migration of leukemia cells Favaro, Patricia Traina, Fabiola Machado-Neto, João Agostinho Lazarini, Mariana Lopes, Matheus Rodrigues Pereira, João Kleber Novais Costa, Fernando Ferreira Infante, Elvira Ridley, Anne J Saad, Sara Teresinha Olalla J. Leukoc. Biol. 94:503-12 15006353 Pubmed 2004 Crystal structures of a Formin Homology-2 domain reveal a tethered dimer architecture Xu, Yingwu Moseley, James B Sagot, Isabelle Poy, Florence Pellman, David Goode, Bruce L Eck, Michael J Cell 116:711-23 19815554 Pubmed 2009 Formin-like 1 (FMNL1) is regulated by N-terminal myristoylation and induces polarized membrane blebbing Han, Yanyan Eppinger, Elfriede Schuster, Ingrid G Weigand, Luise U Liang, Xiaoling Kremmer, E Peschel, Christian Krackhardt, Angela M J. Biol. Chem. 284:33409-17 16292343 Pubmed 2005 The regulation of mDia1 by autoinhibition and its release by Rho*GTP Lammers, Michael Rose, Rolf Scrima, Andrea Wittinghofer, A EMBO J. 24:4176-87 24914801 Pubmed 2014 Formins as effector proteins of Rho GTPases Kühn, Sonja Geyer, Matthias Small GTPases 5:e29513 15864301 Pubmed 2005 Structural and mechanistic insights into the interaction between Rho and mammalian Dia Rose, R Weyand, M Lammers, M Ishizaki, T Ahmadian, M Reza Wittinghofer, Alfred Nature 435:513-8 Association of profilin with monomeric actin Association of profilin with monomeric actin Profilins PFN1 and PFN2 bind to monomeric actin (G-actin), forming a 1:1 complex and subsequently regulate actin filament barbed end assembly downstream of various signaling pathways (Pring et al. 1992, Korenbaum et al. 1998, Nodelman et al. 1999) Authored: Pollard, T, 2007-09-30 10:07:47 Reviewed: Rivero Crespo, Francisco, 2014-12-26 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 201857 1 G-actin [cytosol] G-actin actin:ATP Converted from EntitySet in Reactome Reactome DB_ID: 201859 1 actin [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity ACTG1 [cytosol] ACTB(1-375) [cytosol] UniProt P63261 UniProt P60709 Reactome DB_ID: 113592 1 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome Database ID Release 81 201857 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=201857 Reactome R-HSA-201857 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-201857.3 Converted from EntitySet in Reactome Reactome DB_ID: 203077 1 PFN [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 203080 1 Profilin:G-actin [cytosol] Profilin:G-actin PFN1,PFN2:G-actin Profilin:monomeric actin Reactome DB_ID: 201857 1 Converted from EntitySet in Reactome Reactome DB_ID: 203077 1 Reactome Database ID Release 81 203080 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=203080 Reactome R-HSA-203080 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-203080.1 Reactome Database ID Release 81 203070 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=203070 Reactome R-HSA-203070 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-203070.1 10600384 Pubmed 1999 X-ray structure determination of human profilin II: A comparative structural analysis of human profilins Nodelman, IM Bowman, GD Lindberg, U Schutt, CE J Mol Biol 294:1271-85 1737036 Pubmed 1992 Profilin-actin complexes directly elongate actin filaments at the barbed end Pring, M Weber, A Bubb, M R Biochemistry 31:1827-36 9649308 Pubmed 1998 The role of profilin in actin polymerization and nucleotide exchange Korenbaum, E Nordberg, P Björkegren-Sjögren, C Schutt, C E Lindberg, U Karlsson, R Biochemistry 37:9274-83 RAC1:GTP:FMNL1 binds profilin:G-actin RAC1:GTP:FMNL1 binds profilin:G-actin FMNL1, activated by binding to GTP-bound RAC1, binds actin-associated profilins PFN1 and PFN2 through the proline-rich FH1 domain of FMNL1 (Yayoshi-Yamamoto et al. 2000). The interaction with actin is achieved through the FH2 domain of FMNL1 (Romero et al. 2004, Kovar et al. 2006, Kuhn and Geyer 2014). FMNL1 and profilin-mediated reorganization of actin cytoskeleton is involved in the formation of lamellipodia, which regulates the motility of macrophages (Yayoshi-Yamamoto et al. 2000). FMNL1 was shown to regulate the structure of the Golgi complex, where different transcriptional isoforms of FMNL1 may play different roles (Colon-Franco et al. 2011). Authored: Orlic-Milacic, Marija, 2014-10-24 Authored: Rivero Crespo, Francisco, 2014-12-26 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 203080 2 Reactome DB_ID: 5663231 1 Reactome DB_ID: 5665660 1 RAC1:GTP:FMNL1:Profilin:G-actin [plasma membrane] RAC1:GTP:FMNL1:Profilin:G-actin Reactome DB_ID: 203080 2 Reactome DB_ID: 5663231 1 Reactome Database ID Release 81 5665660 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665660 Reactome R-HSA-5665660 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665660.1 Reactome Database ID Release 81 5665659 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665659 Reactome R-HSA-5665659 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665659.1 16439214 Pubmed 2006 Control of the assembly of ATP- and ADP-actin by formins and profilin Kovar, David R Harris, Elizabeth S Mahaffy, Rachel Higgs, Henry N Pollard, Thomas D Cell 124:423-35 21868368 Pubmed 2011 Dynamic remodeling of the actin cytoskeleton by FMNL1? is required for structural maintenance of the Golgi complex Colón-Franco, Jessica M Gomez, Timothy S Billadeau, Daniel D J. Cell. Sci. 124:3118-26 15507212 Pubmed 2004 Formin is a processive motor that requires profilin to accelerate actin assembly and associated ATP hydrolysis Romero, Stéphane Le Clainche, Christophe Didry, Dominique Egile, Coumaran Pantaloni, Dominique Carlier, Marie-France Cell 119:419-29 SRGAP2 binds RAC1:GTP:FMNL1:profilin:G-actin SRGAP2 binds RAC1:GTP:FMNL1:profilin:G-actin SRGAP2 binds FMNL1 activated by RAC1:GTP by simultaneously interacting with RAC1 and FMNL1. SRGAP2 co-localizes with RAC1, FMNL1, profilin and actin at the plasma membrane after RAC1-mediated activation of FMNL1 (Mason et al. 2011). Authored: Orlic-Milacic, Marija, 2014-10-24 Authored: Rivero Crespo, Francisco, 2014-12-26 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 5665660 1 Reactome DB_ID: 195131 1 UniProt:O75044 SRGAP2 SRGAP2 FNBP2 KIAA0456 SRGAP2 ARHGAP34 SRGAP2A FUNCTION Postsynaptic RAC1 GTPase activating protein (GAP) that plays a key role in neuronal morphogenesis and migration mainly during development of the cerebral cortex (PubMed:20810653, PubMed:27373832, PubMed:28333212). Regulates excitatory and inhibitory synapse maturation and density in cortical pyramidal neurons (PubMed:22559944, PubMed:27373832). SRGAP2/SRGAP2A limits excitatory and inhibitory synapse density through its RAC1-specific GTPase activating activity, while it promotes maturation of both excitatory and inhibitory synapses through its ability to bind to the postsynaptic scaffolding protein HOMER1 at excitatory synapses, and the postsynaptic protein GPHN at inhibitory synapses (By similarity). Mechanistically, acts by binding and deforming membranes, thereby regulating actin dynamics to regulate cell migration and differentiation (PubMed:27373832). Promotes cell repulsion and contact inhibition of locomotion: localizes to protrusions with curved edges and controls the duration of RAC1 activity in contact protrusions (By similarity). In non-neuronal cells, may also play a role in cell migration by regulating the formation of lamellipodia and filopodia (PubMed:20810653, PubMed:21148482).ACTIVITY REGULATION Activity is strongly inhibited by SRGAP2C, which heterodimerize with SRGAP2/SRGAP2A, thereby reducing SRGAP2/SRGAP2A levels through proteasome-dependent degradation.SUBUNIT Homodimer (PubMed:20810653, PubMed:26365803, PubMed:28333212). Heterodimer; forms a heterodimer with SRGAP2C, altering SRGAP2 function (PubMed:22559944, PubMed:27373832, PubMed:28333212). Forms a heterooligomer with SRGAP1 and SRGAP3 through its F-BAR domain (PubMed:22467852). Interacts (via SH3 domain) with GPHN (By similarity). Interacts (via SH3 domain) with FMNL1 (activated by RAC1); regulates the actin filament severing activity of FMNL1 and actin dynamics (PubMed:21148482). Interacts (via SH3 domain) with FMNL3 (PubMed:21148482). Interacts with RAC1; specifically stimulates RAC1 GTPase activity (PubMed:21148482). Interacts (via F-BAR domain) with HOMER1 (By similarity). Interacts with ROBO1 and ROBO2 (PubMed:11672528, PubMed:21148482, PubMed:26365803). Interacts with FASLG (PubMed:19807924). Interacts with PRMT5 (PubMed:20810653).DOMAIN The F-BAR domain mediates oligomerization, binds membranes, and induces plasma membrane protrusions.PTM Methylation at Arg-927 is required for the stimulation of cell migration, dimerization and localization at the plasma membrane protrusions.DISEASE A chromosomal aberration disrupting SRGAP2 has been found in a patient with early infantile epileptic encephalopathy. Balanced translocation t(1;9)(q32;q13) (PubMed:22106086).MISCELLANEOUS There are 3 duplications of SRGAP2 in the human genome as a result of segmental gene duplications. SRGAP2C is the only one to be fixed at a diploid state in the human genome. Moreover, SRGAP2C is functional, interacts with and inhibits SRGAP2 and is human-specific. The appearance of SRGAP2C in the human genome is estimated to 2,4 million years ago, which corresponds to the beginning of neocortex expansion in human evolution and it may have played an important role in this process through its interaction with SRGAP2 function. UniProt O75044 1 EQUAL 1071 EQUAL Reactome DB_ID: 5665803 1 SRGAP2:RAC1:GTP:FMNL1:Profilin:G-actin [plasma membrane] SRGAP2:RAC1:GTP:FMNL1:Profilin:G-actin Reactome DB_ID: 5665660 1 Reactome DB_ID: 195131 1 1 EQUAL 1071 EQUAL Reactome Database ID Release 81 5665803 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665803 Reactome R-HSA-5665803 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665803.1 Reactome Database ID Release 81 5665802 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665802 Reactome R-HSA-5665802 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665802.1 21148482 Pubmed 2011 Bi-modal regulation of a formin by srGAP2 Mason, Frank M Heimsath, Ernest G Higgs, Henry N Soderling, Scott H J. Biol. Chem. 286:6577-86 3.6.5.4 3.6.5.3 3.6.5.2 3.6.5.1 SRGAP2 stimulates RAC1 GTP-ase activity and ends FMNL1-mediated elongation of actin filaments SRGAP2 stimulates RAC1 GTP-ase activity and ends FMNL1-mediated elongation of actin filaments SRGAP2 is a GTPase activating protein that stimulates the GTPase activity of RAC1 bound to FMNL1. GTP hydrolysis produces inactive GDP-bound RAC1 which is unable to bind and activate FMNL1. SRGAP2 thereby limits the duration of FMNL1-mediated elongation of actin filaments downstream of RAC1:GTP (Mason et al. 2011). Authored: Orlic-Milacic, Marija, 2014-10-24 Authored: Rivero Crespo, Francisco, 2014-12-26 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 5665803 1 Reactome DB_ID: 29356 1 water [ChEBI:15377] water ChEBI 15377 Reactome DB_ID: 445010 1 RAC1:GDP [cytosol] RAC1:GDP Reactome DB_ID: 442615 1 1 EQUAL 189 EQUAL Reactome DB_ID: 29420 1 GDP(3-) [ChEBI:58189] GDP(3-) guanosine 5'-diphosphate(3-) 5'-O-[(phosphonatooxy)phosphinato]guanosine guanosine 5'-diphosphate trianion GDP GDP trianion guanosine 5'-diphosphate ChEBI 58189 Reactome Database ID Release 81 445010 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=445010 Reactome R-HSA-445010 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-445010.1 Reactome DB_ID: 203080 2 Reactome DB_ID: 195131 1 1 EQUAL 1071 EQUAL Reactome DB_ID: 29372 1 hydrogenphosphate [ChEBI:43474] hydrogenphosphate [PO3(OH)](2-) HYDROGENPHOSPHATE ION hydrogen phosphate [P(OH)O3](2-) HPO4(2-) phosphate INORGANIC PHOSPHATE GROUP ChEBI 43474 Reactome DB_ID: 5665949 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 5665803 GO 0003924 GO molecular function Reactome Database ID Release 81 5665807 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665807 Reactome Database ID Release 81 5665809 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665809 Reactome R-HSA-5665809 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665809.1 FMNL1 binds CDC42:GTP FMNL1 binds CDC42:GTP FMNL1 binds activated CDC42 and this interaction is implicated in the phagocytic cup formation, but the precise mechanism has not been elucidated (Seth et al. 2006). Authored: Orlic-Milacic, Marija, 2014-10-24 Authored: Rivero Crespo, Francisco, 2014-12-26 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 182921 1 CDC42:GTP [plasma membrane] CDC42:GTP CDC42-GTP Reactome DB_ID: 29438 1 Reactome DB_ID: 449545 1 UniProt:P60953 CDC42 CDC42 CDC42 FUNCTION Plasma membrane-associated small GTPase which cycles between an active GTP-bound and an inactive GDP-bound state. In active state binds to a variety of effector proteins to regulate cellular responses. Involved in epithelial cell polarization processes. Regulates the bipolar attachment of spindle microtubules to kinetochores before chromosome congression in metaphase (PubMed:15642749). Regulates cell migration (PubMed:17038317). In neurons, plays a role in the extension and maintenance of the formation of filopodia, thin and actin-rich surface projections (PubMed:14978216). Required for DOCK10-mediated spine formation in Purkinje cells and hippocampal neurons. In podocytes, facilitates filopodia and podosomes formation upon DOCK11-activation (PubMed:33523862). Upon activation by CaMKII, modulates dendritic spine structural plasticity by relaying CaMKII transient activation to synapse-specific, long-term signaling (By similarity). Also plays a role in phagocytosis through organization of the F-actin cytoskeleton associated with forming phagocytic cups (PubMed:26465210).ACTIVITY REGULATION Regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP, GTPase activating proteins (GAPs) which increase the GTP hydrolysis activity, and GDP dissociation inhibitors which inhibit the dissociation of the nucleotide from the GTPase.SUBUNIT Interacts with CDC42EP1, CDC42EP2, CDC42EP3, CDC42EP4, CDC42EP5, CDC42SE1, CDC42SE2, PARD6A, PARD6B and PARD6G (in a GTP-dependent manner) (PubMed:10490598, PubMed:10816584, PubMed:10954424, PubMed:11260256). Interacts with activated CSPG4 and with BAIAP2 (PubMed:10587647, PubMed:11130076). Interacts with activated CSPG4 and with BAIAP2 (By similarity). Interacts with DOCK11/Zizimin2; the interaction activates CDC42 by exchanging GDP for GTP (By similarity). Interacts with DOCK9; the interaction activates CDC42 by exchanging GDP for GTP (PubMed:12172552, PubMed:19745154). Interacts with DOCK8 (via DHR-2 domain); the interaction activates CDC42 by exchanging GDP for GTP (PubMed:12172552). Interacts with IQGAP1 (By similarity). Interacts with NET1 and ARHGAP33/TCGAP (By similarity). Part of a complex with PARD3, PARD6A or PARD6B and PRKCI or PRKCZ (PubMed:11260256). The GTP-bound form interacts with CCPG1 (By similarity). Interacts with USP6 (PubMed:12612085). Interacts with NEK6 (PubMed:20873783). Part of a collagen stimulated complex involved in cell migration composed of CDC42, CRK, TNK2 and BCAR1/p130cas (PubMed:17038317). Interacts with ITGB1BP1 (PubMed:11807099). Interacts with ARHGDIA; this interaction inactivates and stabilizes CDC42 (PubMed:23434736). Interacts with ARHGDIB; this maintains CDC42 in the inactive, GDP-bound form (PubMed:7512369). Interacts (in GTP-bound form) with FNBP1L and ABI1, but only in the presence of FNBP1L (PubMed:19798448). May interact with ARHGEF16; responsible for the activation of CDC42 by the viral protein HPV16 E6 (PubMed:21139582).PTM (Microbial infection) AMPylation at Tyr-32 and Thr-35 are mediated by bacterial enzymes in case of infection by H.somnus and V.parahaemolyticus, respectively. AMPylation occurs in the effector region and leads to inactivation of the GTPase activity by preventing the interaction with downstream effectors, thereby inhibiting actin assembly in infected cells. It is unclear whether some human enzyme mediates AMPylation; FICD has such ability in vitro but additional experiments remain to be done to confirm results in vivo.PTM Phosphorylated by SRC in an EGF-dependent manner, this stimulates the binding of the Rho-GDP dissociation inhibitor RhoGDI.PTM (Microbial infection) Glycosylated at Tyr-32 by Photorhabdus asymbiotica toxin PAU_02230. Mono-O-GlcNAcylation by PAU_02230 inhibits downstream signaling by an impaired interaction with diverse regulator and effector proteins of CDC42 and leads to actin disassembly.PTM (Microbial infection) Glucosylated at Thr-35 by C.difficile toxins TcdA and TcdB in the colonic epithelium (PubMed:7777059, PubMed:7775453, PubMed:24905543). Monoglucosylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption and cell death, resulting in the loss of colonic epithelial barrier function (PubMed:7777059, PubMed:7775453).PTM (Microbial infection) Glycosylated (O-GlcNAcylated) at Thr-35 by C.novyi toxin TcdA (PubMed:8810274). O-GlcNAcylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption (PubMed:8810274).SIMILARITY Belongs to the small GTPase superfamily. Rho family. CDC42 subfamily. UniProt P60953 1 EQUAL 188 EQUAL Reactome Database ID Release 81 182921 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=182921 Reactome R-HSA-182921 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-182921.1 Reactome DB_ID: 5665949 1 Reactome DB_ID: 5665688 1 CDC42:GTP:FMNL1 [plasma membrane] CDC42:GTP:FMNL1 Reactome DB_ID: 182921 1 Reactome DB_ID: 5665949 1 Reactome Database ID Release 81 5665688 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665688 Reactome R-HSA-5665688 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665688.1 Reactome Database ID Release 81 5665686 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665686 Reactome R-HSA-5665686 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665686.1 16943183 Pubmed 2006 Autoinhibition regulates cellular localization and actin assembly activity of the diaphanous-related formins FRLalpha and mDia1 Seth, Abhinav Otomo, Chinatsu Rosen, Michael K J. Cell Biol. 174:701-13 FMNL2 binds CDC42:GTP FMNL2 binds CDC42:GTP FMNL2 binds activated (GTP-bound) CDC42. FMNL2 can be myristoylated on its N-terminal glycine. Although myristoylation is not necessary for the interaction with CDC42, it contributes to FMNL2 activation. Based on the sequence similarity with mouse formin Dia1, binding of CDC42:GTP relieves the autoinhibition of FMNL2 by displacing the C-terminal autoregulatory DAD domain of FMNL2 from the N-terminal FH3 domain (Rose et al. 2005, Lammers et al. 2005). Since formins function as dimers, it is unclear whether the autoinhibitory interaction between FH3 and DAD domain is intramolecular or intermolecular (Xu et al. 2004, Kuhn and Geyer 2014). FMNL2 can also interact with RAC1 in vitro, but it seems that this interaction is not physiologically relevant (Block et al. 2012). Authored: Orlic-Milacic, Marija, 2014-10-24 Authored: Rivero Crespo, Francisco, 2014-12-26 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 5665952 1 FMNL2 [cytosol] FMNL2 FMNL2 dimer Reactome DB_ID: 5665723 2 UniProt:Q96PY5 FMNL2 FMNL2 FMNL2 FHOD2 KIAA1902 FUNCTION Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the cortical actin filament dynamics.DOMAIN The DAD domain regulates activation via by an autoinhibitory interaction with the GBD/FH3 domain. This autoinhibition is released upon competitive binding of an activated GTPase. The release of DAD allows the FH2 domain to then nucleate and elongate nonbranched actin filaments (By similarity).SIMILARITY Belongs to the formin homology family. UniProt Q96PY5 2 EQUAL 1086 EQUAL Reactome Database ID Release 81 5665952 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665952 Reactome R-HSA-5665952 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665952.1 Reactome DB_ID: 182921 1 Reactome DB_ID: 5665735 1 CDC42:GTP:FMNL2 [plasma membrane] CDC42:GTP:FMNL2 Reactome DB_ID: 5665952 1 Reactome DB_ID: 182921 1 Reactome Database ID Release 81 5665735 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665735 Reactome R-HSA-5665735 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665735.1 Reactome Database ID Release 81 5665727 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665727 Reactome R-HSA-5665727 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665727.1 22608513 Pubmed 2012 FMNL2 drives actin-based protrusion and migration downstream of Cdc42 Block, Jennifer Breitsprecher, Dennis Kühn, Sonja Winterhoff, Moritz Kage, Frieda Geffers, Robert Duwe, Patrick Rohn, Jennifer L Baum, Buzz Brakebusch, Cord Geyer, Matthias Stradal, Theresia E B Faix, Jan Rottner, Klemens Curr. Biol. 22:1005-12 CDC42:GTP:FMNL2 binds Profilin:G-actin CDC42:GTP:FMNL2 binds Profilin:G-actin Once activated by binding to GTP-bound CDC42, FMNL2 interacts with actin bound profilin(s) and drives elongation but not nucleation of actin filaments (Block et al. 2012). The interaction between formins and profilins is achieved through the proline-rich FH1 domain of formins, while the interaction with actin is achieved through the FH2 domain of formins (Romero et al. 2004, Kovar et al. 2006, Kuhn and Geyer 2014). Authored: Orlic-Milacic, Marija, 2014-10-24 Authored: Rivero Crespo, Francisco, 2014-12-26 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 203080 2 Reactome DB_ID: 5665735 1 Reactome DB_ID: 5665752 1 CDC42:FMNL2:Profilin:G-actin [plasma membrane] CDC42:FMNL2:Profilin:G-actin Reactome DB_ID: 203080 2 Reactome DB_ID: 5665735 1 Reactome Database ID Release 81 5665752 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665752 Reactome R-HSA-5665752 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665752.1 Reactome Database ID Release 81 5665751 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665751 Reactome R-HSA-5665751 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665751.1 FMNL2 binds RHOC:GTP FMNL2 binds RHOC:GTP FMNL2 specifically interacts with the GTP-bound RHOC, which relieves FMNL2 autoinhibition and contributes to RHOC-mediated ameboid cell motility involved in cancer cell invasion (Kitzing et al. 2010). Myristoylation of the N-terminal glycine may be required for the full activation of FMNL2 (Moriya et al. 2012). Authored: Orlic-Milacic, Marija, 2014-10-24 Authored: Rivero Crespo, Francisco, 2014-12-26 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 5665750 1 RHOC:GTP [plasma membrane] RHOC:GTP Reactome DB_ID: 29438 1 Reactome DB_ID: 194870 1 UniProt:P08134 RHOC RHOC ARHC RHOC ARH9 FUNCTION Regulates a signal transduction pathway linking plasma membrane receptors to the assembly of focal adhesions and actin stress fibers. Serves as a microtubule-dependent signal that is required for the myosin contractile ring formation during cell cycle cytokinesis. Regulates apical junction formation in bronchial epithelial cells.SUBUNIT Interacts with RTKN (By similarity). Interacts with AKAP13 (PubMed:11546812). Interacts with DIAPH1 (PubMed:15864301). Interacts with PKN2 (PubMed:20974804). Interacts with ROCK1 and ROCK2 (PubMed:8816443). Interacts with ARHGDIA (PubMed:20400958). Interacts with RIPOR1 (PubMed:27807006).PTM (Microbial infection) Glycosylated at Tyr-34 by Photorhabdus asymbiotica toxin PAU_02230. Mono-O-GlcNAcylation by PAU_02230 inhibits downstream signaling by an impaired interaction with diverse regulator and effector proteins of Rho and leads to actin disassembly.PTM (Microbial infection) Glucosylated at Thr-37 by C.difficile toxins TcdA and TcdB in the colonic epithelium (PubMed:24905543). Monoglucosylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption (PubMed:24905543).SIMILARITY Belongs to the small GTPase superfamily. Rho family. UniProt P08134 1 EQUAL 190 EQUAL Reactome Database ID Release 81 5665750 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665750 Reactome R-HSA-5665750 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665750.1 Reactome DB_ID: 5665952 1 Reactome DB_ID: 5665742 1 RHOC:GTP:FMNL2 [plasma membrane] RHOC:GTP:FMNL2 Reactome DB_ID: 5665750 1 Reactome DB_ID: 5665952 1 Reactome Database ID Release 81 5665742 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665742 Reactome R-HSA-5665742 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665742.1 Reactome Database ID Release 81 5665748 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665748 Reactome R-HSA-5665748 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665748.1 20101212 Pubmed 2010 Formin-like 2 drives amoeboid invasive cell motility downstream of RhoC Kitzing, T M Wang, Y Pertz, O Copeland, J W Grosse, R Oncogene 29:2441-8 22790947 Pubmed 2012 Protein N-myristoylation is required for cellular morphological changes induced by two formin family proteins, FMNL2 and FMNL3 Moriya, Koko Yamamoto, Takuo Takamitsu, Emi Matsunaga, Yukari Kimoto, Mayumi Fukushige, Daichi Kimoto, Chihiro Suzuki, Takashi Utsumi, Toshihiko Biosci. Biotechnol. Biochem. 76:1201-9 FMNL3 binds RHOC:GTP FMNL3 binds RHOC:GTP FMNL3 binds activated (GTP-bound) RHOC. RHOC-mediated activation of FMNL3 promotes polarized cell migration which may be involved in cancer cell invasion (Vega et al. 2011). Myristoylation of the N-terminal glycine may be required for the full activation of FMNL3 (Moriya et al. 2012). Authored: Orlic-Milacic, Marija, 2014-10-24 Authored: Rivero Crespo, Francisco, 2014-12-26 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 5665750 1 Reactome DB_ID: 5665954 1 FMNL3 [cytosol] FMNL3 FMNL3 dimer Reactome DB_ID: 5665760 2 UniProt:Q8IVF7 FMNL3 FMNL3 FMNL3 FHOD3 FRL2 WBP3 KIAA2014 FUNCTION Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the control of cell shape and migration. Required for developmental angiogenesis (By similarity). In this process, required for microtubule reorganization and for efficient endothelial cell elongation. In quiescent endothelial cells, triggers rearrangement of the actin cytoskeleton, but does not alter microtubule alignement.SUBUNIT Interacts with SRGAP2 (via SH3 domain).TISSUE SPECIFICITY Expressed in endothelial cells.DOMAIN The DAD domain regulates activation via by an autoinhibitory interaction with the GBD/FH3 domain. This autoinhibition is released upon competitive binding of an activated GTPase. The release of DAD allows the FH2 domain to then nucleate and elongate nonbranched actin filaments (By similarity).SIMILARITY Belongs to the formin homology family. UniProt Q8IVF7 2 EQUAL 1028 EQUAL Reactome Database ID Release 81 5665954 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665954 Reactome R-HSA-5665954 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665954.1 Reactome DB_ID: 5665759 1 RHOC:GTP:FMNL3 [plasma membrane] RHOC:GTP:FMNL3 Reactome DB_ID: 5665750 1 Reactome DB_ID: 5665954 1 Reactome Database ID Release 81 5665759 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665759 Reactome R-HSA-5665759 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665759.1 Reactome Database ID Release 81 5665761 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665761 Reactome R-HSA-5665761 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665761.1 21576392 Pubmed 2011 RhoA and RhoC have distinct roles in migration and invasion by acting through different targets Vega, Francisco M Fruhwirth, Gilbert Ng, Tony Ridley, Anne J J. Cell Biol. 193:655-65 Activated FMNL3 binds G-actin Activated FMNL3 binds G-actin Activated FMNL3 (presumably associated with RHOC:GTP) has the ability to directly bind G-actin through knob and coiled-coil subdomains of the FMNL3 FH2 domain. The proline-rich FH1 domain which precedes the FH2 domain presumably interacts with profilins bound to G-actin (Romero et al. 2004, Kovar et al. 2006, Kuhn and Geyer 2014). FMNL3 contributes to the elongation of actin filaments (Heimsath and Higgs 2012, Thompson et al. 2013). Activated FMNL3 may also trigger microtubule alignment during angiogenesis (Hetheridge et al. 2012). Authored: Orlic-Milacic, Marija, 2014-10-24 Authored: Rivero Crespo, Francisco, 2014-12-26 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 5665759 1 Reactome DB_ID: 203080 2 Reactome DB_ID: 5665773 1 RHOC:GTP:FMNL3:G-actin [plasma membrane] RHOC:GTP:FMNL3:G-actin Reactome DB_ID: 5665759 1 Reactome DB_ID: 203080 2 Reactome Database ID Release 81 5665773 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665773 Reactome R-HSA-5665773 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665773.1 Reactome Database ID Release 81 5665767 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665767 Reactome R-HSA-5665767 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665767.1 23222643 Pubmed 2013 FMNL3 FH2-actin structure gives insight into formin-mediated actin nucleation and elongation Thompson, Morgan E Heimsath, Ernest G Gauvin, Timothy J Higgs, Henry N Kull, F Jon Nat. Struct. Mol. Biol. 20:111-8 22275430 Pubmed 2012 The formin FMNL3 is a cytoskeletal regulator of angiogenesis Hetheridge, Clare Scott, Alice N Swain, Rajeeb K Copeland, John W Higgs, Henry N Bicknell, R Mellor, Harry J. Cell. Sci. 125:1420-8 22094460 Pubmed 2012 The C terminus of formin FMNL3 accelerates actin polymerization and contains a WH2 domain-like sequence that binds both monomers and filament barbed ends Heimsath, Ernest G Higgs, Henry N J. Biol. Chem. 287:3087-98 Profilin:G-actin binds MKL1 Profilin:G-actin binds MKL1 MKL1 (MAL) transcription cofactor is negatively regulated by binding to nonpolymerized actin (G-actin) (Miralles et al. 2003). Authored: Orlic-Milacic, Marija, 2014-10-24 Authored: Rivero Crespo, Francisco, 2014-12-26 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 203080 1 Reactome DB_ID: 5665975 1 UniProt:Q969V6 MRTFA MRTFA KIAA1438 MKL1 MRTFA MAL FUNCTION Transcription coactivator that associates with the serum response factor (SRF) transcription factor to control expression of genes regulating the cytoskeleton during development, morphogenesis and cell migration (PubMed:26224645). The SRF-MRTFA complex activity responds to Rho GTPase-induced changes in cellular globular actin (G-actin) concentration, thereby coupling cytoskeletal gene expression to cytoskeletal dynamics. MRTFA binds G-actin via its RPEL repeats, regulating activity of the MRTFA-SRF complex. Activity is also regulated by filamentous actin (F-actin) in the nucleus.SUBUNIT Interacts with SRF, forming the SRF-MRTFA nuclear complex which binds the 5'-CArG-3' consensus motif (CArG box) on DNA via SRF (PubMed:14565952, PubMed:19350017). Interacts (via RPEL repeats) with globular actin (G-actin), thereby regulating its subcellular location and activity of the complex formed with SRF (PubMed:19350017). Either forms a trivalent (by binding three G-actin monomers) or pentavalent (by binding five G-actin monomers) complex with G-actin (By similarity). Forms a nuclear ternary complex with SCAI and SRF, leading to suppress MRTFA-induced SRF transcriptional activity (PubMed:19350017). Interacts with beta-actin (ACTB); interaction with ACTB prevents interaction with SCAI (By similarity). Interacts with MRTFB (PubMed:14565952).TISSUE SPECIFICITY Ubiquitously expressed, has been detected in lung, placenta, small intestine, liver, kidney, spleen, thymus, colon, muscle, heart and brain (PubMed:11344311). Expressed in peripheral blood mononuclear cells (at protein level) (PubMed:26224645).DOMAIN The N-terminal region is required for nuclear localization and the C-terminal region mediates transcriptional activity.DOMAIN The RPEL repeats mediate binding to globular actin (G-actin); each RPEL repeat-binding to one G-actin monomer. In addition, each intervening spacer sequence region can bind one G-actin monomer, to reach a pentavalent complex.PTM Phosphorylation at Ser-6 by Erk inhibits binding of globular actin (G-actin), unmasking the nuclear localization signal (NLS) and promoting nuclear import.DISEASE A chromosomal aberration involving MRTFA may be a cause of acute megakaryoblastic leukemia. Translocation t(1;22)(p13;q13) with RBM15 (PubMed:11431691, PubMed:11344311). Although both reciprocal fusion transcripts are detected in acute megakaryoblastic leukemia (AMKL, FAB-M7), the RBM15-MRTFA chimeric protein has all the putative functional domains encoded by each gene and is the candidate oncogene (PubMed:11431691, PubMed:11344311). UniProt Q969V6 1 EQUAL 931 EQUAL Reactome DB_ID: 5665995 1 Profilin:G-actin:MKL1 [cytosol] Profilin:G-actin:MKL1 Reactome DB_ID: 203080 1 Reactome DB_ID: 5665975 1 1 EQUAL 931 EQUAL Reactome Database ID Release 81 5665995 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665995 Reactome R-HSA-5665995 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665995.1 Reactome Database ID Release 81 5666001 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666001 Reactome R-HSA-5666001 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666001.1 12732141 Pubmed 2003 Actin dynamics control SRF activity by regulation of its coactivator MAL Miralles, Francesc Posern, Guido Zaromytidou, AI Treisman, Richard Cell 113:329-42 DIAPH1 binds RHOA:GTP DIAPH1 binds RHOA:GTP DIAPH1 is activated by binding of the DIAPH1 dimer to GTP-bound (active) RHOA. Binding to RHOA releaves the autoinhibitory interaction of DIAPH1 FH3 and DAD domains (Otomo et al. 2005). Phosphorylation of RHOA at serine residue S188 may be required for RHOA binding to DIAPH1 (Li and Sewer 2010). The interaction between RHOA and DIAPH1 may also be positively regulated by PI3K signaling (Gao et al. 2009). Authored: Orlic-Milacic, Marija, 2014-10-24 Authored: Rivero Crespo, Francisco, 2014-12-26 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 5665967 1 DIAPH1 [cytosol] DIAPH1 DIAPH1 dimer Reactome DB_ID: 5665970 2 UniProt:O60610 DIAPH1 DIAPH1 DIAPH1 DIAP1 FUNCTION Actin nucleation and elongation factor required for the assembly of F-actin structures, such as actin cables and stress fibers (By similarity). Binds to the barbed end of the actin filament and slows down actin polymerization and depolymerization (By similarity). Required for cytokinesis, and transcriptional activation of the serum response factor (By similarity). DFR proteins couple Rho and Src tyrosine kinase during signaling and the regulation of actin dynamics (By similarity). Functions as a scaffold protein for MAPRE1 and APC to stabilize microtubules and promote cell migration (By similarity). Has neurite outgrowth promoting activity. Acts in a Rho-dependent manner to recruit PFY1 to the membrane (By similarity). In hear cells, it may play a role in the regulation of actin polymerization in hair cells (PubMed:20937854, PubMed:21834987, PubMed:26912466). The MEMO1-RHOA-DIAPH1 signaling pathway plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex (PubMed:20937854, PubMed:21834987). It controls the localization of APC and CLASP2 to the cell membrane, via the regulation of GSK3B activity (PubMed:20937854, PubMed:21834987). In turn, membrane-bound APC allows the localization of the MACF1 to the cell membrane, which is required for microtubule capture and stabilization (PubMed:20937854, PubMed:21834987). Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the control of cell shape (PubMed:20937854, PubMed:21834987). Plays a role in brain development (PubMed:24781755). Also acts as an actin nucleation and elongation factor in the nucleus by promoting nuclear actin polymerization inside the nucleus to drive serum-dependent SRF-MRTFA activity (By similarity).SUBUNIT Homodimer (By similarity). Interacts with the GTP-bound form of RHOA (PubMed:23325789). Interacts with RHOC, PFY1, MAPRE1, BAIAP2 and APC (By similarity). Interacts with SCAI (By similarity). Interacts with DCAF7, via FH2 domain (By similarity). Interacts with NCDN (By similarity). Interacts with OSBPL10, OSBPL2, VIM, TUBB and DYN1 (PubMed:23325789).TISSUE SPECIFICITY Expressed in brain, heart, placenta, lung, kidney, pancreas, liver, skeletal muscle and cochlea. Expressed in platelets (PubMed:26912466).DEVELOPMENTAL STAGE Strongly expressed in ventricular and subventricular zone progenitor cells of the neocortical wall at 12 weeks post-conception.DOMAIN The DAD domain regulates activation via by an autoinhibitory interaction with the GBD/FH3 domain (By similarity). This autoinhibition is released upon competitive binding of an activated GTPase (By similarity). The release of DAD allows the FH2 domain to then nucleate and elongate nonbranched actin filaments (By similarity).PTM Phosphorylation at Thr-768 is stimulated by cAMP and regulates stability, complex formation and mitochondrial movement.SIMILARITY Belongs to the formin homology family. Diaphanous subfamily. UniProt O60610 1 EQUAL 1272 EQUAL Reactome Database ID Release 81 5665967 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665967 Reactome R-HSA-5665967 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665967.1 Reactome DB_ID: 5665993 1 RHOA:GTP [plasma membrane] RHOA:GTP Reactome DB_ID: 29438 1 Reactome DB_ID: 194510 1 UniProt:P61586 RHOA RHOA ARH12 ARHA RHOA RHO12 FUNCTION Small GTPase which cycles between an active GTP-bound and an inactive GDP-bound state. Mainly associated with cytoskeleton organization, in active state binds to a variety of effector proteins to regulate cellular responses such as cytoskeletal dynamics, cell migration and cell cycle. Regulates a signal transduction pathway linking plasma membrane receptors to the assembly of focal adhesions and actin stress fibers (PubMed:8910519, PubMed:9121475, PubMed:31570889). Involved in a microtubule-dependent signal that is required for the myosin contractile ring formation during cell cycle cytokinesis (PubMed:16236794, PubMed:12900402). Plays an essential role in cleavage furrow formation. Required for the apical junction formation of keratinocyte cell-cell adhesion (PubMed:20974804, PubMed:23940119). Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly (PubMed:19934221). The MEMO1-RHOA-DIAPH1 signaling pathway plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. It controls the localization of APC and CLASP2 to the cell membrane, via the regulation of GSK3B activity. In turn, membrane-bound APC allows the localization of the MACF1 to the cell membrane, which is required for microtubule capture and stabilization (PubMed:20937854). Regulates KCNA2 potassium channel activity by reducing its location at the cell surface in response to CHRM1 activation; promotes KCNA2 endocytosis (PubMed:9635436, PubMed:19403695). Acts as an allosteric activator of guanine nucleotide exchange factor ECT2 by binding in its activated GTP-bound form to the PH domain of ECT2 which stimulates the release of PH inhibition and promotes the binding of substrate RHOA to the ECT2 catalytic center (PubMed:31888991). May be an activator of PLCE1 (PubMed:16103226). In neurons, involved in the inhibition of the initial spine growth. Upon activation by CaMKII, modulates dendritic spine structural plasticity by relaying CaMKII transient activation to synapse-specific, long-term signaling (By similarity). Acts as a regulator of platelet alpha-granule release during activation and aggregation of platelets (By similarity).FUNCTION (Microbial infection) Serves as a target for the yopT cysteine peptidase from Yersinia pestis, vector of the plague.ACTIVITY REGULATION Regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP, GTPase activating proteins (GAPs) which increase the GTP hydrolysis activity and GDP dissociation inhibitors which inhibit the dissociation of the nucleotide from the GTPase. Activated by GEFs such as ARHGEF2, ARHGEF3, ARHGEF28 and BCR (PubMed:23940119, PubMed:12221096). Inhibited by GAPs such as ARHGAP30 (PubMed:21565175). Inhibited by GDP dissociation inhibitors such as ARHGDIA (PubMed:20400958).SUBUNIT Interacts with ARHGEF28 (By similarity). Interacts (via GTP-bound form) with RIPOR1 (via N-terminus); this interaction links RHOA to STK24 and STK26 kinases (PubMed:27807006). Interacts with RIPOR2 (via active GTP- or inactive GDP-bound forms) isoform 1 and isoform 2; these interactions are direct, block the loading of GTP to RHOA and decrease upon chemokine CCL19 stimulation in primary T lymphocytes (PubMed:25588844). Binds PRKCL1, ROCK1 and ROCK2 (PubMed:10388627, PubMed:8617235, PubMed:8641286). Interacts with ARHGEF2, ARHGEF3, NET1 and RTKN (PubMed:10940294, PubMed:12221096, PubMed:9857026). Interacts with PLCE1 and AKAP13 (PubMed:11696353, PubMed:12900402). Interacts with DIAPH1 (PubMed:23325789). Interacts (in the constitutively activated, GTP-bound form) with DGKQ (PubMed:10066731). Interacts with RACK1; enhances RHOA activation (PubMed:20499158). Interacts with PKP4; the interaction is detected at the midbody (PubMed:17115030). Interacts (GTP-bound form preferentially) with PKN2; the interaction stimulates autophosphorylation and phosphorylation of PKN2 (PubMed:20974804, PubMed:9121475). Interacts with ARHGDIA; this interaction inactivates and stabilizes RHOA (PubMed:20400958). Interacts with ARHGDIB. Interacts (GTP-bound form) with KCNA2 (via cytoplasmic N-terminal domain) (PubMed:9635436). Interacts (GTP-bound form) with ECT2; the interaction results in allosteric activation of ECT2 (PubMed:31888991).SUBUNIT (Microbial infection) Interacts with yopT from Yersinia pestis.SUBUNIT (Microbial infection) Interacts with human respiratory syncytial virus (HRSV) protein F; this interaction facilitates virus-induced syncytium formation.DOMAIN The basic-rich region is essential for yopT recognition and cleavage.PTM (Microbial infection) Substrate for botulinum ADP-ribosyltransferase.PTM (Microbial infection) Cleaved by yopT protease when the cell is infected by some Yersinia pathogens. This removes the lipid attachment, and leads to its displacement from plasma membrane and to subsequent cytoskeleton cleavage.PTM (Microbial infection) AMPylation at Tyr-34 and Thr-37 are mediated by bacterial enzymes in case of infection by H.somnus and V.parahaemolyticus, respectively. AMPylation occurs in the effector region and leads to inactivation of the GTPase activity by preventing the interaction with downstream effectors, thereby inhibiting actin assembly in infected cells. It is unclear whether some human enzyme mediates AMPylation; FICD has such ability in vitro but additional experiments remain to be done to confirm results in vivo.PTM (Microbial infection) Glycosylated at Tyr-34 by Photorhabdus asymbiotica toxin PAU_02230. Mono-O-GlcNAcylation by PAU_02230 inhibits downstream signaling by an impaired interaction with diverse regulator and effector proteins of Rho and leads to actin disassembly.PTM (Microbial infection) Glucosylated at Thr-37 by C.difficile toxins TcdA and TcdB in the colonic epithelium (PubMed:7777059, PubMed:7775453, PubMed:24905543). Monoglucosylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption and cell death, resulting in the loss of colonic epithelial barrier function (PubMed:7777059, PubMed:7775453).PTM (Microbial infection) Glycosylated (O-GlcNAcylated) at Thr-37 by C.novyi toxin TcdA (PubMed:8810274). O-GlcNAcylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption (PubMed:8810274).PTM Phosphorylation by PRKG1 at Ser-188 inactivates RHOA signaling (PubMed:11162591). Phosphorylation by SLK at Ser-188 in response to AGTR2 activation (By similarity).PTM Ubiquitinated by the BCR(KCTD13) and BCR(TNFAIP1) E3 ubiquitin ligase complexes, leading to its degradation by the proteasome, thereby regulating the actin cytoskeleton and synaptic transmission in neurons.PTM Serotonylation of Gln-63 by TGM2 during activation and aggregation of platelets leads to constitutive activation of GTPase activity.SIMILARITY Belongs to the small GTPase superfamily. Rho family. UniProt P61586 1 EQUAL 190 EQUAL Reactome Database ID Release 81 5665993 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665993 Reactome R-HSA-5665993 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665993.1 Reactome DB_ID: 5665988 1 RHOA:GTP:DIAPH1 [plasma membrane] RHOA:GTP:DIAPH1 Reactome DB_ID: 5665967 1 Reactome DB_ID: 5665993 1 Reactome Database ID Release 81 5665988 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665988 Reactome R-HSA-5665988 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665988.1 Reactome Database ID Release 81 5665989 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665989 Reactome R-HSA-5665989 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665989.1 15866170 Pubmed 2005 Structural basis of Rho GTPase-mediated activation of the formin mDia1 Otomo, Takanori Otomo, Chinatsu Tomchick, DR Machius, M Rosen, Michael K Mol. Cell 18:273-81 20030946 Pubmed 2009 [PI3-kinase mediates activity of RhoA and interaction of RhoA with mDia1 in thrombin-induced platelet aggregation] Gao, Guang-Xun Dong, Hong-Juan Gu, Hong-Tao Gao, Ying Pan, Yao-Zhu Yang, Yang Chen, Xie-Qun Zhongguo Shi Yan Xue Ye Xue Za Zhi 17:1555-9 20591975 Pubmed 2010 RhoA and DIAPH1 mediate adrenocorticotropin-stimulated cortisol biosynthesis by regulating mitochondrial trafficking Li, Donghui Sewer, Marion B Endocrinology 151:4313-23 RHOA:GTP:DIAPH1 binds EVL and sequesters profilin:G-actin from MKL1 RHOA:GTP:DIAPH1 binds EVL and sequesters profilin:G-actin from MKL1 Once activated by binding to RHOA:GTP, DIAPH1 binds profilin:G-actin complexes together with EVL (VASP) homotetramers and promotes elongation of actin filaments (Copeland and Treisman 2002, Grosse et al. 2003, Kursula et al. 2008, Breitsprecher et al. 2008). Binding of nonpolymerized actin (G-actin) to DIAPH1 and EVL releases MKL1 (MAL) transcription co-factor which is inhibited when bound to G-actin (Miralles et al. 2003). Authored: Orlic-Milacic, Marija, 2014-10-24 Authored: Rivero Crespo, Francisco, 2014-12-26 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 5665986 1 EVL [cytosol] EVL VASP VASP homotetramer EVL homotetramer Reactome DB_ID: 426403 4 UniProt:Q9UI08 EVL EVL RNB6 EVL FUNCTION Ena/VASP proteins are actin-associated proteins involved in a range of processes dependent on cytoskeleton remodeling and cell polarity such as axon guidance and lamellipodial and filopodial dynamics in migrating cells. EVL enhances actin nucleation and polymerization.SUBUNIT Homotetramer (By similarity). Binds to the SH3 domains of ABL1, LYN and SRC. Also binds to profilin, with preference for isoform IIa of PFN2, and the WW domain of APBB1/FE65. Binds to SEMA6A. Interacts, via the Pro-rich region, with the C-terminal SH3 domain of DNMBP. Interacts with RAPH1. Binds, via the EVH1 domain, the Pro-rich domain of Listeria monocytogenes actA (By similarity). Binds, via the EVH1 domain, the Pro-rich domain of ZYX. Interacts with FYB1 (PubMed:10747096). Interacts with ZDHHC17 (PubMed:28882895).DOMAIN The EVH2 domain is comprised of 3 regions. Block A is a thymosin-like domain required for G-actin binding. The KLKR motif within this block is essential for the G-actin binding and for actin polymerization. Block B is required for F-actin binding and subcellular location, and Block C for tetramerization.PTM Phosphorylated by PKA; phosphorylation abolishes binding to SH3 domains of ABL and SRC.MISCELLANEOUS Required to transform actin polymerization into active movement for the propulsive force of Listeria monocytogenes.SIMILARITY Belongs to the Ena/VASP family. UniProt Q9UI08 1 EQUAL 416 EQUAL Reactome Database ID Release 81 5665986 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665986 Reactome R-HSA-5665986 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665986.1 Reactome DB_ID: 5665995 2 Reactome DB_ID: 5665988 1 Reactome DB_ID: 5665975 2 1 EQUAL 931 EQUAL Reactome DB_ID: 5665977 1 RHOA:GTP:DIAPH1:EVL:Profilin:G-actin [plasma membrane] RHOA:GTP:DIAPH1:EVL:Profilin:G-actin Reactome DB_ID: 203080 2 Reactome DB_ID: 5665986 1 Reactome DB_ID: 5665988 1 Reactome Database ID Release 81 5665977 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665977 Reactome R-HSA-5665977 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665977.1 Reactome Database ID Release 81 5665982 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665982 Reactome R-HSA-5665982 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665982.1 18923426 Pubmed 2008 Clustering of VASP actively drives processive, WH2 domain-mediated actin filament elongation Breitsprecher, Dennis Kiesewetter, Antje K Linkner, Joern Urbanke, Claus Resch, Guenter P Small, J Victor Faix, Jan EMBO J. 27:2943-54 12429848 Pubmed 2002 The diaphanous-related formin mDia1 controls serum response factor activity through its effects on actin polymerization Copeland, John W Treisman, Richard Mol. Biol. Cell 13:4088-99 12805219 Pubmed 2003 A role for VASP in RhoA-Diaphanous signalling to actin dynamics and SRF activity Grosse, Robert Copeland, John W Newsome, Timothy P Way, Michael Treisman, Richard EMBO J. 22:3050-61 18001770 Pubmed 2008 High-resolution structural analysis of mammalian profilin 2a complex formation with two physiological ligands: the formin homology 1 domain of mDia1 and the proline-rich domain of VASP Kursula, P Kursula, Inari Massimi, Marzia Song, Young-Hwa Downer, Joshua Stanley, Will A Witke, Walter Wilmanns, Matthias J. Mol. Biol. 375:270-90 MKL1 translocates from cytosol to the nucleus MKL1 translocates from cytosol to the nucleus The release of MKL1 (MAL) from nonpolymerized actin (G-actin), after profilin:G-actin complexes bind DIAPH1 and EVL (VASP) downstream of activated RHOA, enables MKL1 to translocate from the cytosol to the nucleus (Miralles et al. 2003). Authored: Orlic-Milacic, Marija, 2014-10-24 Authored: Rivero Crespo, Francisco, 2014-12-26 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 5665975 1 1 EQUAL 931 EQUAL Reactome DB_ID: 3900220 1 nucleoplasm GO 0005654 1 EQUAL 931 EQUAL Reactome Database ID Release 81 5665999 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665999 Reactome R-HSA-5665999 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665999.1 MKL1 binds SRF MKL1 binds SRF In the nucleus, MKL1 binds SRF transcription factor and enables transcription of SRF-target genes (Miralles et al. 2003). Authored: Orlic-Milacic, Marija, 2014-10-24 Authored: Rivero Crespo, Francisco, 2014-12-26 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 3900220 1 1 EQUAL 931 EQUAL Reactome DB_ID: 5666000 1 UniProt:P11831 SRF SRF SRF FUNCTION SRF is a transcription factor that binds to the serum response element (SRE), a short sequence of dyad symmetry located 300 bp to the 5' of the site of transcription initiation of some genes (such as FOS). Together with MRTFA transcription coactivator, controls expression of genes regulating the cytoskeleton during development, morphogenesis and cell migration. The SRF-MRTFA complex activity responds to Rho GTPase-induced changes in cellular globular actin (G-actin) concentration, thereby coupling cytoskeletal gene expression to cytoskeletal dynamics. Required for cardiac differentiation and maturation.SUBUNIT Binds DNA as a multimer, probably a dimer (PubMed:7637780). Interacts with MRTFA, forming the SRF-MRTFA nuclear complex which binds the 5'-CArG-3' consensus motif (CArG box) on DNA via SRF (PubMed:14565952, PubMed:19350017). Forms a nuclear ternary complex with MRTFA and SCAI (PubMed:19350017). Interacts with MRTFB (PubMed:14565952). Interacts with MLLT7/FOXO4, NKX3A and SSRP1 (PubMed:16054032). Interacts with ARID2 (By similarity). Interacts with SRFBP1 (By similarity). Interacts with FOXK1 (PubMed:17670796). Interacts with LPXN (PubMed:18497331). Interacts with OLFM2; the interaction promotes dissociation of SRF from the transcriptional repressor HEY2, facilitates binding of SRF to target genes and promotes smooth muscle differentiation (PubMed:25298399). Interacts with NKX3-1 (By similarity). Interacts with KAT5 (By similarity).PTM Phosphorylated by PRKDC. UniProt P11831 1 EQUAL 508 EQUAL Reactome DB_ID: 5666002 1 SRF:MKL1 [nucleoplasm] SRF:MKL1 Reactome DB_ID: 3900220 1 1 EQUAL 931 EQUAL Reactome DB_ID: 5666000 1 1 EQUAL 508 EQUAL Reactome Database ID Release 81 5666002 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666002 Reactome R-HSA-5666002 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666002.1 Reactome Database ID Release 81 5665998 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5665998 Reactome R-HSA-5665998 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5665998.1 SCAI binds SRF:MKL1 SCAI binds SRF:MKL1 SCAI forms a ternary complex with MKL1 and SRF, inhibiting the transcriptional activity of the SRF:MKL1 complex. SCAI negatively regulates cancer cell invasion facilitated by the SRF:MKL1-mediated transcription downstream of RHOA and DIAPH1, and therefore acts as a tumor suppressor (Brandt et al. 2009). Authored: Orlic-Milacic, Marija, 2014-10-24 Authored: Rivero Crespo, Francisco, 2014-12-26 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 5666002 1 Reactome DB_ID: 5666012 1 UniProt:Q8N9R8 SCAI SCAI C9orf126 SCAI FUNCTION Tumor suppressor which functions to suppress MRTFA-induced SRF transcriptional activity. May function in the RHOA-DIAPH1 signal transduction pathway and regulate cell migration through transcriptional regulation of ITGB1.SUBUNIT Interacts with DIAPH1 (By similarity). Forms a nuclear ternary complex with MRTFA and SRF.SIMILARITY Belongs to the SCAI family. UniProt Q8N9R8 1 EQUAL 606 EQUAL Reactome DB_ID: 5666007 1 SRF:MKL1:SCAI [nucleoplasm] SRF:MKL1:SCAI Reactome DB_ID: 5666002 1 Reactome DB_ID: 5666012 1 1 EQUAL 606 EQUAL Reactome Database ID Release 81 5666007 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666007 Reactome R-HSA-5666007 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666007.1 Reactome Database ID Release 81 5666008 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666008 Reactome R-HSA-5666008 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666008.1 19350017 Pubmed 2009 SCAI acts as a suppressor of cancer cell invasion through the transcriptional control of beta1-integrin Brandt, Dominique T Baarlink, Christian Kitzing, Thomas M Kremmer, E Ivaska, Johanna Nollau, Peter Grosse, Robert Nat. Cell Biol. 11:557-68 SRF:MKL1 binds ITGB1 Gene SRF:MKL1 binds ITGB1 Gene SRF:MKL1 transcription complex binds the promoter region of the integrin beta-1 (ITGB1) gene (Brandt et al. 2009). Authored: Orlic-Milacic, Marija, 2014-10-24 Authored: Rivero Crespo, Francisco, 2014-12-26 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 5666002 1 Reactome DB_ID: 5666054 1 ENSEMBL:ENSG00000150093 ITGB1 ITGB1 MSK12 MDF2 FNRB ENSEMBL ENSG00000150093 Reactome DB_ID: 5666050 1 SRF:MKL1:ITGB1 Gene [nucleoplasm] SRF:MKL1:ITGB1 Gene Reactome DB_ID: 5666002 1 Reactome DB_ID: 5666054 1 Reactome Database ID Release 81 5666050 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666050 Reactome R-HSA-5666050 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666050.1 Reactome Database ID Release 81 5666046 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666046 Reactome R-HSA-5666046 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666046.1 SRF:MKL1 stimulate ITGB1 expression while SCAI inhibits it SRF:MKL1 stimulate ITGB1 expression while SCAI inhibits it SRF:MKL1 binding to the promoter region of the integrin beta-1 gene stimulates ITGB1 expression downstream of RHOA:GTP:DIAPH1-induced actin cytoskeleton changes. Binding of SCAI to SRF:MKL1 inhibits RHOA:GTP:DIAPH1-induced ITGB1 transcription (Brandt et al. 2009). Authored: Orlic-Milacic, Marija, 2014-10-24 Authored: Rivero Crespo, Francisco, 2014-12-26 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 5666054 1 Reactome DB_ID: 57596 1 UniProt:P05556 ITGB1 ITGB1 ITGB1 MSK12 MDF2 FNRB FUNCTION Integrins alpha-1/beta-1, alpha-2/beta-1, alpha-10/beta-1 and alpha-11/beta-1 are receptors for collagen. Integrins alpha-1/beta-1 and alpha-2/beta-2 recognize the proline-hydroxylated sequence G-F-P-G-E-R in collagen. Integrins alpha-2/beta-1, alpha-3/beta-1, alpha-4/beta-1, alpha-5/beta-1, alpha-8/beta-1, alpha-10/beta-1, alpha-11/beta-1 and alpha-V/beta-1 are receptors for fibronectin. Alpha-4/beta-1 recognizes one or more domains within the alternatively spliced CS-1 and CS-5 regions of fibronectin. Integrin alpha-5/beta-1 is a receptor for fibrinogen. Integrin alpha-1/beta-1, alpha-2/beta-1, alpha-6/beta-1 and alpha-7/beta-1 are receptors for lamimin. Integrin alpha-6/beta-1 (ITGA6:ITGB1) is present in oocytes and is involved in sperm-egg fusion (By similarity). Integrin alpha-4/beta-1 is a receptor for VCAM1. It recognizes the sequence Q-I-D-S in VCAM1. Integrin alpha-9/beta-1 is a receptor for VCAM1, cytotactin and osteopontin. It recognizes the sequence A-E-I-D-G-I-E-L in cytotactin. Integrin alpha-3/beta-1 is a receptor for epiligrin, thrombospondin and CSPG4. Alpha-3/beta-1 may mediate with LGALS3 the stimulation by CSPG4 of endothelial cells migration. Integrin alpha-V/beta-1 is a receptor for vitronectin. Beta-1 integrins recognize the sequence R-G-D in a wide array of ligands. When associated with alpha-7 integrin, regulates cell adhesion and laminin matrix deposition. Involved in promoting endothelial cell motility and angiogenesis. Involved in osteoblast compaction through the fibronectin fibrillogenesis cell-mediated matrix assembly process and the formation of mineralized bone nodules. May be involved in up-regulation of the activity of kinases such as PKC via binding to KRT1. Together with KRT1 and RACK1, serves as a platform for SRC activation or inactivation. Plays a mechanistic adhesive role during telophase, required for the successful completion of cytokinesis. Integrin alpha-3/beta-1 provides a docking site for FAP (seprase) at invadopodia plasma membranes in a collagen-dependent manner and hence may participate in the adhesion, formation of invadopodia and matrix degradation processes, promoting cell invasion. ITGA4:ITGB1 binds to fractalkine (CX3CL1) and may act as its coreceptor in CX3CR1-dependent fractalkine signaling (PubMed:23125415, PubMed:24789099). ITGA4:ITGB1 and ITGA5:ITGB1 bind to PLA2G2A via a site (site 2) which is distinct from the classical ligand-binding site (site 1) and this induces integrin conformational changes and enhanced ligand binding to site 1 (PubMed:18635536, PubMed:25398877). ITGA5:ITGB1 acts as a receptor for fibrillin-1 (FBN1) and mediates R-G-D-dependent cell adhesion to FBN1 (PubMed:12807887, PubMed:17158881). ITGA5:ITGB1 is a receptor for IL1B and binding is essential for IL1B signaling (PubMed:29030430). ITGA5:ITGB3 is a receptor for soluble CD40LG and is required for CD40/CD40LG signaling (PubMed:31331973). Plays an important role in myoblast differentiation and fusion during skeletal myogenesis (By similarity).FUNCTION (Microbial infection) Integrin ITGA2:ITGB1 acts as a receptor for Human echoviruses 1 and 8.FUNCTION (Microbial infection) Acts as a receptor for Cytomegalovirus/HHV-5.FUNCTION (Microbial infection) Acts as a receptor for Epstein-Barr virus/HHV-4.FUNCTION (Microbial infection) Integrin ITGA5:ITGB1 acts as a receptor for Human parvovirus B19.FUNCTION (Microbial infection) Integrin ITGA2:ITGB1 acts as a receptor for Human rotavirus.FUNCTION (Microbial infection) Acts as a receptor for Mammalian reovirus.FUNCTION (Microbial infection) In case of HIV-1 infection, integrin ITGA5:ITGB1 binding to extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions.FUNCTION (Microbial infection) Interacts with CotH proteins expressed by fungi of the order mucorales, the causative agent of mucormycosis, which plays an important role in epithelial cell invasion by the fungi (PubMed:32487760). Integrin ITGA3:ITGB1 may act as a receptor for R.delemar CotH7 in alveolar epithelial cells, which may be an early step in pulmonary mucormycosis disease progression (PubMed:32487760).SUBUNIT Heterodimer of an alpha and a beta subunit. Beta-1 associates with either alpha-1, alpha-2, alpha-3, alpha-4, alpha-5, alpha-6, alpha-7, alpha-8, alpha-9, alpha-10, alpha-11 or alpha-V. ITGA6:ITGB1 is found in a complex with CD9; interaction takes place in oocytes and is involved in sperm-egg fusion (By similarity). Interacts with seprase FAP (seprase); the interaction occurs at the cell surface of invadopodia membrane in a collagen-dependent manner. Binds LGALS3BP and NMRK2, when associated with alpha-7, but not with alpha-5. Interacts with FGR and HCK. Interacts (via the cytoplasmic region) with RAB25 (via the hypervariable C-terminal region). Interacts with RAB21. Interacts with KRT1 in the presence of RACK1 and SRC. Interacts with JAML; integrin alpha-4/beta-1 may regulate leukocyte to endothelial cells adhesion by controlling JAML homodimerization. Interacts with FLNA, FLNB and RANBP9. Interacts with MYO10. Interacts with DAB2. Interacts with FERMT2; the interaction is inhibited in presence of ITGB1BP1. Interacts with ITGB1BP1 (via C-terminal region); the interaction is a prerequisite for focal adhesion disassembly. Interacts with TLN1; the interaction is prevented by competitive binding of ITGB1BP1. Interacts with ACAP1; required for ITGB1 recycling. Interacts with ASAP3. Interacts with EMP2; the interaction may be direct or indirect and ITGB1 has a heterodimer form (By similarity). ITGA5:ITGB1 interacts with CCN3. ITGA4:ITGB1 is found in a ternary complex with CX3CR1 and CX3CL1 (PubMed:23125415). ITGA5:ITGB1 interacts with FBN1 (PubMed:12807887, PubMed:17158881). ITGA5:ITGB1 interacts with IL1B (PubMed:29030430). ITGA4:ITGB1 interacts with MDK; this interaction mediates MDK-induced osteoblast cells migration through PXN phosphorylation (PubMed:15466886). ITGA6:ITGB1 interacts with MDK; this interaction mediates MDK-induced neurite-outgrowth (PubMed:15466886). ITGA5:ITGB1 interacts with ACE2 (PubMed:33102950). Interacts with TMEM182 and LAMB1 (By similarity).SUBUNIT (Microbial infection) Integrin ITGA2:ITGB1 interacts with human echoviruses 1 and 8 capsid proteins.SUBUNIT (Microbial infection) Interacts with human cytomegalovirus/HHV-5 envelope glycoprotein B/gB.SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus/HHV-4 gB protein.SUBUNIT (Microbial infection) Integrin ITGA5:ITGB1 interacts with human parvovirus B19 capsid protein.SUBUNIT (Microbial infection) Integrin ITGA2:ITGB1 interacts with human rotavirus VP4 protein.SUBUNIT (Microbial infection) Interacts with mammalian reovirus capsid proteins.SUBUNIT (Microbial infection) Integrin ITGA5:ITGB1 interacts with HIV-1 Tat.SUBUNIT (Microbial infection) ITGA5:ITGB1 interacts with SARS coronavirus-2/SARS-CoV-2 spike protein.SUBUNIT (Microbial infection) Interacts with R.delemar CotH7 on the surface of alveolar epithelial cells.INDUCTION Induced in alveolar epithelial cells during exposure to the fungus R.delemar, a causative agent of mucormycosis.PTM The cysteine residues are involved in intrachain disulfide bonds.BIOTECHNOLOGY Antibodies against integrin beta-1 ITGB1 protects epithelial cells from invasion by the fungus R.delemar, a causative agent of mucormycosis, and could thus potentially be used to treat mucormycosis disease (PubMed:32487760). Antibodies against the protein also protect a neutropenic mouse model against mucormycosis (PubMed:32487760).SIMILARITY Belongs to the integrin beta chain family. UniProt P05556 21 EQUAL 798 EQUAL Reactome Database ID Release 81 5666049 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666049 Reactome R-HSA-5666049 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666049.3 ACTIVATION Reactome Database ID Release 81 5666053 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666053 Reactome R-HSA-5666053 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666053.1 Reactome DB_ID: 5666050 INHIBITION Reactome Database ID Release 81 5666047 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666047 Reactome R-HSA-5666047 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666047.1 Reactome DB_ID: 5666007 RHOB:GTP recruits DIAPH1 or DIAPH3 to endosomes RHOB:GTP recruits DIAPH1 or DIAPH3 to endosomes Activated RHOB (RHOB:GTP) recruits DIAPH1 or DIAPH3 to endosomes where they regulate actin coat formation around endosomes and endosome motility/trafficking (Fernandez-Borja et al. 2005, Wallar et al. 2007). Authored: Orlic-Milacic, Marija, 2014-10-24 Authored: Rivero Crespo, Francisco, 2014-12-26 Edited: Orlic-Milacic, Marija, 2015-02-02 Converted from EntitySet in Reactome Reactome DB_ID: 5666066 1 DIAPH1,DIAPH3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 5666081 1 endosome membrane GO 0010008 RHOB:GTP [endosome membrane] RHOB:GTP Reactome DB_ID: 29438 1 Reactome DB_ID: 5666064 1 UniProt:P62745 RHOB RHOB ARH6 ARHB RHOB FUNCTION Mediates apoptosis in neoplastically transformed cells after DNA damage. Not essential for development but affects cell adhesion and growth factor signaling in transformed cells. Plays a negative role in tumorigenesis as deletion causes tumor formation. Involved in intracellular protein trafficking of a number of proteins. Targets PKN1 to endosomes and is involved in trafficking of the EGF receptor from late endosomes to lysosomes. Also required for stability and nuclear trafficking of AKT1/AKT which promotes endothelial cell survival during vascular development. Serves as a microtubule-dependent signal that is required for the myosin contractile ring formation during cell cycle cytokinesis. Required for genotoxic stress-induced cell death in breast cancer cells.SUBUNIT Binds ROCK1 and ROCK2 (By similarity). Also binds PKN1/PRK1 (PubMed:9478917). Interacts with ARGGEF3 (PubMed:12221096). Interacts with RTKN (By similarity). Interacts with AKAP13 (PubMed:11546812). Interacts with RIPOR1 (PubMed:27807006).INDUCTION Up-regulated by DNA damaging agents like H(2)O(2) or ionizing radiation (IR).PTM Prenylation specifies the subcellular location of RHOB. The farnesylated form is localized to the plasma membrane while the geranylgeranylated form is localized to the endosome.PTM (Microbial infection) Glycosylated at Tyr-34 by Photorhabdus asymbiotica toxin PAU_02230. Mono-O-GlcNAcylation by PAU_02230 inhibits downstream signaling by an impaired interaction with diverse regulator and effector proteins of Rho and leads to actin disassembly.PTM (Microbial infection) Glucosylated at Thr-37 by C.difficile toxins TcdA and TcdB in the colonic epithelium (PubMed:24905543). Monoglucosylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption (PubMed:24905543).MISCELLANEOUS RHOB is one of the targets of farnesyltransferase inhibitors which are currently under investigation as cancer therapeutics. These elevate the levels of geranylgeranylated RHOB and cause mislocalization, leading to apoptosis and antineoplastic effects.SIMILARITY Belongs to the small GTPase superfamily. Rho family. UniProt P62745 1 EQUAL 193 EQUAL Reactome Database ID Release 81 5666081 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666081 Reactome R-HSA-5666081 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666081.1 Reactome DB_ID: 5666074 1 RHOB:GTP:DIAPH1,DIAPH3 [endosome membrane] RHOB:GTP:DIAPH1,DIAPH3 Converted from EntitySet in Reactome Reactome DB_ID: 5666066 1 Reactome DB_ID: 5666081 1 Reactome Database ID Release 81 5666074 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666074 Reactome R-HSA-5666074 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666074.1 Reactome Database ID Release 81 5666070 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666070 Reactome R-HSA-5666070 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666070.1 17198702 Pubmed 2007 RhoB and the mammalian Diaphanous-related formin mDia2 in endosome trafficking Wallar, Bradley J Deward, Aaron D Resau, James H Alberts, Arthur S Exp. Cell Res. 313:560-71 15944396 Pubmed 2005 RhoB regulates endosome transport by promoting actin assembly on endosomal membranes through Dia1 Fernandez-Borja, M Janssen, Lennert Verwoerd, Desiree Hordijk, Peter Neefjes, Jacques J. Cell. Sci. 118:2661-70 RHOD:GTP recruits DAIPH2-3 to endosomes RHOD:GTP recruits DAIPH2-3 to endosomes Activated RHOD (RHOD:GTP) binds DIAPH2 transcription isoform DIAPH2-3 (DIAPH2C) and recruits it to endosomes. RHOD and DIAPH2 regulate endosome motility through SRC-dependent regulation of actin dynamics (Gasman et al. 2003). Authored: Orlic-Milacic, Marija, 2014-10-24 Authored: Rivero Crespo, Francisco, 2014-12-26 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 5666087 1 DIAPH2-3 [cytosol] DIAPH2-3 DIAPH2-3 dimer DIAPH2C DIAPH2C dimer Reactome DB_ID: 5666089 2 UniProt:O60879-3 DIAPH2 DIAPH2 DIAPH2 DIA FUNCTION Could be involved in oogenesis. Involved in the regulation of endosome dynamics. Implicated in a novel signal transduction pathway, in which isoform 3 and CSK are sequentially activated by RHOD to regulate the motility of early endosomes through interactions with the actin cytoskeleton.SUBUNIT Isoform 3 interacts with RHOD in the GTP-bound form.TISSUE SPECIFICITY Expressed in testis, ovary, small intestine, prostate, lung, liver, kidney and leukocytes.DEVELOPMENTAL STAGE Expressed from E16 in ovary and testis and during P6-P16 during differentiation of ovarian follicles.DOMAIN The DAD domain regulates activation via by an autoinhibitory interaction with the GBD/FH3 domain. This autoinhibition is released upon competitive binding of an activated GTPase. The release of DAD allows the FH2 domain to then nucleate and elongate nonbranched actin filaments (By similarity).SIMILARITY Belongs to the formin homology family. Diaphanous subfamily. UniProt O60879-3 1 EQUAL 1097 EQUAL Reactome Database ID Release 81 5666087 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666087 Reactome R-HSA-5666087 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666087.1 Reactome DB_ID: 5666092 1 RHOD:GTP [endosome membrane] RHOD:GTP Reactome DB_ID: 29438 1 Reactome DB_ID: 5666090 1 UniProt:O00212 RHOD RHOD ARHD RHOD FUNCTION Involved in endosome dynamics. May coordinate membrane transport with the function of the cytoskeleton. Involved in the internalization and trafficking of activated tyrosine kinase receptors such as PDGFRB. Participates in the reorganization of actin cytoskeleton; the function seems to involve WHAMM and includes regulation of filopodia formation and actin filament bundling. Can modulate the effect of DAPK3 in reorganization of actin cytoskeleton and focal adhesion dissolution.SUBUNIT Interacts (in GTP-bound form) with DIAPH2 isoform 3, DAPK3, FILIP1 and WHAMM. Interacts with PAK5. Interacts (independent of GTP-loaded status) with ANKFY1.TISSUE SPECIFICITY Heart, placenta, liver, skeletal muscle, and pancreas and, with weaker intensity, in several other tissues.SIMILARITY Belongs to the small GTPase superfamily. Rho family. UniProt O00212 1 EQUAL 207 EQUAL Reactome Database ID Release 81 5666092 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666092 Reactome R-HSA-5666092 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666092.1 Reactome DB_ID: 5666096 1 RHOD:GTP:DIAPH2-3 [endosome membrane] RHOD:GTP:DIAPH2-3 Reactome DB_ID: 5666087 1 Reactome DB_ID: 5666092 1 Reactome Database ID Release 81 5666096 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666096 Reactome R-HSA-5666096 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666096.1 Reactome Database ID Release 81 5666088 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666088 Reactome R-HSA-5666088 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666088.1 12577064 Pubmed 2003 RhoD regulates endosome dynamics through Diaphanous-related Formin and Src tyrosine kinase Gasman, Stéphane Kalaidzidis, Yannis Zerial, Marino Nat. Cell Biol. 5:195-204 RHOD:GTP:DIAPH2-3 recruits SRC-1 to endosomes RHOD:GTP:DIAPH2-3 recruits SRC-1 to endosomes RHOD:GTP:DIAPH2-3 complex recruits SRC to endosomes. SRC recruitment is necessary for RHOD:GTP:DIAPH2-3-mediated regulation of endosome-associated actin cytoskeleton and endosome motility (Gasman et al. 2003). SRC directly binds to DIAPH2 (Tominaga et al. 2000). Authored: Orlic-Milacic, Marija, 2014-10-24 Authored: Rivero Crespo, Francisco, 2014-12-26 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 5666096 1 Reactome DB_ID: 354153 1 UniProt:P12931-1 SRC SRC SRC SRC1 FUNCTION Non-receptor protein tyrosine kinase which is activated following engagement of many different classes of cellular receptors including immune response receptors, integrins and other adhesion receptors, receptor protein tyrosine kinases, G protein-coupled receptors as well as cytokine receptors. Participates in signaling pathways that control a diverse spectrum of biological activities including gene transcription, immune response, cell adhesion, cell cycle progression, apoptosis, migration, and transformation. Due to functional redundancy between members of the SRC kinase family, identification of the specific role of each SRC kinase is very difficult. SRC appears to be one of the primary kinases activated following engagement of receptors and plays a role in the activation of other protein tyrosine kinase (PTK) families. Receptor clustering or dimerization leads to recruitment of SRC to the receptor complexes where it phosphorylates the tyrosine residues within the receptor cytoplasmic domains. Plays an important role in the regulation of cytoskeletal organization through phosphorylation of specific substrates such as AFAP1. Phosphorylation of AFAP1 allows the SRC SH2 domain to bind AFAP1 and to localize to actin filaments. Cytoskeletal reorganization is also controlled through the phosphorylation of cortactin (CTTN) (Probable). When cells adhere via focal adhesions to the extracellular matrix, signals are transmitted by integrins into the cell resulting in tyrosine phosphorylation of a number of focal adhesion proteins, including PTK2/FAK1 and paxillin (PXN) (PubMed:21411625). In addition to phosphorylating focal adhesion proteins, SRC is also active at the sites of cell-cell contact adherens junctions and phosphorylates substrates such as beta-catenin (CTNNB1), delta-catenin (CTNND1), and plakoglobin (JUP). Another type of cell-cell junction, the gap junction, is also a target for SRC, which phosphorylates connexin-43 (GJA1). SRC is implicated in regulation of pre-mRNA-processing and phosphorylates RNA-binding proteins such as KHDRBS1 (Probable). Also plays a role in PDGF-mediated tyrosine phosphorylation of both STAT1 and STAT3, leading to increased DNA binding activity of these transcription factors (By similarity). Involved in the RAS pathway through phosphorylation of RASA1 and RASGRF1 (PubMed:11389730). Plays a role in EGF-mediated calcium-activated chloride channel activation (PubMed:18586953). Required for epidermal growth factor receptor (EGFR) internalization through phosphorylation of clathrin heavy chain (CLTC and CLTCL1) at 'Tyr-1477'. Involved in beta-arrestin (ARRB1 and ARRB2) desensitization through phosphorylation and activation of GRK2, leading to beta-arrestin phosphorylation and internalization. Has a critical role in the stimulation of the CDK20/MAPK3 mitogen-activated protein kinase cascade by epidermal growth factor (Probable). Might be involved not only in mediating the transduction of mitogenic signals at the level of the plasma membrane but also in controlling progression through the cell cycle via interaction with regulatory proteins in the nucleus (PubMed:7853507). Plays an important role in osteoclastic bone resorption in conjunction with PTK2B/PYK2. Both the formation of a SRC-PTK2B/PYK2 complex and SRC kinase activity are necessary for this function. Recruited to activated integrins by PTK2B/PYK2, thereby phosphorylating CBL, which in turn induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function (PubMed:8755529, PubMed:14585963). Promotes energy production in osteoclasts by activating mitochondrial cytochrome C oxidase (PubMed:12615910). Phosphorylates DDR2 on tyrosine residues, thereby promoting its subsequent autophosphorylation (PubMed:16186108). Phosphorylates RUNX3 and COX2 on tyrosine residues, TNK2 on 'Tyr-284' and CBL on 'Tyr-731' (PubMed:20100835, PubMed:21309750). Enhances DDX58/RIG-I-elicited antiviral signaling (PubMed:19419966). Phosphorylates PDPK1 at 'Tyr-9', 'Tyr-373' and 'Tyr-376' (PubMed:14585963). Phosphorylates BCAR1 at 'Tyr-128' (PubMed:22710723). Phosphorylates CBLC at multiple tyrosine residues, phosphorylation at 'Tyr-341' activates CBLC E3 activity (PubMed:20525694). Involved in anchorage-independent cell growth (PubMed:19307596). Required for podosome formation (By similarity). Mediates IL6 signaling by activating YAP1-NOTCH pathway to induce inflammation-induced epithelial regeneration (PubMed:25731159).ACTIVITY REGULATION Phosphorylation by CSK at Tyr-530 inhibits kinase activity. Inhibitory phosphorylation at Tyr-530 is enhanced by heme. Further phosphorylation by CDK1 partially reactivates CSK-inactivated SRC and facilitates complete reactivation by protein tyrosine phosphatase PTPRC. Integrin engagement stimulates kinase activity. Phosphorylation by PTK2/FAK1 enhances kinase activity. Butein and pseudosubstrate-based peptide inhibitors like CIYKYYF act as inhibitors. Phosphorylation at Tyr-419 increases kinase activity.SUBUNIT Part of a complex comprised of PTPRA, BCAR1, BCAR3 (via SH2 domain) and SRC; the formation of the complex is dependent on integrin mediated-tyrosine phosphorylation of PTPRA (PubMed:22801373). Interacts with DDEF1/ASAP1; via the SH3 domain (By similarity). Interacts with CCPG1 (By similarity). Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTTN (By similarity). Interacts with ERBB2, STAT1 and PNN (By similarity). Interacts with DDR1, DDR2 and DAB2 (By similarity). Interacts with CDCP1, TGFB1I1 and TOM1L2 (PubMed:15851033, PubMed:16479011, PubMed:17202804). Interacts with the cytoplasmic domain of MUC1, phosphorylates it and increases binding of MUC1 with beta-catenin (PubMed:11152665). Interacts with RALGPS1; via the SH3 domain (PubMed:10747847). Interacts with CAV2 (tyrosine phosphorylated form) (PubMed:12091389, PubMed:15504032). Interacts (via the SH3 domain and the protein kinase domain) with ARRB1; the interaction is independent of the phosphorylation state of SRC C-terminus (By similarity). Interacts with ARRB1 and ARRB2 (PubMed:10753943, PubMed:9924018). Interacts with SRCIN1 (PubMed:17525734). Interacts with NDFIP2 and more weakly with NDFIP1 (PubMed:20534535). Interacts with PIK3CA and/or PIK3C2B, PTK2/FAK1 and ESR1 (dimethylated on arginine) (PubMed:18657504, PubMed:21411625). Interacts with FASLG (PubMed:19807924). Interacts (via SH2 domain) with the 'Tyr-402' phosphorylated form of PTK2B/PYK2 (PubMed:14585963). Interacts (via SH2 domain) with FLT3 (tyrosine phosphorylated) (By similarity). Interacts with PDGFRA (tyrosine phosphorylated) (By similarity). Interacts with CSF1R (By similarity). Interacts (via SH2 and SH3 domain) with TNK2 (PubMed:21309750). Interacts (via protein kinase domain) with the tyrosine phosphorylated form of RUNX3 (via runt domain) (PubMed:20100835). Interacts with TRAF3 (via RING-type zinc finger domain) (PubMed:19419966). Interacts with DDX58, MAVS and TBK1 (PubMed:19419966). Interacts (via SH2 domain) with RACK1; the interaction is enhanced by tyrosine phosphorylation of RACK1 and inhibits SRC activity (PubMed:9584165, PubMed:11279199). Interacts with EPHB1; activates the MAPK/ERK cascade to regulate cell migration (PubMed:12925710). Interacts with FCAMR (PubMed:8759729). Interacts (via SH2 domain) with the 'Tyr-9' phosphorylated form of PDPK1 (PubMed:18024423). Interacts with AMOTL2; this interaction regulates the translocation of phosphorylated SRC to peripheral cell-matrix adhesion sites (PubMed:17293535). Interacts with TRAP1 (PubMed:23564345). Interacts with CBLC; the interaction is enhanced when SRC is phosphorylated at Tyr-419 (PubMed:14661060, PubMed:22888118). Interacts with ARHGEF5 (By similarity). Interacts (via cytoplasmic domain) with CEACAM1 (via SH2 domain); this interaction is regulated by trans-homophilic cell adhesion (PubMed:7478590). Interacts with MPP2 (PubMed:19665017). Interacts with PRR7 (PubMed:21460222). Interacts (via kinase domain and to a lesser extent the SH2 domain) directly with PDLIM4; this interaction results in PTPN13-mediated dephosphorylation of this protein leading to its inactivation (PubMed:19307596). Interacts with P85 (PIK3R1 or PIK3R2) (PubMed:28903391). Interacts with HNRNPA2B1 (PubMed:31320558). Interacts with IL6ST/gp130 (PubMed:25731159). Interacts (via SH3 domain) with PELP1 in the presence of 17-beta-estradiol. Interacts with AMBRA1 (By similarity).SUBUNIT (Microbial infection) Interacts with HEV ORF3 protein; via the SH3 domain.SUBUNIT (Microbial infection) Interacts (via SH2 domain) with HCV non-structural protein 5A (via N-terminus).TISSUE SPECIFICITY Expressed ubiquitously. Platelets, neurons and osteoclasts express 5-fold to 200-fold higher levels than most other tissues.DOMAIN The SH2 and SH3 domains are important for the intramolecular and intermolecular interactions that regulate catalytic activity, localization, and substrate recruitment.PTM Myristoylated at Gly-2, and this is essential for targeting to membranes.PTM Dephosphorylated at Tyr-530 by PTPRJ (By similarity). Phosphorylated on Tyr-530 by c-Src kinase (CSK). The phosphorylated form is termed pp60c-src. Dephosphorylated by PTPRJ at Tyr-419. Normally maintained in an inactive conformation with the SH2 domain engaged with Tyr-530, the SH3 domain engaged with the SH2-kinase linker, and Tyr-419 dephosphorylated. Dephosphorylation of Tyr-530 as a result of protein tyrosine phosphatase (PTP) action disrupts the intramolecular interaction between the SH2 domain and Tyr-530, Tyr-419 can then become autophosphorylated, resulting in SRC activation. Phosphorylation of Tyr-530 by CSK allows this interaction to reform, resulting in SRC inactivation. CDK5-mediated phosphorylation at Ser-75 targets SRC to ubiquitin-dependent degradation and thus leads to cytoskeletal reorganization. Phosphorylated by PTK2/FAK1; this enhances kinase activity. Phosphorylated by PTK2B/PYK2; this enhances kinase activity. Upon activation of IL6ST by IL6, Tyr-419 is phosphorylated and Tyr-530 dephosphorylated (PubMed:25731159).PTM S-nitrosylation is important for activation of its kinase activity.PTM Ubiquitinated in response to CDK5-mediated phosphorylation. Ubiquitination mediated by CBLC requires SRC autophosphorylation at Tyr-419 and may lead to lysosomal degradation.DISEASE SRC kinase activity has been shown to be increased in several tumor tissues and tumor cell lines such as colon carcinoma cells.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. SRC subfamily. UniProt P12931-1 2 EQUAL 536 EQUAL Reactome DB_ID: 5666105 1 RHOD:GTP:DIAPH2:SRC-1 [endosome membrane] RHOD:GTP:DIAPH2:SRC-1 Reactome DB_ID: 5666096 1 Reactome DB_ID: 354153 1 2 EQUAL 536 EQUAL Reactome Database ID Release 81 5666105 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666105 Reactome R-HSA-5666105 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666105.1 Reactome Database ID Release 81 5666104 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666104 Reactome R-HSA-5666104 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666104.1 10678165 Pubmed 2000 Diaphanous-related formins bridge Rho GTPase and Src tyrosine kinase signaling Tominaga, T Sahai, E Chardin, P McCormick, F Courtneidge, S A Alberts, A S Mol. Cell 5:13-25 CDC42:GTP recruits DIAPH2-2 to kinetochores CDC42:GTP recruits DIAPH2-2 to kinetochores Activated CDC42 (CDC42:GTP) can localize to kinetochores of metaphase cells and recruit DIAPH2 transcriptional isoform DIAPH2-2 (DIA-12C, mDia3) to kinetochores. The CDC42:GTP:DIAPH2-2 complex regulates the attachment of microtubules to kinetochores (Yasuda et al. 2004). Authored: Orlic-Milacic, Marija, 2014-10-24 Authored: Rivero Crespo, Francisco, 2014-12-26 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 375305 1 Kinetochore [cytosol] Kinetochore Reactome DB_ID: 375317 1 UniProt:P49450 CENPA CENPA CENPA FUNCTION Histone H3-like nucleosomal protein that is specifically found in centromeric nucleosomes (PubMed:7962047, PubMed:9024683, PubMed:11756469, PubMed:14667408, PubMed:15702419, PubMed:15475964, PubMed:15282608, PubMed:17651496, PubMed:19114591, PubMed:27499292, PubMed:20739937). Replaces conventional H3 in the nucleosome core of centromeric chromatin at the inner plate of the kinetochore (PubMed:18072184). The presence of CENPA subtly modifies the nucleosome structure and the way DNA is wrapped around the nucleosome and gives rise to protruding DNA ends that are less well-ordered and rigid compared to nucleosomes containing histone H3 (PubMed:27499292, PubMed:26878239). May serve as an epigenetic mark that propagates centromere identity through replication and cell division (PubMed:15475964, PubMed:15282608, PubMed:26878239, PubMed:20739937, PubMed:21478274). Required for recruitment and assembly of kinetochore proteins, and as a consequence required for progress through mitosis, chromosome segregation and cytokinesis (PubMed:11756469, PubMed:14667408, PubMed:18072184, PubMed:23818633, PubMed:25556658, PubMed:27499292).SUBUNIT Component of centromeric nucleosomes, where DNA is wrapped around a histone octamer core (PubMed:23818633, PubMed:26878239, PubMed:20739937, PubMed:21743476). The octamer contains two molecules each of H2A, H2B, CENPA and H4 assembled in one CENPA-H4 heterotetramer and two H2A-H2B heterodimers (PubMed:23818633, PubMed:26878239, PubMed:20739937, PubMed:21743476). CENPA modulates the DNA-binding characteristics of nucleosomes so that protruding DNA ends have higher flexibility than in nucleosomes containing conventional histone H3 (PubMed:27499292, PubMed:21743476). Inhibits binding of histone H1 to nucleosomes, since histone H1 binds preferentially to rigid DNA linkers that protrude from nucleosomes (PubMed:27499292). Nucleosomes containing CENPA also contain histone H2A variants such as MACROH2A and H2A.Z/H2AZ1 (Probable). The CENPA-H4 heterotetramer is more compact and structurally more rigid than corresponding H3-H4 heterotetramers (PubMed:15282608, PubMed:20739937). Can assemble into nucleosomes that contain both CENPA and histone H3.3; these nucleosomes interact with a single CENPC chain (PubMed:25408271). Heterotrimer composed of HJURP, CENPA and histone H4, where HJURP interacts with the dimer formed by CENPA and histone H4 and prevents tetramerization of CENPA and H4 (PubMed:21478274). Component of the CENPA-NAC complex, at least composed of CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU (PubMed:16622419). Interacts (via CATD domain) with HJURP; the interaction is direct and is required for its localization to centromeres (PubMed:15282608, PubMed:19410544, PubMed:19410545, PubMed:23818633, PubMed:25556658). Interacts with CENPC, CENPN and CENPT; interaction is direct. Part of a centromere complex consisting of CENPA, CENPT and CENPW (PubMed:19533040). Identified in centromere complexes containing histones H2A, H2B and H4, and at least CENPA, CENPB, CENPC, CENPT, CENPN, HJURP, SUPT16H, SSRP1 and RSF1 (PubMed:27499292). Can self-associate (PubMed:9024683). The CENPA-H4 heterotetramer can bind DNA by itself (in vitro) (PubMed:20739937). Interacts with CDK1, PPP1CA and RBBP7 (PubMed:25556658).SUBUNIT (Microbial infection) Interacts directly with herpes virus HHV-1 protein ICP0.DEVELOPMENTAL STAGE Expression varies across the cell cycle, with high levels in G2 phase (at the mRNA level).DOMAIN The CATD (CENPA targeting domain) region is responsible for the more compact structure of nucleosomes containing CENPA (PubMed:15282608). It is necessary and sufficient to mediate the localization into centromeres (PubMed:7962047, PubMed:15282608).PTM Ubiquitinated (Probable). Interaction with herpes virus HSV-1 ICP0 protein, leads to its degradation by the proteasome pathway.PTM Trimethylated by NTMT1 at the N-terminal glycine after cleavage of Met-1. Methylation is low before incorporation into nucleosomes and increases with cell cycle progression, with the highest levels in mitotic nucleosomes.PTM Phosphorylated by CDK1 at Ser-68 during early mitosis; this abolishes association with chromatin and centromeres, prevents interaction with HJURP and thereby prevents premature assembly of CENPA into centromeres (PubMed:25556658). Dephosphorylated at Ser-68 by PPP1CA during late mitosis (PubMed:25556658). Phosphorylation of Ser-7 by AURKA and AURKB during prophase is required for localization of AURKA and AURKB at inner centromere and is essential for normal cytokinesis (PubMed:11756469, PubMed:14667408, PubMed:18239465). Initial phosphorylation during prophase is mediated by AURKA and is maintained by AURKB.PTM Poly-ADP-ribosylated by PARP1.MISCELLANEOUS Antibodies against CENPA are present in sera from patients with autoimmune diseases that developed autoantibodies against centrosomal proteins.SIMILARITY Belongs to the histone H3 family. UniProt P49450 1 EQUAL 140 EQUAL Reactome DB_ID: 376244 1 UniProt:Q8WYP5 AHCTF1 AHCTF1 ELYS MSTP108 AHCTF1 TMBS62 FUNCTION Required for the assembly of a functional nuclear pore complex (NPC) on the surface of chromosomes as nuclei form at the end of mitosis. May initiate NPC assembly by binding to chromatin and recruiting the Nup107-160 subcomplex of the NPC. Also required for the localization of the Nup107-160 subcomplex of the NPC to the kinetochore during mitosis and for the completion of cytokinesis.SUBUNIT Associates with the Nup107-160 subcomplex of the NPC.DOMAIN The N-terminus forms a highly conserved seven-bladed beta propeller decorated with long loops and mediates anchorage to the Nup107-160 subcomplex of the nuclear pore, synergistically with the central alpha domain. The disordered C-terminus is responsible for the interactions with chromatin (By similarity).SIMILARITY Belongs to the ELYS family. UniProt Q8WYP5 1 EQUAL 2266 EQUAL Reactome DB_ID: 196206 1 PP2A [cytosol] PP2A Converted from EntitySet in Reactome Reactome DB_ID: 165990 1 PP2A-subunit A [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Converted from EntitySet in Reactome Reactome DB_ID: 165977 1 PP2A-catalytic subunit C [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Converted from EntitySet in Reactome Reactome DB_ID: 196216 1 PP2A regulatory subunit B56 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 81 196206 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=196206 Reactome R-HSA-196206 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-196206.1 Reactome DB_ID: 377732 1 UniProt:P30622 CLIP1 CLIP1 CYLN1 CLIP1 RSN FUNCTION Binds to the plus end of microtubules and regulates the dynamics of the microtubule cytoskeleton. Promotes microtubule growth and microtubule bundling. Links cytoplasmic vesicles to microtubules and thereby plays an important role in intracellular vesicle trafficking. Plays a role macropinocytosis and endosome trafficking.SUBUNIT Interacts with MTOR; phosphorylates and regulates CLIP1 (PubMed:12231510). Interacts (via CAP-Gly domains) with tubulin (PubMed:17563362, PubMed:17889670). Interacts with SLAIN2 (PubMed:21646404). Interacts (via zinc finger) with DCTN1 (PubMed:17828275, PubMed:20679239). Interacts with TUBA1B, MAPRE1 and MAPRE3 (PubMed:17563362). Binds preferentially to tyrosinated microtubules, and only marginally to detyrosinated microtubules (By similarity).TISSUE SPECIFICITY Detected in dendritic cells (at protein level). Highly expressed in the Reed-Sternberg cells of Hodgkin disease.DOMAIN Intramolecular interaction between the zinc finger domain and the CAP-Gly domains may inhibit interaction with tubulin.PTM Phosphorylated. Phosphorylation induces conformational changes by increasing the affinity of the N-terminus for C-terminus, resulting in inhibition of its function thus decreasing its binding to microtubules and DCTN1. Exhibits a folded, autoinhibited conformation when phosphorylated and an open conformation when dephosphorylated with increased binding affinity to microtubules and DCTN1. Phosphorylation regulates its recruitment to tyrosinated microtubules and the recruitment of vesicular cargo to microtubules in neurons (By similarity). Phosphorylation by MTOR may positively regulate CLIP1 association with microtubules (PubMed:12231510). UniProt P30622 1 EQUAL 1438 EQUAL Reactome DB_ID: 376255 1 UniProt:P46060 RANGAP1 RANGAP1 SD KIAA1835 RANGAP1 FUNCTION GTPase activator for RAN (PubMed:8146159, PubMed:8896452, PubMed:16428860). Converts cytoplasmic GTP-bound RAN to GDP-bound RAN, which is essential for RAN-mediated nuclear import and export (PubMed:8896452, PubMed:27160050). Mediates dissociation of cargo from nuclear export complexes containing XPO1, RAN and RANBP2 after nuclear export (PubMed:27160050).SUBUNIT Homodimer (PubMed:8146159). Interacts with RAN (PubMed:7891706, PubMed:8896452, PubMed:16428860). Forms a complex with RANBP2/NUP358, NXF1 and NXT1 (PubMed:14729961). Forms a tight complex in association with RANBP2/NUP358 and UBE2I/UBC9, the ubiquitin-conjugating enzyme E2 (PubMed:15037602, PubMed:27160050, PubMed:15931224, PubMed:22194619). Interacts with UBE2I; the interaction conjugates SUMO1 to RANGAP1, and subsequently stabilizes interactions of sumoylated RANGAP1 with RANBP2/NUP358 (PubMed:15037602, PubMed:27160050, PubMed:15931224). The complex composed of RANBP2, SUMO1, RANGAP1 and UBE2I associates with nuclear pore complexes (PubMed:15037602, PubMed:15931224). Identified in a complex composed of RAN, RANBP2, sumoylated RANGAP1, UBE2I and XPO1 (PubMed:27160050). Identified in a complex composed of RAN, RANGAP1 and RANBP1 (PubMed:16428860). Interacts with TRAF6 (PubMed:18093978). Interacts with SUMO1 and SENP1 (PubMed:17099698). Interacts (when sumoylated) with MYCBP2; interaction inhibits MYCBP2 E3 ubiquitin-protein ligase activity and promotes MYCBP2 translocation to the nucleus (PubMed:26304119).TISSUE SPECIFICITY Highly expressed in brain, thymus and testis.PTM Phosphorylation occurs before nuclear envelope breakdown and continues throughout mitosis. Phosphorylated by the M-phase kinase cyclin B/Cdk1, in vitro. Differential timimg of dephosphorylation occurs during phases of mitosis. The phosphorylated form remains associated with RANBP2/NUP358 and the SUMO E2-conjugating enzyme, UBE2I, on nuclear pore complex (NPC) diassembly and during mitosis.PTM Sumoylated (PubMed:11854305, PubMed:15037602, PubMed:26304119, PubMed:27160050). Sumoylation is necessary for targeting to the nuclear envelope (NE), and for association with mitotic spindles and kinetochores during mitosis (PubMed:11854305). Also required for interaction with RANBP2 and is mediated by UBE2I (PubMed:27160050). Desumoylated by HINT1 (By similarity).SIMILARITY Belongs to the RNA1 family. UniProt P46060 2 EQUAL 587 EQUAL Reactome DB_ID: 376242 1 UniProt:Q562F6 SGO2 SGO2 SGO2 SGOL2 FUNCTION Cooperates with PPP2CA to protect centromeric cohesin from separase-mediated cleavage in oocytes specifically during meiosis I. Has a crucial role in protecting REC8 at centromeres from cleavage by separase. During meiosis, protects centromeric cohesion complexes until metaphase II/anaphase II transition, preventing premature release of meiosis-specific REC8 cohesin complexes from anaphase I centromeres. Is thus essential for an accurate gametogenesis. May act by targeting PPP2CA to centromeres, thus leading to cohesin dephosphorylation (By similarity). Essential for recruiting KIF2C to the inner centromere and for correcting defective kinetochore attachments. Involved in centromeric enrichment of AUKRB in prometaphase.SUBUNIT Directly interacts with PPP2CA. Part of an astrin (SPAG5) -kinastrin (SKAP) complex containing KNSTRN, SPAG5, PLK1, DYNLL1 and SGO2. Interacts with CDCA8.MISCELLANEOUS Shugoshin is Japanese for guardian spirit (as it is known to be a protector of centromeric cohesin).SIMILARITY Belongs to the shugoshin family. UniProt Q562F6 1 EQUAL 1265 EQUAL Reactome DB_ID: 377879 1 Chromosome passenger complex [cytosol] Chromosome passenger complex Reactome DB_ID: 50851 1 UniProt:O15392 BIRC5 BIRC5 API4 BIRC5 IAP4 FUNCTION Multitasking protein that has dual roles in promoting cell proliferation and preventing apoptosis (PubMed:9859993, PubMed:21364656, PubMed:20627126, PubMed:25778398, PubMed:28218735). Component of a chromosome passage protein complex (CPC) which is essential for chromosome alignment and segregation during mitosis and cytokinesis (PubMed:16322459). Acts as an important regulator of the localization of this complex; directs CPC movement to different locations from the inner centromere during prometaphase to midbody during cytokinesis and participates in the organization of the center spindle by associating with polymerized microtubules (PubMed:20826784). Involved in the recruitment of CPC to centromeres during early mitosis via association with histone H3 phosphorylated at 'Thr-3' (H3pT3) during mitosis (PubMed:20929775). The complex with RAN plays a role in mitotic spindle formation by serving as a physical scaffold to help deliver the RAN effector molecule TPX2 to microtubules (PubMed:18591255). May counteract a default induction of apoptosis in G2/M phase (PubMed:9859993). The acetylated form represses STAT3 transactivation of target gene promoters (PubMed:20826784). May play a role in neoplasia (PubMed:10626797). Inhibitor of CASP3 and CASP7 (PubMed:21536684). Essential for the maintenance of mitochondrial integrity and function (PubMed:25778398). Isoform 2 and isoform 3 do not appear to play vital roles in mitosis (PubMed:12773388, PubMed:16291752). Isoform 3 shows a marked reduction in its anti-apoptotic effects when compared with the displayed wild-type isoform (PubMed:10626797).SUBUNIT Monomer or homodimer. Exists as a homodimer in the apo state and as a monomer in the CPC-bound state. The monomer protects cells against apoptosis more efficiently than the dimer. Only the dimeric form is capable of enhancing tubulin stability in cells. When phosphorylated, interacts with LAMTOR5/HBXIP; the resulting complex binds pro-CASP9, as well as active CASP9, but much less efficiently. Component of the chromosomal passenger complex (CPC) composed of at least BIRC5/survivin, CDCA8/borealin, INCENP, AURKB or AURKC; in the complex forms a triple-helix bundle-based subcomplex with INCENP and CDCA8 (PubMed:17956729). Interacts with JTB. Interacts (via BIR domain) with histone H3 phosphorylated at 'Thr-3' (H3pT3). Interacts with EVI5. Interacts with GTP-bound RAN in both the S and M phases of the cell cycle. Interacts with USP9X. Interacts with tubulin. Interacts with BIRC2/c-IAP1. The acetylated form at Lys-129 interacts with STAT3. The monomeric form deacetylated at Lys-129 interacts with XPO1/CRM1. The monomeric form interacts with XIAP/BIRC4. Both the dimeric and monomeric form can interact with DIABLO/SMAC. Interacts with BIRC6/bruce. Interacts with FBXL7; this interaction facilitates the polyubiquitination and subsequent proteasomal degradation of BIRC5 by the SCF(FBXL7) E3 ubiquitin-protein ligase complex (PubMed:25778398, PubMed:28218735).TISSUE SPECIFICITY Expressed only in fetal kidney and liver, and to lesser extent, lung and brain (PubMed:10626797). Abundantly expressed in adenocarcinoma (lung, pancreas, colon, breast, and prostate) and in high-grade lymphomas (PubMed:14741722, PubMed:16329164). Also expressed in various renal cell carcinoma cell lines (PubMed:10626797). Expressed in cochlea including the organ of Corti, the lateral wall, the interdental cells of the Limbus as well as in Schwann cells and cells of the cochlear nerve and the spiral ganglions (at protein level). Not expressed in cells of the inner and outer sulcus or the Reissner's membrane (at protein level) (PubMed:21364656, PubMed:20627126).DEVELOPMENTAL STAGE Expression is cell cycle-dependent and peaks at mitosis.INDUCTION Up-regulated by COMP.DOMAIN The BIR repeat is necessary and sufficient for LAMTOR5 binding.PTM Ubiquitinated by the Cul9-RING ubiquitin-protein ligase complex, leading to its degradation. Ubiquitination is required for centrosomal targeting.PTM In vitro phosphorylation at Thr-117 by AURKB prevents interaction with INCENP and localization to mitotic chromosomes (PubMed:14610074). Phosphorylation at Thr-48 by CK2 is critical for its mitotic and anti-apoptotic activities (PubMed:21252625). Phosphorylation at Thr-34 by CDK15 is critical for its anti-apoptotic activity (PubMed:24866247). Phosphorylation at Ser-20 by AURKC is critical for regulation of proper chromosome alignment and segregation, and possibly cytokinesis.PTM Acetylation at Lys-129 by CBP results in its homodimerization, while deacetylation promotes the formation of monomers which heterodimerize with XPO1/CRM1 which facilitates its nuclear export. The acetylated form represses STAT3 transactivation. The dynamic equilibrium between its acetylation and deacetylation at Lys-129 determines its interaction with XPO1/CRM1, its subsequent subcellular localization, and its ability to inhibit STAT3 transactivation.SIMILARITY Belongs to the IAP family. UniProt O15392 1 EQUAL 142 EQUAL Reactome DB_ID: 174231 1 UniProt:Q96GD4 AURKB AURKB AIK2 STK1 AIM1 STK12 ARK2 AIRK2 STK5 AURKB FUNCTION Serine/threonine-protein kinase component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis (PubMed:11516652, PubMed:12925766, PubMed:14610074, PubMed:14722118). The CPC complex has essential functions at the centromere in ensuring correct chromosome alignment and segregation and is required for chromatin-induced microtubule stabilization and spindle assembly (PubMed:11516652, PubMed:12925766, PubMed:14610074, PubMed:14722118, PubMed:26829474). Involved in the bipolar attachment of spindle microtubules to kinetochores and is a key regulator for the onset of cytokinesis during mitosis (PubMed:15249581). Required for central/midzone spindle assembly and cleavage furrow formation (PubMed:12458200, PubMed:12686604). Key component of the cytokinesis checkpoint, a process required to delay abscission to prevent both premature resolution of intercellular chromosome bridges and accumulation of DNA damage: phosphorylates CHMP4C, leading to retain abscission-competent VPS4 (VPS4A and/or VPS4B) at the midbody ring until abscission checkpoint signaling is terminated at late cytokinesis (PubMed:22422861, PubMed:24814515). AURKB phosphorylates the CPC complex subunits BIRC5/survivin, CDCA8/borealin and INCENP (PubMed:11516652, PubMed:12925766, PubMed:14610074). Phosphorylation of INCENP leads to increased AURKB activity (PubMed:11516652, PubMed:12925766, PubMed:14610074). Other known AURKB substrates involved in centromeric functions and mitosis are CENPA, DES/desmin, GPAF, KIF2C, NSUN2, RACGAP1, SEPTIN1, VIM/vimentin, HASPIN, and histone H3 (PubMed:11784863, PubMed:12689593, PubMed:14602875, PubMed:11856369, PubMed:16103226, PubMed:21658950, PubMed:11756469). A positive feedback loop involving HASPIN and AURKB contributes to localization of CPC to centromeres (PubMed:21658950). Phosphorylation of VIM controls vimentin filament segregation in cytokinetic process, whereas histone H3 is phosphorylated at 'Ser-10' and 'Ser-28' during mitosis (H3S10ph and H3S28ph, respectively) (PubMed:11784863, PubMed:11856369). A positive feedback between HASPIN and AURKB contributes to CPC localization (PubMed:21658950). AURKB is also required for kinetochore localization of BUB1 and SGO1 (PubMed:15020684, PubMed:17617734). Phosphorylation of p53/TP53 negatively regulates its transcriptional activity (PubMed:20959462). Key regulator of active promoters in resting B- and T-lymphocytes: acts by mediating phosphorylation of H3S28ph at active promoters in resting B-cells, inhibiting RNF2/RING1B-mediated ubiquitination of histone H2A and enhancing binding and activity of the USP16 deubiquitinase at transcribed genes (By similarity). Acts as an inhibitor of CGAS during mitosis: catalyzes phosphorylation of the N-terminus of CGAS during the G2-M transition, blocking CGAS liquid phase separation and activation, and thereby preventing CGAS-induced autoimmunity (PubMed:33542149).ACTIVITY REGULATION Activity is greatly increased when AURKB is within the CPC complex (PubMed:12925766, PubMed:14722118, PubMed:15249581). In particular, AURKB-phosphorylated INCENP acts as an activator of AURKB (PubMed:14722118, PubMed:15249581). Positive feedback between HASPIN and AURKB contributes to CPC localization (PubMed:14722118, PubMed:15249581).SUBUNIT Component of the chromosomal passenger complex (CPC) composed of at least BIRC5/survivin, CDCA8/borealin, INCENP, AURKB or AURKC; predominantly independent AURKB- and AURKC-containing complexes exist (PubMed:11516652, PubMed:12925766, PubMed:14722118, PubMed:15249581, PubMed:18591255, PubMed:27332895, PubMed:20562864). Associates with RACGAP1 during M phase (PubMed:12689593). Interacts with CDCA1, EVI5, JTB, NDC80, PSMA3, SEPTIN1, SIRT2 and TACC1 (PubMed:14602875, PubMed:14674694, PubMed:15064709, PubMed:16179162, PubMed:16764853, PubMed:17726514, PubMed:21225229). Interacts with SPDYC; this interaction may be required for proper localization of active, Thr-232-phosphorylated AURKB form during prometaphase and metaphase (PubMed:20605920). Interacts with p53/TP53 (PubMed:20959462). Interacts (via the middle kinase domain) with NOC2L (via the N- and C-terminus domains) (PubMed:20959462). Interacts with TTC28 (PubMed:23036704). Interacts with RNF2/RING1B (By similarity).TISSUE SPECIFICITY High level expression seen in the thymus. It is also expressed in the spleen, lung, testis, colon, placenta and fetal liver. Expressed during S and G2/M phase and expression is up-regulated in cancer cells during M phase.INDUCTION Expression is cell cycle-regulated, with a low in G1/S, an increase during G2 and M. Expression decreases again after M phase.PTM The phosphorylation of Thr-232 requires the binding to INCENP and occurs by means of an autophosphorylation mechanism (PubMed:14722118). Thr-232 phosphorylation is indispensable for the AURKB kinase activity (PubMed:14722118, PubMed:26829474).PTM Acetylated at Lys-215 by KAT5 at kinetochores, increasing AURKB activity and promoting accurate chromosome segregation in mitosis.PTM Ubiquitinated by different BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complexes (PubMed:17543862, PubMed:19995937). Ubiquitinated by the BCR(KLHL9-KLHL13) E3 ubiquitin ligase complex, ubiquitination leads to removal from mitotic chromosomes and is required for cytokinesis (PubMed:17543862). During anaphase, the BCR(KLHL21) E3 ubiquitin ligase complex recruits the CPC complex from chromosomes to the spindle midzone and mediates the ubiquitination of AURKB (PubMed:17543862). Ubiquitination of AURKB by BCR(KLHL21) E3 ubiquitin ligase complex may not lead to its degradation by the proteasome (PubMed:19995937).DISEASE Disruptive regulation of expression is a possible mechanism of the perturbation of chromosomal integrity in cancer cells through its dominant-negative effect on cytokinesis.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. Aurora subfamily. UniProt Q96GD4 1 EQUAL 344 EQUAL Reactome DB_ID: 375288 1 UniProt:Q53HL2 CDCA8 CDCA8 CDCA8 PESCRG3 FUNCTION Component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis. The CPC complex has essential functions at the centromere in ensuring correct chromosome alignment and segregation and is required for chromatin-induced microtubule stabilization and spindle assembly. Major effector of the TTK kinase in the control of attachment-error-correction and chromosome alignment.SUBUNIT May form homooligomers and homodimers. Component of the chromosomal passenger complex (CPC) composed of at least BIRC5/survivin, CDCA8/borealin, INCENP, AURKB or AURKC; in the complex forms a triple-helix bundle-based subcomplex with INCENP and BIRC5 (PubMed:17956729). Interacts with SENP3, UBE2I and RANBP2. Interacts (phosphorylated) with SGO1 and SGO2; the association is dependent on CDK1.DEVELOPMENTAL STAGE Cell-cycle regulated. Increases during G2/M phase and then reduces after exit from M phase.DOMAIN The C-terminal region (aa 207-280) represents the dimerization motif.PTM Phosphorylated by TTK, essentially at Thr-88, Thr94, Thr-169 and Thr-230. Phosphorylation (probably by CDK1) promotes targeting of the CPC to centromeric DNA.PTM Sumoylated by UBE2I and RANBP2. Desumoylated by SENP3 through the removal of SUMO2 and SUMO3.MISCELLANEOUS Cells lacking CDCA8 display a slight decrease in histone H3 'Ser-10' phosphorylation, suggesting that the CPC complex mediates phosphorylation of 'Ser-10' of histone H3.SIMILARITY Belongs to the borealin family. UniProt Q53HL2 1 EQUAL 280 EQUAL Reactome DB_ID: 375311 1 UniProt:Q9NQS7 INCENP INCENP INCENP FUNCTION Component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis. The CPC complex has essential functions at the centromere in ensuring correct chromosome alignment and segregation and is required for chromatin-induced microtubule stabilization and spindle assembly. Acts as a scaffold regulating CPC localization and activity. The C-terminus associates with AURKB or AURKC, the N-terminus associated with BIRC5/survivin and CDCA8/borealin tethers the CPC to the inner centromere, and the microtubule binding activity within the central SAH domain directs AURKB/C toward substrates near microtubules (PubMed:15316025, PubMed:12925766, PubMed:27332895). The flexibility of the SAH domain is proposed to allow AURKB/C to follow substrates on dynamic microtubules while ensuring CPC docking to static chromatin (By similarity). Activates AURKB and AURKC (PubMed:27332895). Required for localization of CBX5 to mitotic centromeres (PubMed:21346195). Controls the kinetochore localization of BUB1 (PubMed:16760428).SUBUNIT Component of the chromosomal passenger complex (CPC) composed of at least BIRC5/survivin, CDCA8/borealin, INCENP, AURKB or AURKC; in the complex binds directly to AURKB or AURKC via the IN box, and forms a triple-helix bundle-based subcomplex with BIRC5 and CDCA8 via its N-terminus (PubMed:17956729, PubMed:27332895). The reported homodimerization is questioned as the SAH domain is shown to be monomeric (By similarity). Interacts with H2AZ1 (By similarity). Interacts with CBX1 and CBX3. Interacts with tubulin beta chain. Interacts with EVI5. Interacts with CBX5; POGZ and INCENP compete for interaction with CBX5; regulates INCENP (and probably CPC) localization to centromeres in interphase and not required for proper mitotic progression or sister chromatid cohesion. Interacts with POGZ. Interacts with JTB.DOMAIN The IN box mediates interaction with AURKB and AURKC.DOMAIN The SAH (single alpha-helix) region is characterized by a high content of charged residues which are predicted to stabilize the alpha-helical structure by ionic bonds. It can refold after extension suggesting an in vivo force-dependent function. The isolated SAH domain is monomeric.PTM Phosphorylation by AURKB or AURKC at its C-terminal part is important for AURKB or AURKC activation by INCENP.SIMILARITY Belongs to the INCENP family.CAUTION PubMed:11139336 experiments have been carried out partly in chicken and partly in human.CAUTION Originally predicted to contain a coiled coil domain but shown to contain a stable SAH domain instead. UniProt Q9NQS7 1 EQUAL 918 EQUAL Reactome Database ID Release 81 377879 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=377879 Reactome R-HSA-377879 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-377879.1 Reactome DB_ID: 376240 1 UniProt:Q15691 MAPRE1 MAPRE1 MAPRE1 FUNCTION Plus-end tracking protein (+TIP) that binds to the plus-end of microtubules and regulates the dynamics of the microtubule cytoskeleton (PubMed:12388762, PubMed:16109370, PubMed:19632184, PubMed:21646404, PubMed:23001180, PubMed:28726242, PubMed:28814570, PubMed:34608293). Promotes cytoplasmic microtubule nucleation and elongation (PubMed:12388762, PubMed:16109370, PubMed:19632184, PubMed:21646404, PubMed:28726242, PubMed:28814570). Involved in mitotic spindle positioning by stabilizing microtubules and promoting dynamic connection between astral microtubules and the cortex during mitotic chromosome segregation (PubMed:12388762, PubMed:34608293). Also acts as a regulator of minus-end microtubule organization: interacts with the complex formed by AKAP9 and PDE4DIP, leading to recruit CAMSAP2 to the Golgi apparatus, thereby tethering non-centrosomal minus-end microtubules to the Golgi, an important step for polarized cell movement (PubMed:28814570). Promotes elongation of CAMSAP2-decorated microtubule stretches on the minus-end of microtubules (PubMed:28814570). Acts as a regulator of autophagosome transport via interaction with CAMSAP2 (PubMed:28726242). May play a role in cell migration (By similarity).SUBUNIT Homodimer (PubMed:15616574). Heterodimer with MAPRE3 (PubMed:19255245). Interacts with DCTN1, DCTN2, TERF1 and dynein intermediate chain (PubMed:10226031, PubMed:11943150, PubMed:12388762, PubMed:14514668, PubMed:23874158, PubMed:16109370, PubMed:16949363). Interaction with DIAPH1 and DIAPH2 (By similarity). Interacts with APC (via C-terminal domain), CLASP2, DST, KIF2C and STIM1; probably required for their targeting to the growing microtubule plus ends (PubMed:7606712, PubMed:12388762, PubMed:14514668, PubMed:15631994, PubMed:19543227, PubMed:15616574, PubMed:19632184). Interacts with MTUS2; interaction is direct and probably targets MTUS2 to microtubules (PubMed:19543227). Interacts with APC2 (PubMed:10644998). Interacts with CLASP1 (PubMed:15631994). Interacts with CDK5RAP2 (PubMed:19553473). Interacts with MACF1 (By similarity). Interacts with RABL2/RABL2A; binds preferentially to GTP-bound RABL2 (By similarity). Interacts with KCNAB2 (By similarity). Interacts (via C-terminus) with CLIP1 (PubMed:17563362, PubMed:21646404). Interacts with SLAIN2 and SLAIN1 (PubMed:21646404). Interacts with KIF18B; this interaction is required for efficient accumulation of KIF18B at microtubule plus ends (PubMed:21820309). Interacts with MISP (PubMed:23509069). Interacts with KNSTRN (PubMed:23035123). Interacts with NCKAP5L (PubMed:26485573). Interacts with CAMSAP2 (PubMed:28726242). Interacts with PDE4DIP isoform 13/MMG8/SMYLE; this interaction is required for its recruitment to the Golgi apparatus (PubMed:25217626, PubMed:28814570). Forms a pericentrosomal complex with AKAP9, CDK5RAP2 and PDE4DIP isoform 13/MMG8/SMYLE; within this complex, MAPRE1 binding to CDK5RAP2 may be mediated by PDE4DIP (PubMed:29162697). Interacts with AKNA (By similarity). Interacts with GAS2L1, GAS2L2, and GAS2L3 (PubMed:24706950). Interacts with RARRES1 and AGBL2 (PubMed:21303978).TISSUE SPECIFICITY Ubiquitously expressed.DOMAIN Composed of two functionally independent domains. The N-terminal domain forms a hydrophobic cleft involved in microtubule binding and the C-terminal is involved in the formation of mutually exclusive complexes with APC and DCTN1.PTM Acetylation at Lys-220 by KAT2B/PCAF promotes dynamic kinetochore-microtubule interactions in early mitosis.PTM Crotonylated by KAT5 during mitosis, promoting astral microtubule plasticity and dynamic connection between astral microtubules and the cortex during mitotic chromosome segregation, thereby ensuring accurate spindle positioning in mitosis (PubMed:34608293). Decrotonylated by HDAC3 (PubMed:34608293).SIMILARITY Belongs to the MAPRE family. UniProt Q15691 2 EQUAL 268 EQUAL Reactome DB_ID: 141433 1 UniProt:Q9Y6D9 MAD1L1 MAD1L1 MAD1 TXBP181 MAD1L1 FUNCTION Component of the spindle-assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at the metaphase plate (PubMed:10049595, PubMed:20133940, PubMed:29162720). Forms a heterotetrameric complex with the closed conformation form of MAD2L1 (C-MAD2) at unattached kinetochores during prometaphase, recruits an open conformation of MAD2L1 (O-MAD2) and promotes the conversion of O-MAD2 to C-MAD2, which ensures mitotic checkpoint signaling (PubMed:29162720).SUBUNIT Homodimer (PubMed:9546394, PubMed:29162720). Dimerizes via its N- and C- terminal regions (PubMed:29162720). Heterodimerizes with MAD2L1 in order to form a tetrameric MAD1L1-MAD2L1 core complex (PubMed:22351768, PubMed:9546394, PubMed:18981471, PubMed:12006501). Interacts with the closed conformation form of MAD2L1 (C-MAD2) and open conformation form of MAD2L1 (O-MAD2) (PubMed:29162720). It is unclear whether MAD1L1 dimerization promotes the conversion of closed to open conformation of MAD2L1 (PubMed:29162720). Formation of a heterotetrameric core complex containing two molecules each of MAD1L1 and of MAD2L1 promotes binding of another molecule of MAD2L1 to each MAD2L1, resulting in a heterohexamer (PubMed:12006501). Perturbation of the original MAD1L1-MAD2L1 structure by the spindle checkpoint may decrease MAD2L1 affinity for MAD1L1 (PubMed:12006501). CDC20 can compete with MAD1L1 for MAD2L1 binding, until the attachment and/or tension dampen the checkpoint signal, preventing further release of MAD2L1 on to CDC20 (PubMed:12006501). Also able to interact with the BUB1/BUB3 complex (PubMed:10198256). Interacts with NEK2 (PubMed:14978040). Interacts with TTK (PubMed:29162720). Interacts with TPR; the interactions occurs in a microtubule-independent manner (PubMed:18981471, PubMed:19273613, PubMed:20133940). Interacts with IK (PubMed:22351768). Interacts with the viral Tax protein (PubMed:9546394). Interacts with PRAP1 (PubMed:24374861).INDUCTION Increased by p53/TP53.PTM Phosphorylated; by BUB1 (PubMed:10198256). Become hyperphosphorylated in late S through M phases or after mitotic spindle damage (PubMed:9546394). Phosphorylated; by TTK (PubMed:29162720).DISEASE Defects in MAD1L1 are involved in the development and/or progression of various types of cancer.SIMILARITY Belongs to the MAD1 family. UniProt Q9Y6D9 1 EQUAL 718 EQUAL Reactome DB_ID: 376245 1 UniProt:Q02224 CENPE CENPE CENPE FUNCTION Microtubule plus-end-directed kinetochore motor which plays an important role in chromosome congression, microtubule-kinetochore conjugation and spindle assembly checkpoint activation. Drives chromosome congression (alignment of chromosomes at the spindle equator resulting in the formation of the metaphase plate) by mediating the lateral sliding of polar chromosomes along spindle microtubules towards the spindle equator and by aiding the establishment and maintenance of connections between kinetochores and spindle microtubules (PubMed:7889940, PubMed:23891108, PubMed:25395579). The transport of pole-proximal chromosomes towards the spindle equator is favored by microtubule tracks that are detyrosinated (PubMed:25908662). Acts as a processive bi-directional tracker of dynamic microtubule tips; after chromosomes have congressed, continues to play an active role at kinetochores, enhancing their links with dynamic microtubule ends (PubMed:23955301). Suppresses chromosome congression in NDC80-depleted cells and contributes positively to congression only when microtubules are stabilized (PubMed:25743205). Plays an important role in the formation of stable attachments between kinetochores and spindle microtubules (PubMed:17535814) The stabilization of kinetochore-microtubule attachment also requires CENPE-dependent localization of other proteins to the kinetochore including BUB1B, MAD1 and MAD2. Plays a role in spindle assembly checkpoint activation (SAC) via its interaction with BUB1B resulting in the activation of its kinase activity, which is important for activating SAC. Necessary for the mitotic checkpoint signal at individual kinetochores to prevent aneuploidy due to single chromosome loss (By similarity).SUBUNIT Monomer (PubMed:15236970). Interacts with CENPF (PubMed:9763420). Interacts with BUB1B (PubMed:9763420, PubMed:19625775). Interacts with SEPT7 (PubMed:18460473). Interacts with KIF18A (PubMed:19625775). Interacts with PRC1 (PubMed:15297875). Interacts with NUF2; this interaction determines kinetochore localization (PubMed:17535814). Interacts with SKAP; this interaction greatly favors SKAP binding to microtubules (PubMed:22110139). Interacts with TRAPPC12 (PubMed:25918224). Interacts with CTCF (PubMed:25395579).DOMAIN The protein is composed of a N-terminal kinesin-motor domain involved in the chromosome movements, a long coil-coiled region involved in the homodimerization and an inhibitory C-tail involved in autoinhibition of the N-terminal catalytic part.PTM The C-terminal inhibitory domain is phosphorylated. Phosphorylation relieves autoinhibition of the kinetochore motor (By similarity).PTM Sumoylated with SUMO2 and SUMO3. The sumoylation mediates the association to the kinetochore.SIMILARITY Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. UniProt Q02224 1 EQUAL 2698 EQUAL Reactome DB_ID: 376256 1 UniProt:Q99661 KIF2C KIF2C KIF2C KNSL6 FUNCTION In complex with KIF18B, constitutes the major microtubule plus-end depolymerizing activity in mitotic cells (PubMed:21820309). Regulates the turnover of microtubules at the kinetochore and functions in chromosome segregation during mitosis (PubMed:19060894). Plays a role in chromosome congression and is required for the lateral to end-on conversion of the chromosome-microtubule attachment (PubMed:23891108).SUBUNIT Interacts with CENPH. Interacts with MTUS2/TIP150; the interaction is direct. Interacts with MAPRE1; the interaction is direct, regulated by phosphorylation and is probably required for targeting to growing microtubule plus ends. Interacts with KIF18B at microtubule tips; this interaction increases the affinity of both partners for microtubule plus ends and is required for robust microtubule depolymerization. Phosphorylation by AURKA or AURKB strongly reduces KIF18B-binding.TISSUE SPECIFICITY Expressed at high levels in thymus and testis, at low levels in small intestine, the mucosal lining of colon, and placenta, and at very low levels in spleen and ovary; expression is not detected in prostate, peripheral blood Leukocytes, heart, brain, lung, liver, skeletal muscle, kidney or pancreas. Isoform 2 is testis-specific.DEVELOPMENTAL STAGE Isoform 2 is expressed in fetal testis.DOMAIN The microtubule tip localization signal (MtLS) motif; mediates interaction with MAPRE1 and targeting to the growing microtubule plus ends.PTM Phosphorylation by AURKB, regulates association with centromeres and kinetochores and the microtubule depolymerization activity.PTM Ubiquitinated.SIMILARITY Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. MCAK/KIF2 subfamily. UniProt Q99661 1 EQUAL 725 EQUAL Reactome DB_ID: 376227 1 UniProt:Q5FBB7 SGO1 SGO1 SGO1 SGOL1 FUNCTION Plays a central role in chromosome cohesion during mitosis by preventing premature dissociation of cohesin complex from centromeres after prophase, when most of cohesin complex dissociates from chromosomes arms. May act by preventing phosphorylation of the STAG2 subunit of cohesin complex at the centromere, ensuring cohesin persistence at centromere until cohesin cleavage by ESPL1/separase at anaphase. Essential for proper chromosome segregation during mitosis and this function requires interaction with PPP2R1A. Its phosphorylated form is necessary for chromosome congression and for the proper attachment of spindle microtubule to the kinetochore. Necessary for kinetochore localization of PLK1 and CENPF. May play a role in the tension sensing mechanism of the spindle-assembly checkpoint by regulating PLK1 kinetochore affinity. Isoform 3 plays a role in maintaining centriole cohesion involved in controlling spindle pole integrity. Involved in centromeric enrichment of AUKRB in prometaphase.SUBUNIT Interacts with PPP2CA (or PPP2CB), PPP2R1B, PPP2R5A, PPP2R5B, PPP2R5C, PPP2R5D, PPP2R5E, SET, LRRC59, RBM10 (or RBM5), RPL10A, RPL28, RPL7, RPL7A and RPLP1. Interaction with protein phosphatase 2A occurs most probably through direct binding to the regulatory B56 subunits: PPP2R1B, PPP2R5A, PPP2R5B, PPP2R5C, PPP2R5D, PPP2R5E. Interacts with PPP2R1A and NEK2. Isoform 3 interacts with PLK1. Interacts with CDCA8.TISSUE SPECIFICITY Widely expressed. Highly expressed in testis. Expressed in lung, small intestine, breast, liver and placenta. Strongly overexpressed in 90% of breast cancers tested.DEVELOPMENTAL STAGE Appears in prophase cells and remains present until metaphase. Strongly decreases at the onset of anaphase and completely disappears at telophase. Not present in interphase cells (at protein level).DOMAIN The KEN box and D-box 3 are required for its ubiquitination and degradation.PTM Ubiquitinated and degraded during mitotic exit by APC/C-Cdh1.PTM Phosphorylation by NEK2 is essential for chromosome congression in mitosis and for the proper attachment of spindle microtubule to the kinetochore. Phosphorylated by PLK1 and AUKRB.MISCELLANEOUS Shugoshin is Japanese for guardian spirit (as it is known to be a protector of centromeric cohesin).SIMILARITY Belongs to the shugoshin family. UniProt Q5FBB7 1 EQUAL 561 EQUAL Reactome DB_ID: 376231 1 UniProt:Q8WVK7 SKA2 SKA2 FAM33A SKA2 FUNCTION Component of the SKA1 complex, a microtubule-binding subcomplex of the outer kinetochore that is essential for proper chromosome segregation (PubMed:17093495, PubMed:19289083, PubMed:23085020). Required for timely anaphase onset during mitosis, when chromosomes undergo bipolar attachment on spindle microtubules leading to silencing of the spindle checkpoint (PubMed:17093495). The SKA1 complex is a direct component of the kinetochore-microtubule interface and directly associates with microtubules as oligomeric assemblies (PubMed:19289083). The complex facilitates the processive movement of microspheres along a microtubule in a depolymerization-coupled manner (PubMed:17093495, PubMed:19289083). In the complex, it is required for SKA1 localization (PubMed:19289083). Affinity for microtubules is synergistically enhanced in the presence of the ndc-80 complex and may allow the ndc-80 complex to track depolymerizing microtubules (PubMed:23085020).SUBUNIT Component of the SKA1 complex, composed of SKA1, SKA2 and SKA3. Forms a heterodimer with SKA1; the heterodimer interacting with SKA3. The core SKA1 complex is composed of 2 SKA1-SKA2 heterodimers, each heterodimer interacting with a molecule of the SKA3 homodimer. The core SKA1 complex associates with microtubules and forms oligomeric assemblies. Interacts directly with SKA1. Binds directly to microtubules; but with a much lower affinity than SKA1. May interact with NR3C1; the relevance of such interaction remains unclear in vivo.SIMILARITY Belongs to the SKA2 family. UniProt Q8WVK7 1 EQUAL 121 EQUAL Reactome DB_ID: 377736 1 UniProt:Q9BPU9 B9D2 B9D2 MKSR2 B9D2 FUNCTION Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes.SUBUNIT Part of the tectonic-like complex (also named B9 complex). Interacts with TUBG1 (By similarity).SIMILARITY Belongs to the B9D family. UniProt Q9BPU9 1 EQUAL 175 EQUAL Reactome DB_ID: 376249 1 UniProt:P43034 PAFAH1B1 PAFAH1B1 MDCR LIS1 MDS PAFAHA PAFAH1B1 FUNCTION Regulatory subunit (beta subunit) of the cytosolic type I platelet-activating factor (PAF) acetylhydrolase (PAF-AH (I)), an enzyme that catalyzes the hydrolyze of the acetyl group at the sn-2 position of PAF and its analogs and participates in PAF inactivation. Regulates the PAF-AH (I) activity in a catalytic dimer composition-dependent manner (By similarity). Required for proper activation of Rho GTPases and actin polymerization at the leading edge of locomoting cerebellar neurons and postmigratory hippocampal neurons in response to calcium influx triggered via NMDA receptors (By similarity). Positively regulates the activity of the minus-end directed microtubule motor protein dynein. May enhance dynein-mediated microtubule sliding by targeting dynein to the microtubule plus end. Required for several dynein- and microtubule-dependent processes such as the maintenance of Golgi integrity, the peripheral transport of microtubule fragments and the coupling of the nucleus and centrosome. Required during brain development for the proliferation of neuronal precursors and the migration of newly formed neurons from the ventricular/subventricular zone toward the cortical plate. Neuronal migration involves a process called nucleokinesis, whereby migrating cells extend an anterior process into which the nucleus subsequently translocates. During nucleokinesis dynein at the nuclear surface may translocate the nucleus towards the centrosome by exerting force on centrosomal microtubules. May also play a role in other forms of cell locomotion including the migration of fibroblasts during wound healing. Required for dynein recruitment to microtubule plus ends and BICD2-bound cargos (PubMed:22956769). May modulate the Reelin pathway through interaction of the PAF-AH (I) catalytic dimer with VLDLR (By similarity).SUBUNIT Component of the cytosolic PAF-AH (I) heterotetrameric enzyme, which is composed of PAFAH1B1 (beta), PAFAH1B2 (alpha2) and PAFAH1B3 (alpha1) subunits. The catalytic activity of the enzyme resides in the alpha1 (PAFAH1B3) and alpha2 (PAFAH1B2) subunits, whereas the beta subunit (PAFAH1B1) has regulatory activity. Trimer formation is not essential for the catalytic activity. Interacts with the catalytic dimer of PAF-AH (I) heterotetrameric enzyme: interacts with PAFAH1B2 homodimer (alpha2/alpha2 homodimer), PAFAH1B3 homodimer (alpha1/alpha1 homodimer) and PAFAH1B2-PAFAH1B3 heterodimer (alpha2/alpha1 heterodimer) (By similarity). Interacts with IQGAP1, KATNB1 and NUDC. Interacts with DAB1 when DAB1 is phosphorylated in response to RELN/reelin signaling (By similarity). Can self-associate. Interacts with DCX, dynein, dynactin, NDE1, NDEL1 and RSN. Interacts with DISC1, and this interaction is enhanced by NDEL1. Interacts with INTS13. Interacts with DCDC1 (PubMed:22159412).TISSUE SPECIFICITY Fairly ubiquitous expression in both the frontal and occipital areas of the brain.DOMAIN Dimerization mediated by the LisH domain may be required to activate dynein.MISCELLANEOUS Originally the subunits of the type I platelet-activating factor (PAF) acetylhydrolase was named alpha (PAFAH1B1), beta (PAFAH1B2) and gamma (PAFAH1B3) (By similarity) (Ref.4). Now these subunits have been renamed beta (PAFAH1B1), alpha2 (PAFAH1B2) and alpha1 (PAFAH1B3) respectively (By similarity).SIMILARITY Belongs to the WD repeat LIS1/nudF family. UniProt P43034 1 EQUAL 410 EQUAL Reactome DB_ID: 376250 1 UniProt:Q2NKX8 ERCC6L ERCC6L ERCC6L PICH FUNCTION DNA helicase that acts as a tension sensor that associates with catenated DNA which is stretched under tension until it is resolved during anaphase (PubMed:17218258, PubMed:23973328). Functions as ATP-dependent DNA translocase (PubMed:23973328, PubMed:28977671). Can promote Holliday junction branch migration (in vitro) (PubMed:23973328).SUBUNIT Interacts with PLK1, which phosphorylates it (PubMed:17218258, PubMed:17671160, PubMed:28977671). Both proteins are mutually dependent on each other for correct subcellular localization (PubMed:17218258, PubMed:17671160). Interacts (via N-terminal TPR repeat) with BEND3 (via BEN domains 1 and 3); the interaction is direct (PubMed:28977671).PTM Phosphorylation by PLK1 prevents the association with chromosome arms and restricts its localization to the kinetochore-centromere region.SIMILARITY Belongs to the SNF2/RAD54 helicase family.CAUTION Was initially thought to play a role in the spindle checkpoint. However, it was later shown that phenotypes initially observed are due to off-target effects of the siRNA used which results in MAD2L1 down-regulation and mis-localization. UniProt Q2NKX8 1 EQUAL 1250 EQUAL Reactome DB_ID: 141412 1 UniProt:Q12834 CDC20 CDC20 CDC20 FUNCTION Required for full ubiquitin ligase activity of the anaphase promoting complex/cyclosome (APC/C) and may confer substrate specificity upon the complex. Is regulated by MAD2L1: in metaphase the MAD2L1-CDC20-APC/C ternary complex is inactive and in anaphase the CDC20-APC/C binary complex is active in degrading substrates. The CDC20-APC/C complex positively regulates the formation of synaptic vesicle clustering at active zone to the presynaptic membrane in postmitotic neurons. CDC20-APC/C-induced degradation of NEUROD2 induces presynaptic differentiation.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Component of a complex with CDC20, CDC27, SPATC1 and TUBG1 (By similarity). Interacts with NEUROD2 (By similarity). Interacts with dimeric MAD2L1 in its closed conformation form (PubMed:9811605, PubMed:9637688, PubMed:15525512, PubMed:19098431, PubMed:29162720). Interacts with BUB1B (PubMed:15525512, PubMed:18997788, PubMed:19098431). The phosphorylated form interacts with APC/C (PubMed:9811605, PubMed:9734353, PubMed:9637688). Interacts with NINL (PubMed:17403670). May interact with MAD2L2 (PubMed:11459826). Interacts with CDK5RAP2 (PubMed:19282672). Interacts with SIRT2 (PubMed:22014574). Interacts with isoform 1 of NEK2 (PubMed:20034488). Interacts with HSF1 (via phosphorylated form); this interaction occurs in mitosis in a MAD2L1-dependent manner and prevents PLK1-stimulated degradation of HSF1 by blocking the recruitment of the SCF(BTRC) ubiquitin ligase complex (PubMed:18794143). Interacts (via the N-terminal substrate-binding domain) with FBXO5 (By similarity). Interacts with CCNF (PubMed:27653696).DEVELOPMENTAL STAGE Synthesis is initiated at G1/S, protein level peaks in M phase and protein is abruptly degraded at M/G1 transition.PTM Acetylated. Deacetylated at Lys-66 by SIRT2; deacetylation enhances the interaction of CDC20 with CDC27, leading to activation of anaphase promoting complex/cyclosome (APC/C).PTM Phosphorylated during mitosis, probably by maturation promoting factor (MPF). Phosphorylated by BUB1 at Ser-41; Ser-72; Ser-92; Ser-153; Thr-157 and Ser-161. Phosphorylated by NEK2.PTM Dephosphorylated by CTDP1.PTM Ubiquitinated and degraded by the proteasome during spindle assembly checkpoint. Deubiquitinated by USP44, leading to stabilize the MAD2L1-CDC20-APC/C ternary complex, thereby preventing premature activation of the APC/C. Ubiquitinated at Lys-490 during prometaphase. Ubiquitination at Lys-485 and Lys-490 has no effect on its ability to bind the APC/C complex.SIMILARITY Belongs to the WD repeat CDC20/Fizzy family. UniProt Q12834 1 EQUAL 499 EQUAL Reactome DB_ID: 376254 1 UniProt:O95229 ZWINT ZWINT ZWINT FUNCTION Part of the MIS12 complex, which is required for kinetochore formation and spindle checkpoint activity. Required to target ZW10 to the kinetochore at prometaphase.SUBUNIT Interacts with ZW10 and MIS12. Interacts with the NDC80 subunit of the NDC80 complex specifically during mitosis. Also interacts with KNL1, CETN3, DSN1 and PMF1. UniProt O95229 1 EQUAL 277 EQUAL Reactome DB_ID: 157703 1 UniProt:P49792 RANBP2 RANBP2 RANBP2 NUP358 FUNCTION E3 SUMO-protein ligase which facilitates SUMO1 and SUMO2 conjugation by UBE2I (PubMed:11792325, PubMed:12032081, PubMed:15378033, PubMed:22194619, PubMed:15931224). Involved in transport factor (Ran-GTP, karyopherin)-mediated protein import via the F-G repeat-containing domain which acts as a docking site for substrates (PubMed:7775481). Binds single-stranded RNA (in vitro) (PubMed:7775481). May bind DNA (PubMed:7775481). Component of the nuclear export pathway (PubMed:10078529). Specific docking site for the nuclear export factor exportin-1 (PubMed:10078529). Sumoylates PML at 'Lys-490' which is essential for the proper assembly of PML-NB (PubMed:22155184). Recruits BICD2 to the nuclear envelope and cytoplasmic stacks of nuclear pore complex known as annulate lamellae during G2 phase of cell cycle (PubMed:20386726). Probable inactive PPIase with no peptidyl-prolyl cis-trans isomerase activity (PubMed:20676357, PubMed:23353830).PATHWAY Protein modification; protein sumoylation.SUBUNIT Part of the nuclear pore complex (PubMed:11839768, PubMed:20386726, PubMed:23353830, PubMed:7603572). Forms a complex with NXT1, NXF1 and RANGAP1 (PubMed:14729961). Forms a tight complex with RANBP1 and UBE2I (PubMed:15388847, PubMed:10078529, PubMed:15826666). Interacts with SUMO1 but not SUMO2 (PubMed:15388847, PubMed:10078529, PubMed:15826666). Interacts with PRKN (PubMed:16332688). Interacts with sumoylated RANGAP1 (PubMed:15378033, PubMed:10078529, PubMed:15826666). Interacts with CDCA8 (PubMed:19413330). Interacts with PML (isoform PML-4) (PubMed:22155184). Interacts with BICD2 (PubMed:20386726). Interacts with MCM3AP isoform GANP (PubMed:20005110). Interacts with COX11 (PubMed:34400285).DOMAIN Contains FG repeats. FG repeats are interaction sites for karyopherins (importins, exportins) and form probably an affinity gradient, guiding the transport proteins unidirectionally with their cargo through the NPC. FG repeat regions are highly flexible and lack ordered secondary structure. The overall conservation of FG repeats regarding exact sequence, spacing, and repeat unit length is limited.DOMAIN The PPIase cyclophilin-type domain has high structural similarity with PPIA, but has extremely low and barely detectable proline isomerase activity (in vitro) (PubMed:23353830). Only about half of the residues that surround the PPIA active site cleft are conserved.PTM Polyubiquitinated by PRKN, which leads to proteasomal degradation.PTM The inner channel of the NPC has a different redox environment from the cytoplasm and allows the formation of interchain disulfide bonds between some nucleoporins, the significant increase of these linkages upon oxidative stress reduces the permeability of the NPC.DISEASE A chromosomal aberration involving RANBP2 is a cause of chromosome 8p11 myeloproliferative syndrome. Translocation t(2;8)(q12;p11) with FGFR1. Chromosome 8p11 myeloproliferative syndrome is characterized by myeloid hyperplasia, eosinophilia and T-cell or B-cell lymphoblastic lymphoma. In general it progresses to acute myeloid leukemia.SIMILARITY Belongs to the RanBP2 E3 ligase family.CAUTION Despite the presence of a PPIase cyclophilin-type domain, it has probably no peptidyl-prolyl cis-trans isomerase activity. UniProt P49792 1 EQUAL 3224 EQUAL Reactome DB_ID: 377882 1 Mitotic checkpoint complex [cytosol] Mitotic checkpoint complex Reactome DB_ID: 141400 1 UniProt:Q13257 MAD2L1 MAD2L1 MAD2 MAD2L1 FUNCTION Component of the spindle-assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at the metaphase plate (PubMed:29162720, PubMed:15024386). In the closed conformation (C-MAD2) forms a heterotetrameric complex with MAD1L1 at unattached kinetochores during prometaphase, the complex recruits open conformation molecules of MAD2L1 (O-MAD2) and then promotes the conversion of O-MAD2 to C-MAD2 (PubMed:29162720). Required for the execution of the mitotic checkpoint which monitors the process of kinetochore-spindle attachment and inhibits the activity of the anaphase promoting complex by sequestering CDC20 until all chromosomes are aligned at the metaphase plate (PubMed:10700282, PubMed:11804586, PubMed:15024386).SUBUNIT Monomer and homodimer (PubMed:18022367, PubMed:18318601). Heterodimerizes with MAD2L1 in order to form a tetrameric MAD1L1-MAD2L1 core complex (PubMed:12574116, PubMed:18981471, PubMed:12006501, PubMed:15024386). In the closed and open conformation, interacts with MAD1L1 (PubMed:29162720). Formation of a heterotetrameric core complex containing two molecules each of MAD1L1 and of MAD2L1 promotes binding of another molecule of MAD2L1 to each MAD2L1, resulting in a heterohexamer (PubMed:12006501). Interacts with MAD2L1BP (PubMed:12456649, PubMed:18022368). Interacts with ADAM17/TACE (PubMed:10527948). Interacts with CDC20 (PubMed:9637688, PubMed:12574116, PubMed:18981471, PubMed:10700282). Dimeric MAD2L1 in the closed conformation interacts with CDC20 (PubMed:29162720). Monomeric MAD2L1 in the open conformation does not interact with CDC20 (PubMed:11804586). CDC20 competes with MAD1L1 for MAD2L1 binding (PubMed:11804586). In the closed conformation, interacts with BUB1B (PubMed:29162720). Interacts with TTK (PubMed:29162720). Interacts with TPR (PubMed:18981471). Binds to UBD (via ubiquitin-like 1 domain) during mitosis (PubMed:16495226, PubMed:25422469). Interacts with isoform 1 and isoform 2 of NEK2 (PubMed:20034488). Interacts with HSF1; this interaction occurs in mitosis (PubMed:18794143). Interacts with isoform 3 of MAD1L1; this interaction leads to the cytoplasmic sequestration of MAD2L1 (PubMed:19010891).DOMAIN The protein has two highly different native conformations, an inactive open conformation that cannot bind CDC20 and that predominates in cytosolic monomers, and an active closed conformation. The protein in the closed conformation preferentially dimerizes with another molecule in the open conformation, but can also form a dimer with a molecule in the closed conformation. Formation of a heterotetrameric core complex containing two molecules of MAD1L1 and of MAD2L1 in the closed conformation promotes binding of another molecule of MAD2L1 in the open conformation and the conversion of the open to the closed form, and thereby promotes interaction with CDC20.PTM Phosphorylated on multiple serine residues. The level of phosphorylation varies during the cell cycle and is highest during mitosis. Phosphorylation abolishes interaction with MAD1L1 and reduces interaction with CDC20. Phosphorylated by NEK2.SIMILARITY Belongs to the MAD2 family. UniProt Q13257 2 EQUAL 205 EQUAL Reactome DB_ID: 141436 1 UniProt:O60566 BUB1B BUB1B SSK1 MAD3L BUBR1 BUB1B FUNCTION Essential component of the mitotic checkpoint. Required for normal mitosis progression. The mitotic checkpoint delays anaphase until all chromosomes are properly attached to the mitotic spindle. One of its checkpoint functions is to inhibit the activity of the anaphase-promoting complex/cyclosome (APC/C) by blocking the binding of CDC20 to APC/C, independently of its kinase activity. The other is to monitor kinetochore activities that depend on the kinetochore motor CENPE. Required for kinetochore localization of CENPE. Negatively regulates PLK1 activity in interphase cells and suppresses centrosome amplification. Also implicated in triggering apoptosis in polyploid cells that exit aberrantly from mitotic arrest. May play a role for tumor suppression.ACTIVITY REGULATION Kinase activity stimulated by CENPE.SUBUNIT Interacts with CENPE (PubMed:12925705, PubMed:19625775). Interacts with PLK1 (PubMed:16760428, PubMed:17785528, PubMed:17376779, PubMed:19503101). Part of a complex containing BUB3, CDC20 and BUB1B (PubMed:11702782). Interacts with anaphase-promoting complex/cyclosome (APC/C) (PubMed:10477750). Interacts with KNL1 (PubMed:17981135). Interacts with KAT2B (PubMed:19407811). Interacts with RIPK3 (PubMed:29883609). Interacts with the closed conformation form of MAD2L1 (PubMed:29162720).TISSUE SPECIFICITY Highly expressed in thymus followed by spleen. Preferentially expressed in tissues with a high mitotic index.INDUCTION Induced during mitosis.DOMAIN The D-box targets the protein for rapid degradation by ubiquitin-dependent proteolysis during the transition from mitosis to interphase.DOMAIN The BUB1 N-terminal domain directs kinetochore localization and binding to BUB3.PTM Proteolytically cleaved by caspase-3 in a cell cycle specific manner. The cleavage might be involved in the durability of the cell cycle delay. Caspase-3 cleavage is associated with abrogation of the mitotic checkpoint. The major site of cleavage is at Asp-610.PTM Acetylation at Lys-250 regulates its degradation and timing in anaphase entry.PTM Ubiquitinated. Degraded by the proteasome.PTM Sumoylated with SUMO2 and SUMO3. The sumoylation mediates the association with CENPE at the kinetochore.PTM Autophosphorylated in vitro. Intramolecular autophosphorylation is stimulated by CENPE. Phosphorylated during mitosis and hyperphosphorylated in mitotically arrested cells. Phosphorylation at Ser-670 and Ser-1043 occurs at kinetochores upon mitotic entry with dephosphorylation at the onset of anaphase.DISEASE Defects in BUB1B are associated with tumor formation.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. BUB1 subfamily. UniProt O60566 1 EQUAL 1050 EQUAL Reactome DB_ID: 141412 1 1 EQUAL 499 EQUAL Reactome DB_ID: 141416 1 UniProt:O43684 BUB3 BUB3 BUB3 FUNCTION Has a dual function in spindle-assembly checkpoint signaling and in promoting the establishment of correct kinetochore-microtubule (K-MT) attachments. Promotes the formation of stable end-on bipolar attachments. Necessary for kinetochore localization of BUB1. Regulates chromosome segregation during oocyte meiosis. The BUB1/BUB3 complex plays a role in the inhibition of anaphase-promoting complex or cyclosome (APC/C) when spindle-assembly checkpoint is activated and inhibits the ubiquitin ligase activity of APC/C by phosphorylating its activator CDC20. This complex can also phosphorylate MAD1L1.SUBUNIT Interacts with BUB1 and BUBR1. The BUB1/BUB3 complex interacts with MAD1L1. Interacts with ZNF207/BuGZ; leading to promote stability and kinetochore loading of BUB3.PTM Poly-ADP-ribosylated by PARP1.SIMILARITY Belongs to the WD repeat BUB3 family. UniProt O43684 1 EQUAL 328 EQUAL Reactome Database ID Release 81 377882 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=377882 Reactome R-HSA-377882 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-377882.1 Reactome DB_ID: 375311 1 1 EQUAL 918 EQUAL Reactome DB_ID: 72361 1 UniProt:P42677 RPS27 RPS27 RPS27 MPS1 FUNCTION Component of the small ribosomal subunit (PubMed:8706699). Required for proper rRNA processing and maturation of 18S rRNAs (PubMed:25424902).SUBUNIT Component of the small ribosomal subunit.TISSUE SPECIFICITY Expressed in a wide variety of actively proliferating cells and tumor tissues.SIMILARITY Belongs to the eukaryotic ribosomal protein eS27 family.CAUTION Was originally (PubMed:8407955) thought to be a protein that could have played a role as a potentially important mediator of cellular proliferative responses to various growth factors and other environmental signals. Capable of specific binding to a cAMP response element in DNA. UniProt P42677 2 EQUAL 84 EQUAL Reactome DB_ID: 165539 1 UniProt:O14980 XPO1 XPO1 XPO1 CRM1 FUNCTION Mediates the nuclear export of cellular proteins (cargos) bearing a leucine-rich nuclear export signal (NES) and of RNAs. In the nucleus, in association with RANBP3, binds cooperatively to the NES on its target protein and to the GTPase RAN in its active GTP-bound form (Ran-GTP). Docking of this complex to the nuclear pore complex (NPC) is mediated through binding to nucleoporins. Upon transit of a nuclear export complex into the cytoplasm, disassembling of the complex and hydrolysis of Ran-GTP to Ran-GDP (induced by RANBP1 and RANGAP1, respectively) cause release of the cargo from the export receptor. The directionality of nuclear export is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. Involved in U3 snoRNA transport from Cajal bodies to nucleoli. Binds to late precursor U3 snoRNA bearing a TMG cap.FUNCTION (Microbial infection) Mediates the export of unspliced or incompletely spliced RNAs out of the nucleus from different viruses including HIV-1, HTLV-1 and influenza A. Interacts with, and mediates the nuclear export of HIV-1 Rev and HTLV-1 Rex proteins. Involved in HTLV-1 Rex multimerization.SUBUNIT Found in a U snRNA export complex with PHAX/RNUXA, NCBP1/CBP80, NCBP2/CBP20, RAN, XPO1 and m7G-capped RNA (By similarity). Component of a nuclear export receptor complex composed of KPNB1, RAN, SNUPN and XPO1. Found in a trimeric export complex with SNUPN, RAN and XPO1. Found in a nuclear export complex with RANBP3 and RAN. Found in a 60S ribosomal subunit export complex with NMD3, RAN, XPO1. Interacts with DDX3X, NMD3, NUP42, NUP88, NUP214, RANBP3 and TERT. Interacts with NEMF (via its N-terminus). Interacts with the monomeric form of BIRC5/survivin deacetylated at 'Lys-129'. Interacts with DTNBP1 and SERTAD2; the interactions translocate DTNBP1 and SERTAD2 out of the nucleus. Interacts with ATF2. Interacts with SLC35G1 and STIM1. Interacts with DCAF8. Interacts with CPEB3 (PubMed:22730302). Interacts with HAX1 (PubMed:23164465). Interacts with BOK; translocates to the cytoplasm (PubMed:16302269). Interacts with HSP90AB1 (PubMed:22022502).SUBUNIT (Microbial infection) Interacts with HIV-1 Rev.SUBUNIT (Microbial infection) Interacts with HTLV-1 Rex.SUBUNIT (Microbial infection) Interacts with influenza A nucleoprotein.SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus protein BMLF1.SUBUNIT (Microbial infection) Part of a tetrameric complex composed of CRM1, importin alpha/beta dimer and the Venezuelan equine encephalitis virus (VEEV) capsid; this complex blocks the receptor-mediated transport through the nuclear pore.SUBUNIT (Microbial infection) Interacts with SARS-CoV virus protein ORF9b; this interaction mediates protein ORF9b export out of the nucleus.TISSUE SPECIFICITY Expressed in heart, brain, placenta, lung, liver, skeletal muscle, pancreas, spleen, thymus, prostate, testis, ovary, small intestine, colon and peripheral blood leukocytes. Not expressed in the kidney.MISCELLANEOUS Cellular target of leptomycin B (LMB), a XPO1/CRM1 nuclear export inhibitor.SIMILARITY Belongs to the exportin family. UniProt O14980 1 EQUAL 1071 EQUAL Reactome DB_ID: 377738 1 CCAN network [cytosol] CCAN network Reactome DB_ID: 377886 1 CENP-O complex [cytosol] CENP-O complex Reactome DB_ID: 375315 1 UniProt:Q71F23 CENPU CENPU CENPU MLF1IP ICEN24 KLIP1 PBIP1 FUNCTION Component of the CENPA-NAC (nucleosome-associated) complex, a complex that plays a central role in assembly of kinetochore proteins, mitotic progression and chromosome segregation. The CENPA-NAC complex recruits the CENPA-CAD (nucleosome distal) complex and may be involved in incorporation of newly synthesized CENPA into centromeres. Plays an important role in the correct PLK1 localization to the mitotic kinetochores. A scaffold protein responsible for the initial recruitment and maintenance of the kinetochore PLK1 population until its degradation. Involved in transcriptional repression.SUBUNIT Component of the CENPA-NAC complex, at least composed of CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU. The CENPA-NAC complex interacts with the CENPA-CAD complex, composed of CENPI, CENPK, CENPL, CENPO, CENPP, CENPQ, CENPR and CENPS. Interacts with MLF1. Interacts with PLK1.SUBUNIT (Microbial infection) Interacts with the N-terminal domain of Kaposi's sarcoma-associated herpesvirus latent nuclear antigen (LNA).TISSUE SPECIFICITY Expressed at high levels in the testis, fetal liver, thymus, bone marrow and at lower levels in the lymph nodes, placenta, colon and spleen. Present in all cell lines examined, including B-cells, T-cells, epithelial cells and fibroblast cells. Expressed at high levels in glioblastoma cell lines.PTM Phosphorylated by PLK1 at Thr-78, creating a self-tethering site that specifically interacts with the polo-box domain of PLK1.SIMILARITY Belongs to the CENP-U/AME1 family. UniProt Q71F23 1 EQUAL 418 EQUAL Reactome DB_ID: 3006405 1 UniProt:Q13352 ITGB3BP ITGB3BP NRIF3 ITGB3BP CENPR FUNCTION Transcription coregulator that can have both coactivator and corepressor functions. Isoform 1, but not other isoforms, is involved in the coactivation of nuclear receptors for retinoid X (RXRs) and thyroid hormone (TRs) in a ligand-dependent fashion. In contrast, it does not coactivate nuclear receptors for retinoic acid, vitamin D, progesterone receptor, nor glucocorticoid. Acts as a coactivator for estrogen receptor alpha. Acts as a transcriptional corepressor via its interaction with the NFKB1 NF-kappa-B subunit, possibly by interfering with the transactivation domain of NFKB1. Induces apoptosis in breast cancer cells, but not in other cancer cells, via a caspase-2 mediated pathway that involves mitochondrial membrane permeabilization but does not require other caspases. May also act as an inhibitor of cyclin A-associated kinase. Also acts a component of the CENPA-CAD (nucleosome distal) complex, a complex recruited to centromeres which is involved in assembly of kinetochore proteins, mitotic progression and chromosome segregation. May be involved in incorporation of newly synthesized CENPA into centromeres via its interaction with the CENPA-NAC complex.SUBUNIT Homodimer; mediated by the coiled coil domain. Isoform 3, but not other isoforms, interacts with the cytoplasmic tail of integrin ITGB3. The relevance of the interaction with ITGB3 is however uncertain, since isoform 3 is mainly nuclear. Interacts with CCNA2 and MTA1. Interacts with NFKB1 NF-kappa-B subunit. Component of the CENPA-CAD complex, composed of CENPI, CENPK, CENPL, CENPO, CENPP, CENPQ, CENPR and CENPS. The CENPA-CAD complex interacts with the CENPA-NAC complex, at least composed of CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU. Interacts with TASOR (By similarity).TISSUE SPECIFICITY Widely expressed. Expressed in spleen, thymus, prostate, ovary, small intestine and white blood cells. Highly expressed in testis and colon. Isoform 4 is expressed in platelets, lymphocytes and granulocytes.INDUCTION By estrogen.DOMAIN The DD1 domain (also called RepD1 domain) mediates the corepressor function and is essential in the triggering of apoptosis.DOMAIN Contains one Leu-Xaa-Xaa-Leu-Leu (LXXLL) motif, a motif known to be important for the association with nuclear receptors. Such motif, which is required for an efficient association with nuclear receptors, is however not essential.DOMAIN Contains one Leu-Xaa-Xaa-Ile-Leu (LXXIL) motif, which is essential for the association with nuclear receptors. UniProt Q13352 1 EQUAL 177 EQUAL Reactome DB_ID: 375301 1 UniProt:Q9BU64 CENPO CENPO ICEN36 MCM21R CENPO FUNCTION Component of the CENPA-CAD (nucleosome distal) complex, a complex recruited to centromeres which is involved in assembly of kinetochore proteins, mitotic progression and chromosome segregation. May be involved in incorporation of newly synthesized CENPA into centromeres via its interaction with the CENPA-NAC complex. Modulates the kinetochore-bound levels of NDC80 complex.SUBUNIT Component of the CENPA-CAD complex, composed of CENPI, CENPK, CENPL, CENPO, CENPP, CENPQ, CENPR and CENPS. The CENPA-CAD complex interacts with the CENPA-NAC complex, at least composed of CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU.SIMILARITY Belongs to the CENP-O/MCM21 family. UniProt Q9BU64 1 EQUAL 300 EQUAL Reactome DB_ID: 375298 1 UniProt:Q7L2Z9 CENPQ CENPQ C6orf139 CENPQ FUNCTION Component of the CENPA-CAD (nucleosome distal) complex, a complex recruited to centromeres which is involved in assembly of kinetochore proteins, mitotic progression and chromosome segregation. May be involved in incorporation of newly synthesized CENPA into centromeres via its interaction with the CENPA-NAC complex (PubMed:16622420). Plays an important role in chromosome congression and in the recruitment of CENP-O complex (which comprises CENPO, CENPP, CENPQ and CENPU), CENPE and PLK1 to the kinetochores (PubMed:25395579).SUBUNIT Component of the CENPA-CAD complex, composed of CENPI, CENPK, CENPL, CENPO, CENPP, CENPQ, CENPR and CENPS. The CENPA-CAD complex interacts with the CENPA-NAC complex, at least composed of CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU.PTM Phosphorylation at Ser-50 is essential for CENPE recruitment to kinetochores and orderly chromosome congression.SIMILARITY Belongs to the CENP-Q/OKP1 family. UniProt Q7L2Z9 1 EQUAL 268 EQUAL Reactome DB_ID: 375299 1 UniProt:Q6IPU0 CENPP CENPP CENPP FUNCTION Component of the CENPA-CAD (nucleosome distal) complex, a complex recruited to centromeres which is involved in assembly of kinetochore proteins, mitotic progression and chromosome segregation. May be involved in incorporation of newly synthesized CENPA into centromeres via its interaction with the CENPA-NAC complex.SUBUNIT Component of the CENPA-CAD complex, composed of CENPI, CENPK, CENPL, CENPO, CENPP, CENPQ, CENPR and CENPS. The CENPA-CAD complex interacts with the CENPA-NAC complex, at least composed of CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU.SIMILARITY Belongs to the CENP-P/CTF19 family. UniProt Q6IPU0 1 EQUAL 288 EQUAL Reactome Database ID Release 81 377886 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=377886 Reactome R-HSA-377886 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-377886.1 Reactome DB_ID: 375295 1 UniProt:Q8N0S6 CENPL CENPL ICEN33 C1orf155 CENPL FUNCTION Component of the CENPA-CAD (nucleosome distal) complex, a complex recruited to centromeres which is involved in assembly of kinetochore proteins, mitotic progression and chromosome segregation. May be involved in incorporation of newly synthesized CENPA into centromeres via its interaction with the CENPA-NAC complex.SUBUNIT Component of the CENPA-CAD complex, composed of CENPI, CENPK, CENPL, CENPO, CENPP, CENPQ, CENPR and CENPS. The CENPA-CAD complex interacts with the CENPA-NAC complex, at least composed of CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU.SIMILARITY Belongs to the CENP-L/IML3 family. UniProt Q8N0S6 1 EQUAL 344 EQUAL Reactome DB_ID: 375292 1 UniProt:Q03188 CENPC CENPC ICEN7 CENPC1 CENPC FUNCTION Component of the CENPA-NAC (nucleosome-associated) complex, a complex that plays a central role in assembly of kinetochore proteins, mitotic progression and chromosome segregation. The CENPA-NAC complex recruits the CENPA-CAD (nucleosome distal) complex and may be involved in incorporation of newly synthesized CENPA into centromeres. CENPC recruits DNA methylation and DNMT3B to both centromeric and pericentromeric satellite repeats and regulates the histone code in these regions.SUBUNIT Oligomer. Component of the CENPA-NAC complex, at least composed of CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU (PubMed:16622419). The CENPA-NAC complex interacts with the CENPA-CAD complex, composed of CENPI, CENPK, CENPL, CENPO, CENPP, CENPQ, CENPR and CENPS. Binds to DAXX (PubMed:9645950). Interacts with DNMT3B (PubMed:19482874). Interacts directly with CENPA (PubMed:19503796). Identified in a centromere complex containing histones H2A, H2B and H4, and at least CENPA, CENPB, CENPC, CENPT, CENPN, HJURP, SUPT16H, SSRP1 and RSF1 (PubMed:27499292). Interacts with MEIKIN (By similarity).DEVELOPMENTAL STAGE Expression varies across the cell cycle, with high levels in G2 phase (at the mRNA level).DOMAIN The MIF2 homology domain II targets centromeres and binds the alpha satellite DNA in vivo. The MIF2 homology domain III can induce CENPC dimerization/oligomerization.SIMILARITY Belongs to the CENP-C/MIF2 family. UniProt Q03188 1 EQUAL 943 EQUAL Reactome DB_ID: 375290 1 UniProt:Q9NSP4 CENPM CENPM CENPM ICEN39 C22orf18 PANE1 FUNCTION Component of the CENPA-NAC (nucleosome-associated) complex, a complex that plays a central role in assembly of kinetochore proteins, mitotic progression and chromosome segregation. The CENPA-NAC complex recruits the CENPA-CAD (nucleosome distal) complex and may be involved in incorporation of newly synthesized CENPA into centromeres.SUBUNIT Component of the CENPA-NAC complex, at least composed of CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU. The CENPA-NAC complex interacts with the CENPA-CAD complex, composed of CENPI, CENPK, CENPL, CENPO, CENPP, CENPQ, CENPR and CENPS.TISSUE SPECIFICITY Isoform 3 is highly expressed in spleen, and intermediately in heart, prostate and ovary. Isoform 3 is highly expressed in resting CD19 B-cells and B-lineage chronic lymphocytic leukemia (B-CLL) cells and weakly expressed in activated B-cells. Isoform 1 is selectively expressed in activated CD19 cells and weakly in resting CD19 B-cells. UniProt Q9NSP4 1 EQUAL 180 EQUAL Reactome DB_ID: 375316 1 UniProt:Q96BT3 CENPT CENPT CENPT ICEN22 C16orf56 FUNCTION Component of the CENPA-NAC (nucleosome-associated) complex, a complex that plays a central role in assembly of kinetochore proteins, mitotic progression and chromosome segregation. The CENPA-NAC complex recruits the CENPA-CAD (nucleosome distal) complex and may be involved in incorporation of newly synthesized CENPA into centromeres. Part of a nucleosome-associated complex that binds specifically to histone H3-containing nucleosomes at the centromere, as opposed to nucleosomes containing CENPA. Component of the heterotetrameric CENP-T-W-S-X complex that binds and supercoils DNA, and plays an important role in kinetochore assembly. CENPT has a fundamental role in kinetochore assembly and function. It is one of the inner kinetochore proteins, with most further proteins binding downstream. Required for normal chromosome organization and normal progress through mitosis.SUBUNIT Component of the CENPA-CAD complex, composed of CENPI, CENPK, CENPL, CENPO, CENPP, CENPQ, CENPR and CENPS. The CENPA-CAD complex is probably recruited on centromeres by the CENPA-NAC complex, at least composed of CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU (PubMed:16622419, PubMed:19533040, PubMed:19412974). Identified in a centromeric complex containing histones H2A, H2B, H3 and H4, and at least CENPA, CENPB, CENPC, CENPT, CENPN, HJURP, SUPT16H, SSRP1 and RSF1 (PubMed:19412974, PubMed:21695110, PubMed:27499292). Interacts (via N-terminus) with the NDC80 complex (Probable). Heterodimer with CENPW; this dimer coassembles with CENPS-CENPX heterodimers at centromeres to form the tetrameric CENP-T-W-S-X complex (PubMed:19533040, PubMed:19070575, PubMed:21529714, PubMed:21695110, PubMed:22304917).DOMAIN The largest part of the sequence forms an elongated and flexible stalk structure that is connected to a C-terminal globular domain with a histone-type fold.PTM Dynamically phosphorylated at Ser-47 and probably also other sites during the cell cycle. Phosphorylated at Ser-47 during G2 phase, metaphase and anaphase, but not during telophase or G1 phase.SIMILARITY Belongs to the CENP-T/CNN1 family. UniProt Q96BT3 1 EQUAL 561 EQUAL Reactome DB_ID: 375310 1 UniProt:Q8N2Z9 CENPS CENPS MHF1 APITD1 FAAP16 CENPS FUNCTION DNA-binding component of the Fanconi anemia (FA) core complex. Required for the normal activation of the FA pathway, leading to monoubiquitination of the FANCI-FANCD2 complex in response to DNA damage, cellular resistance to DNA cross-linking drugs, and prevention of chromosomal breakage (PubMed:20347428, PubMed:20347429). In complex with CENPX (MHF heterodimer), crucial cofactor for FANCM in both binding and ATP-dependent remodeling of DNA. Stabilizes FANCM (PubMed:20347428, PubMed:20347429). In complex with CENPX and FANCM (but not other FANC proteins), rapidly recruited to blocked forks and promotes gene conversion at blocked replication forks (PubMed:20347428). In complex with CENPT, CENPW and CENPX (CENP-T-W-S-X heterotetramer), involved in the formation of a functional kinetochore outer plate, which is essential for kinetochore-microtubule attachment and faithful mitotic progression (PubMed:19620631). As a component of MHF and CENP-T-W-S-X complexes, binds DNA and bends it to form a nucleosome-like structure (PubMed:20347428, PubMed:22304917). DNA-binding function is fulfilled in the presence of CENPX, with the following preference for DNA substates: Holliday junction &gt; double-stranded &gt; splay arm &gt; single-stranded. Does not bind DNA on its own (PubMed:20347428, PubMed:20347429).SUBUNIT Heterodimer with CENPX, sometimes called MHF; this interaction stabilizes both partners (PubMed:19620631, PubMed:20347428, PubMed:20347429, PubMed:24522885). MHF heterodimers can assemble to form tetrameric structures (PubMed:22304917). MHF also coassemble with CENPT-CENPW heterodimers at centromeres to form the tetrameric CENP-T-W-S-X complex (PubMed:22304917, PubMed:24522885). Forms a discrete complex with FANCM and CENPX, called FANCM-MHF; this interaction, probably mediated by direct binding between CENPS and FANCM, leads to synergistic activation of double-stranded DNA binding and strongly stimulates FANCM-mediated DNA remodeling (PubMed:20347428, PubMed:20347429). Recruited by FANCM to the Fanconi anemia (FA) core complex, which consists of CENPS, CENPX, FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, FANCM, FAAP24 and FAAP100. The FA core complex associates with Bloom syndrome (BLM) complex, which consists of at least BLM, DNA topoisomerase 3-alpha (TOP3A), RMI1/BLAP75, RPA1/RPA70 and RPA2/RPA32. The super complex between FA and BLM is called BRAFT (PubMed:20347428, PubMed:20347429). Component of the CENPA-CAD complex, composed of CENPI, CENPK, CENPL, CENPO, CENPP, CENPQ, CENPR and CENPS. The CENPA-CAD complex is probably recruited on centromeres by the CENPA-NAC complex, composed of at least CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU (PubMed:16622419).TISSUE SPECIFICITY Ubiquitously expressed.DEVELOPMENTAL STAGE Expression varies across the cell cycle, with highest levels in G2 phase (at protein level). No statistically significant changes at the transcript level.SIMILARITY Belongs to the TAF9 family. CENP-S/MHF1 subfamily. UniProt Q8N2Z9 1 EQUAL 138 EQUAL Reactome DB_ID: 377884 1 CENP-(H,I, K) complex [cytosol] CENP-(H,I, K) complex Reactome DB_ID: 375293 1 UniProt:Q92674 CENPI CENPI FSHPRH1 CENPI ICEN19 LRPR1 FUNCTION Component of the CENPA-CAD (nucleosome distal) complex, a complex recruited to centromeres which is involved in assembly of kinetochore proteins, mitotic progression and chromosome segregation. May be involved in incorporation of newly synthesized CENPA into centromeres via its interaction with the CENPA-NAC complex. Required for the localization of CENPF, MAD1L1 and MAD2 (MAD2L1 or MAD2L2) to kinetochores. Involved in the response of gonadal tissues to follicle-stimulating hormone.SUBUNIT Component of the CENPA-CAD complex, composed of CENPI, CENPK, CENPL, CENPO, CENPP, CENPQ, CENPR and CENPS. The CENPA-CAD complex interacts with the CENPA-NAC complex, at least composed of CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU. Interacts with SENP6.INDUCTION By follicle-stimulating hormone (FSH).PTM Sumoylated. Sumoylated form can be polyubiquitinated by RNF4, leading to its degradation. Desumoylation by SENP6 prevents its degradation.SIMILARITY Belongs to the CENP-I/CTF3 family. UniProt Q92674 1 EQUAL 756 EQUAL Reactome DB_ID: 375296 1 UniProt:Q9BS16 CENPK CENPK ICEN37 FKSG14 CENPK FUNCTION Component of the CENPA-CAD (nucleosome distal) complex, a complex recruited to centromeres which is involved in assembly of kinetochore proteins, mitotic progression and chromosome segregation. May be involved in incorporation of newly synthesized CENPA into centromeres via its interaction with the CENPA-NAC complex. Acts in coordination with KNL1 to recruit the NDC80 complex to the outer kinetochore.SUBUNIT Component of the CENPA-CAD complex, composed of CENPI, CENPK, CENPL, CENPO, CENPP, CENPQ, CENPR and CENPS. The CENPA-CAD complex interacts with the CENPA-NAC complex, at least composed of CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU. Interacts directly with CENPH.TISSUE SPECIFICITY Detected in several fetal organs with highest levels in fetal liver. In adults, it is weakly expressed in lung and placenta.DISEASE Chromosomal aberrations involving CENPK are a cause of acute leukemias. Translocation t(5;11)(q12;q23) with KMT2A/MLL1.SIMILARITY Belongs to the CENP-K/MCM22 family. UniProt Q9BS16 1 EQUAL 269 EQUAL Reactome DB_ID: 375294 1 UniProt:Q9H3R5 CENPH CENPH CENPH ICEN35 FUNCTION Component of the CENPA-NAC (nucleosome-associated) complex, a complex that plays a central role in assembly of kinetochore proteins, mitotic progression and chromosome segregation. The CENPA-NAC complex recruits the CENPA-CAD (nucleosome distal) complex and may be involved in incorporation of newly synthesized CENPA into centromeres. Required for chromosome congression and efficiently align the chromosomes on a metaphase plate.SUBUNIT Self-associates. Component of the CENPA-NAC complex, at least composed of CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU. The CENPA-NAC complex interacts with the CENPA-CAD complex, composed of CENPI, CENPK, CENPL, CENPO, CENPP, CENPQ, CENPR and CENPS. Interacts directly with CENPK. Interacts with KIF2C and NDC80. Interacts with TRIM36 (By similarity).SIMILARITY Belongs to the CENP-H/MCM16 family. UniProt Q9H3R5 1 EQUAL 247 EQUAL Reactome Database ID Release 81 377884 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=377884 Reactome R-HSA-377884 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-377884.1 Reactome DB_ID: 375306 1 UniProt:Q96H22 CENPN CENPN ICEN32 C16orf60 BM-309 CENPN FUNCTION Component of the CENPA-NAC (nucleosome-associated) complex, a complex that plays a central role in assembly of kinetochore proteins, mitotic progression and chromosome segregation. The CENPA-NAC complex recruits the CENPA-CAD (nucleosome distal) complex and may be involved in incorporation of newly synthesized CENPA into centromeres. CENPN is the first protein to bind specifically to CENPA nucleosomes and the direct binding of CENPA nucleosomes by CENPN is required for centromere assembly. Required for chromosome congression and efficiently align the chromosomes on a metaphase plate.SUBUNIT Component of the CENPA-NAC complex, at least composed of CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU (PubMed:16622420, PubMed:16622419). The CENPA-NAC complex interacts with the CENPA-CAD complex, composed of CENPI, CENPK, CENPL, CENPO, CENPP, CENPQ, CENPR and CENPS. Interacts directly with CENPA (PubMed:19543270). Identified in a centromere complex containing histones H2A, H2B and H4, and at least CENPA, CENPB, CENPC, CENPT, CENPN, HJURP, SUPT16H, SSRP1 and RSF1 (PubMed:27499292).SIMILARITY Belongs to the CENP-N/CHL4 family. UniProt Q96H22 1 EQUAL 339 EQUAL Reactome Database ID Release 81 377738 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=377738 Reactome R-HSA-377738 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-377738.1 Reactome DB_ID: 377885 1 RZZ complex [cytosol] RZZ complex Reactome DB_ID: 376233 1 UniProt:P50748 KNTC1 KNTC1 KNTC1 KIAA0166 FUNCTION Essential component of the mitotic checkpoint, which prevents cells from prematurely exiting mitosis. Required for the assembly of the dynein-dynactin and MAD1-MAD2 complexes onto kinetochores (PubMed:11146660, PubMed:11590237, PubMed:15824131). Its function related to the spindle assembly machinery is proposed to depend on its association in the mitotic RZZ complex.SUBUNIT Interacts with ZW10; the interaction is required for stable association with the kinetochore. Component of the RZZ complex composed of KNTC1/ROD, ZW10 and ZWILCH; in the complex interacts directly with ZWILCH.TISSUE SPECIFICITY High expression in testis. UniProt P50748 1 EQUAL 2209 EQUAL Reactome DB_ID: 376234 1 UniProt:Q9H900 ZWILCH ZWILCH ZWILCH FUNCTION Essential component of the mitotic checkpoint, which prevents cells from prematurely exiting mitosis. Required for the assembly of the dynein-dynactin and MAD1-MAD2 complexes onto kinetochores. Its function related to the spindle assembly machinery is proposed to depend on its association in the mitotic RZZ complex (PubMed:15824131).SUBUNIT Component of the RZZ complex composed of KNTC1/ROD, ZW10 and ZWILCH; in the complex interacts directly with KNTC1/ROD.MISCELLANEOUS ZWILCH gene is deleted in a patient suffering from colorectal cancer with chromosomal instability.SIMILARITY Belongs to the ZWILCH family. UniProt Q9H900 1 EQUAL 591 EQUAL Reactome DB_ID: 377880 1 UniProt:O43264 ZW10 ZW10 ZW10 FUNCTION Essential component of the mitotic checkpoint, which prevents cells from prematurely exiting mitosis. Required for the assembly of the dynein-dynactin and MAD1-MAD2 complexes onto kinetochores. Its function related to the spindle assembly machinery is proposed to depend on its association in the mitotic RZZ complex (PubMed:11590237, PubMed:15485811, PubMed:15824131). Involved in regulation of membrane traffic between the Golgi and the endoplasmic reticulum (ER); the function is proposed to depend on its association in the interphase NRZ complex which is believed to play a role in SNARE assembly at the ER (PubMed:15029241).SUBUNIT Interacts with NBAS and KNTC1/ROD; the interactions are mutually exclusive and indicative for its association in two different vesicle tethering complexes (PubMed:11590237, PubMed:15824131, PubMed:20462495). Component of the RZZ complex composed of KNTC1/ROD, ZW10 and ZWILCH (PubMed:12686595, PubMed:20462495). Component of the NRZ complex composed of NBAS, ZW10 and RINT1/TIP20L; NRZ associates with SNAREs STX18, USE1L, BNIP1/SEC20L and SEC22B (the assembly has been described as syntaxin 18 complex). Interacts directly with RINT1/TIP20L bound to BNIP1/SEC20L (PubMed:15029241, PubMed:15272311, PubMed:20462495, PubMed:19369418). Interacts with C19orf25 and ZWINT (PubMed:15485811, PubMed:15824131., PubMed:16732327). Interacts with ZFYVE1 (PubMed:30970241). Interacts with RAB18 and this interaction is enhanced in the presence of ZFYVE1 (PubMed:30970241).TISSUE SPECIFICITY Widely expressed.DEVELOPMENTAL STAGE No significant variation in expression during cell cycle.MISCELLANEOUS Overexpression as well as silencing of ZW10 disrupts the morphology of the ER-Golgi intermediate compartment as well as the Golgi apparatus and slows down ER-Golgi transport.SIMILARITY Belongs to the ZW10 family. UniProt O43264 2 EQUAL 779 EQUAL Reactome Database ID Release 81 377885 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=377885 Reactome R-HSA-377885 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-377885.1 Reactome DB_ID: 376230 1 UniProt:Q7Z460 CLASP1 CLASP1 KIAA0622 MAST1 CLASP1 FUNCTION Microtubule plus-end tracking protein that promotes the stabilization of dynamic microtubules. Involved in the nucleation of noncentrosomal microtubules originating from the trans-Golgi network (TGN). Required for the polarization of the cytoplasmic microtubule arrays in migrating cells towards the leading edge of the cell. May act at the cell cortex to enhance the frequency of rescue of depolymerizing microtubules by attaching their plus-ends to cortical platforms composed of ERC1 and PHLDB2. This cortical microtubule stabilizing activity is regulated at least in part by phosphatidylinositol 3-kinase signaling. Also performs a similar stabilizing function at the kinetochore which is essential for the bipolar alignment of chromosomes on the mitotic spindle.SUBUNIT Interacts with CLIP2, ERC1, MAPRE1, MAPRE3, microtubules, PHLDB2 and RSN. The interaction with ERC1 may be mediated by PHLDB2. Interacts with GCC2; recruits CLASP1 to Golgi membranes. Interacts with MACF1 (By similarity).SIMILARITY Belongs to the CLASP family. UniProt Q7Z460 1 EQUAL 1538 EQUAL Reactome DB_ID: 376239 1 UniProt:Q8NI77 KIF18A KIF18A KIF18A OK/SW-cl.108 FUNCTION Microtubule-depolymerizing kinesin which plays a role in chromosome congression by reducing the amplitude of preanaphase oscillations and slowing poleward movement during anaphase, thus suppressing chromosome movements. May stabilize the CENPE-BUB1B complex at the kinetochores during early mitosis and maintains CENPE levels at kinetochores during chromosome congression.SUBUNIT Interacts with CENPE and ESR1.INDUCTION By estrogen.PTM Glycosylated.PTM Ubiquitinated.SIMILARITY Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. UniProt Q8NI77 1 EQUAL 898 EQUAL Reactome DB_ID: 376252 1 UniProt:O75122 CLASP2 CLASP2 KIAA0627 CLASP2 FUNCTION Microtubule plus-end tracking protein that promotes the stabilization of dynamic microtubules (PubMed:26003921). Involved in the nucleation of noncentrosomal microtubules originating from the trans-Golgi network (TGN). Required for the polarization of the cytoplasmic microtubule arrays in migrating cells towards the leading edge of the cell. May act at the cell cortex to enhance the frequency of rescue of depolymerizing microtubules by attaching their plus-ends to cortical platforms composed of ERC1 and PHLDB2 (PubMed:16824950). This cortical microtubule stabilizing activity is regulated at least in part by phosphatidylinositol 3-kinase signaling. Also performs a similar stabilizing function at the kinetochore which is essential for the bipolar alignment of chromosomes on the mitotic spindle (PubMed:16866869, PubMed:16914514). Acts as a mediator of ERBB2-dependent stabilization of microtubules at the cell cortex.SUBUNIT Interacts with microtubules (PubMed:11290329, PubMed:15631994, PubMed:15955847, PubMed:26003921). Interacts with MAPRE1; probably required for targeting to the growing microtubule plus ends (PubMed:15631994, PubMed:19632184, PubMed:26003921). Interacts with CLIP2, ERC1, MAPRE3, PHLDB2 and RSN (PubMed:11290329, PubMed:15631994). The interaction with ERC1 may be mediated by PHLDB2 (PubMed:16824950). Interacts with GCC2; recruits CLASP2 to Golgi membranes (PubMed:17543864). Interacts with MACF1 (By similarity).TISSUE SPECIFICITY Brain-specific.DOMAIN The two SXIP sequence motifs mediate interaction with MAPRE1; this is necessary for targeting to growing microtubule plus ends.DOMAIN Two TOG regions display structural characteristics similar to HEAT repeat domains and mediate interaction with microtubules.PTM Phosphorylated by GSK3B. Phosphorylation reduces MAPRE1 binding (PubMed:26003921). Phosphorylation by GSK3B may negatively regulate binding to microtubule lattices in lamella.SIMILARITY Belongs to the CLASP family. UniProt O75122 1 EQUAL 1294 EQUAL Reactome DB_ID: 376228 1 UniProt:Q96BD8 SKA1 SKA1 C18orf24 SKA1 FUNCTION Component of the SKA1 complex, a microtubule-binding subcomplex of the outer kinetochore that is essential for proper chromosome segregation (PubMed:17093495, PubMed:19289083, PubMed:23085020). Required for timely anaphase onset during mitosis, when chromosomes undergo bipolar attachment on spindle microtubules leading to silencing of the spindle checkpoint (PubMed:17093495). The SKA1 complex is a direct component of the kinetochore-microtubule interface and directly associates with microtubules as oligomeric assemblies (PubMed:19289083). The complex facilitates the processive movement of microspheres along a microtubule in a depolymerization-coupled manner (PubMed:19289083). Affinity for microtubules is synergistically enhanced in the presence of the ndc-80 complex and may allow the ndc-80 complex to track depolymerizing microtubules (PubMed:23085020). In the complex, it mediates the interaction with microtubules (PubMed:19289083, PubMed:23085020).SUBUNIT Component of the SKA1 complex, composed of SKA1, SKA2 and SKA3 (PubMed:17093495). Forms a heterodimer with SKA2; the heterodimer interacting with SKA3 (PubMed:17093495, PubMed:19289083, PubMed:23085020). The core SKA1 complex is composed of 2 SKA1-SKA2 heterodimers, each heterodimer interacting with a molecule of the SKA3 homodimer (PubMed:19289083). The core SKA1 complex associates with microtubules and forms oligomeric assemblies (PubMed:17093495, PubMed:19289083). Interacts with microtubules; the interaction is direct (PubMed:19289083, PubMed:23085020). Interacts with SKA2 (PubMed:19289083). Interacts with SKA3 (PubMed:19289083, PubMed:23085020).SIMILARITY Belongs to the SKA1 family. UniProt Q96BD8 2 EQUAL 255 EQUAL Reactome DB_ID: 377733 1 UniProt:Q96EA4 SPDL1 SPDL1 SPDL1 CCDC99 FUNCTION Required for the localization of dynein and dynactin to the mitotic kintochore. Dynein is believed to control the initial lateral interaction between the kinetochore and spindle microtubules and to facilitate the subsequent formation of end-on kinetochore-microtubule attachments mediated by the NDC80 complex. Also required for correct spindle orientation. Does not appear to be required for the removal of spindle assembly checkpoint (SAC) proteins from the kinetochore upon bipolar spindle attachment (PubMed:17576797, PubMed:19468067). Acts as an adapter protein linking the dynein motor complex to various cargos and converts dynein from a non-processive to a highly processive motor in the presence of dynactin. Facilitates the interaction between dynein and dynactin and activates dynein processivity (the ability to move along a microtubule for a long distance without falling off the track) (PubMed:25035494). Plays a role in cell migration (PubMed:30258100).SUBUNIT Interacts with KNTC1 and ZW10. These interactions appear weak and may be transient or indirect (PubMed:19468067). Interacts with dynein intermediate chain and dynactin (DCTN1) (PubMed:25035494). Interacts with the catalytically active form of USP45 (PubMed:30258100).PTM Monoubiquitinated with'Lys-48' linkage (PubMed:30258100). Deubiquitinated by USP45 (PubMed:30258100).SIMILARITY Belongs to the Spindly family. UniProt Q96EA4 1 EQUAL 605 EQUAL Reactome DB_ID: 376232 1 UniProt:O00139 KIF2A KIF2A KNS2 KIF2A KIF2 FUNCTION Plus end-directed microtubule-dependent motor required for normal brain development. May regulate microtubule dynamics during axonal growth. Required for normal progression through mitosis. Required for normal congress of chromosomes at the metaphase plate. Required for normal spindle dynamics during mitosis. Promotes spindle turnover. Implicated in formation of bipolar mitotic spindles. Has microtubule depolymerization activity.SUBUNIT Interacts with AURKA, PSRC1 and PLK1.MISCELLANEOUS HeLa cells lacking KIF2A show asymmetric or monopolar mitotic spindles. Osteosarcoma cells (U2OS) lacking KIF2A or KIF2B show disorganised or monopolar mitotic spindles.SIMILARITY Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. MCAK/KIF2 subfamily. UniProt O00139 1 EQUAL 706 EQUAL Reactome DB_ID: 377729 1 UniProt:Q14008 CKAP5 CKAP5 KIAA0097 CKAP5 FUNCTION Binds to the plus end of microtubules and regulates microtubule dynamics and microtubule organization. Acts as processive microtubule polymerase. Promotes cytoplasmic microtubule nucleation and elongation. Plays a major role in organizing spindle poles. In spindle formation protects kinetochore microtubules from depolymerization by KIF2C and has an essential role in centrosomal microtubule assembly independently of KIF2C activity. Contributes to centrosome integrity. Acts as component of the TACC3/ch-TOG/clathrin complex proposed to contribute to stabilization of kinetochore fibers of the mitotic spindle by acting as inter-microtubule bridge. The TACC3/ch-TOG/clathrin complex is required for the maintenance of kinetochore fiber tension (PubMed:23532825). Enhances the strength of NDC80 complex-mediated kinetochore-tip microtubule attachments (PubMed:27156448).SUBUNIT Interacts with TACC1 (PubMed:11903063). Interacts with SLAIN2 and SLAIN1 (PubMed:21646404). Interacts with HNRNPA2B1 (PubMed:15703215). Interacts with TACC3 independently of clathrin (PubMed:25596274). Interacts with TACC3 and clathrin forming the TACC3/ch-TOG/clathrin complex located at spindle inter-microtubules bridges (PubMed:21297582, PubMed:23532825). Interacts with NDC80; indicative for an association with the NDC80 complex (PubMed:27156448).TISSUE SPECIFICITY Overexpressed in hepatomas and colonic tumors. Also expressed in skeletal muscle, brain, heart, placenta, lung, liver, kidney and pancreas. Expression is elevated in the brain; highly expressed in the Purkinje cell bodies of the cerebellum.DOMAIN The TOG (tumor overexpressed gene) domains are arranged in a N-terminal pentameric array with each domain composed of six (for the most part non-canonical) HEAT repeats forming a oblong paddle-like structure. Intra-HEAT loops are positioned along a face of the TOG domain and bind to a single alpha/beta-tubulin heterodimer. The TOG domains in the array seem to be structurally and functionally polarized. Differential functions may range from microtubule (MT) lattice binding and/or free tubulin heterodimer binding to potentiating stable incorporation of tubulin into the MT lattice.SIMILARITY Belongs to the TOG/XMAP215 family. UniProt Q14008 1 EQUAL 2032 EQUAL Reactome DB_ID: 2029145 1 Dynein complex [cytosol] Dynein complex Converted from EntitySet in Reactome Reactome DB_ID: 2029119 2 DICs [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity DYNC1I2 [cytosol] DYNC1I1 [cytosol] UniProt Q13409 UniProt O14576 Converted from EntitySet in Reactome Reactome DB_ID: 2029122 2 DLIs [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity DYNC1LI1 [cytosol] DYNC1LI2 [cytosol] UniProt Q9Y6G9 UniProt O43237 Converted from EntitySet in Reactome Reactome DB_ID: 2029105 2 DLCs [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity DYNLL2 [cytosol] DYNLL1 [cytosol] UniProt Q96FJ2 UniProt P63167 Reactome DB_ID: 2029144 1 DHC dimer [cytosol] DHC dimer Reactome DB_ID: 380285 2 UniProt:Q14204 DYNC1H1 DYNC1H1 DNCH1 DYHC KIAA0325 DYNC1H1 DNCL DNECL DHC1 FUNCTION Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules. Dynein has ATPase activity; the force-producing power stroke is thought to occur on release of ADP. Plays a role in mitotic spindle assembly and metaphase plate congression (PubMed:27462074).SUBUNIT Homodimer. The cytoplasmic dynein 1 complex consists of two catalytic heavy chains (HCs) and a number of non-catalytic subunits presented by intermediate chains (ICs), light intermediate chains (LICs) and light chains (LCs); the composition seems to vary in respect to the IC, LIC and LC composition. The heavy chain homodimer serves as a scaffold for the probable homodimeric assembly of the respective non-catalytic subunits. The ICs and LICs bind directly to the HC dimer and dynein LCs assemble on the IC dimer. Interacts with DYNC1LI1; DYNC1LI1 and DYNC1LI2 bind mutually exclusive to DYNC1H1. Interacts with DYNC1LI2; DYNC1LI1 and DYNC1LI2 bind mutually exclusive to DYNC1H1. Interacts with DYNC1I2 (By similarity). Interacts with BICD2 (PubMed:25512093). Interacts with isoform 2 of CRACR2A (PubMed:31092558). Interacts with DNALI1 (By similarity).DOMAIN Dynein heavy chains probably consist of an N-terminal stem (which binds cargo and interacts with other dynein components), and the head or motor domain. The motor contains six tandemly-linked AAA domains in the head, which form a ring. A stalk-like structure (formed by two of the coiled coil domains) protrudes between AAA 4 and AAA 5 and terminates in a microtubule-binding site. A seventh domain may also contribute to this ring; it is not clear whether the N-terminus or the C-terminus forms this extra domain. There are four well-conserved and two non-conserved ATPase sites, one per AAA domain. Probably only one of these (within AAA 1) actually hydrolyzes ATP, the others may serve a regulatory function.SIMILARITY Belongs to the dynein heavy chain family. UniProt Q14204 1 EQUAL 4646 EQUAL Reactome Database ID Release 81 2029144 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2029144 Reactome R-HSA-2029144 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2029144.2 Reactome Database ID Release 81 2029145 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2029145 Reactome R-HSA-2029145 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2029145.1 Reactome DB_ID: 377745 1 KMN network [cytosol] KMN network Reactome DB_ID: 375441 1 Mis12 complex [cytosol] Mis12 complex Reactome DB_ID: 375313 1 UniProt:Q9H081 MIS12 MIS12 MIS12 FUNCTION Part of the MIS12 complex which is required for normal chromosome alignment and segregation and for kinetochore formation during mitosis (PubMed:12515822, PubMed:15502821, PubMed:16585270). Essential for proper kinetochore microtubule attachments (PubMed:23891108).SUBUNIT Component of the MIS12 complex composed of MIS12, DSN1, NSL1 and PMF1. Also interacts with KNL1, CBX3, CBX5, NDC80 and ZWINT.SIMILARITY Belongs to the mis12 family. UniProt Q9H081 1 EQUAL 205 EQUAL Reactome DB_ID: 375320 1 UniProt:Q6P1K2 PMF1 PMF1 PMF1 FUNCTION Part of the MIS12 complex which is required for normal chromosome alignment and segregation and kinetochore formation during mitosis. May act as a cotranscription partner of NFE2L2 involved in regulation of polyamine-induced transcription of SSAT.SUBUNIT Component of the MIS12 complex composed of MIS12, DSN1, NSL1 and PMF1. Interacts with COPS7A. Interacts via its coiled-coil domain with the leucine-zipper domain of NFE2L2. The interaction with NFE2L2 is required for the transcriptional regulation of SSAT.TISSUE SPECIFICITY Highest levels of expression in heart and skeletal muscle, with significant levels expressed in kidney and liver.INDUCTION By polyamine analogs in analog-sensitive H157 cells. UniProt Q6P1K2 2 EQUAL 205 EQUAL Reactome DB_ID: 375309 1 UniProt:Q96IY1 NSL1 NSL1 DC31 MIS14 DC8 C1orf48 NSL1 FUNCTION Part of the MIS12 complex which is required for normal chromosome alignment and segregation and kinetochore formation during mitosis.SUBUNIT Component of the MIS12 complex composed of MIS12, DSN1, NSL1/DC8 and PMF1. Interacts with KNL1. UniProt Q96IY1 1 EQUAL 281 EQUAL Reactome DB_ID: 375308 1 UniProt:Q9H410 DSN1 DSN1 DSN1 C20orf172 MIS13 FUNCTION Part of the MIS12 complex which is required for normal chromosome alignment and segregation and kinetochore formation during mitosis.SUBUNIT Component of the MIS12 complex composed of MIS12, DSN1, NSL1 and PMF1. Also interacts with KNL1, CBX3 and CBX5. Interacts with KNSTRN. UniProt Q9H410 1 EQUAL 356 EQUAL Reactome Database ID Release 81 375441 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=375441 Reactome R-HSA-375441 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-375441.1 Reactome DB_ID: 375322 1 UniProt:Q8NG31 KNL1 KNL1 CASC5 KNL1 KIAA1570 FUNCTION Performs two crucial functions during mitosis: it is essential for spindle-assembly checkpoint signaling and for correct chromosome alignment. Required for attachment of the kinetochores to the spindle microtubules. Directly links BUB1 and BUB1B to kinetochores. Part of the MIS12 complex, which may be fundamental for kinetochore formation and proper chromosome segregation during mitosis. Acts in coordination with CENPK to recruit the NDC80 complex to the outer kinetochore.SUBUNIT Interacts with DSN1, MIS12, BUB1, BUB1B, NSL1 and ZWINT.TISSUE SPECIFICITY Highly expressed in testis, where it is localized in germ cells, in particular in spermatocytes and in the pre-acrosome of round spermatids. Detected in the acrosome of ejaculated spermatozoa. Detected in adult thymus, bone marrow, colon, small intestine, appendix and placenta, and in fetal liver and thymus.DISEASE A chromosomal aberration involving KNL1 is associated with acute myeloblastic leukemia (AML). Translocation t(11;15)(q23;q14) with KMT2A. May give rise to a KMT2A-KNL1 fusion protein. UniProt Q8NG31 1 EQUAL 2342 EQUAL Reactome DB_ID: 375444 1 NDC80 complex [cytosol] NDC80 complex Reactome DB_ID: 375300 1 UniProt:Q9BZD4 NUF2 NUF2 CDCA1 NUF2 NUF2R FUNCTION Acts as a component of the essential kinetochore-associated NDC80 complex, which is required for chromosome segregation and spindle checkpoint activity (PubMed:12438418, PubMed:14654001, PubMed:15062103, PubMed:15235793, PubMed:15239953, PubMed:15548592, PubMed:17535814). Required for kinetochore integrity and the organization of stable microtubule binding sites in the outer plate of the kinetochore (PubMed:15548592). The NDC80 complex synergistically enhances the affinity of the SKA1 complex for microtubules and may allow the NDC80 complex to track depolymerizing microtubules (PubMed:23085020).SUBUNIT Component of the NDC80 complex, which consists of NDC80/HEC1, CDCA1, SPBC24 and SPBC25. The NDC80 complex is formed by two subcomplexes composed of NDC80/HEC1-CDCA1 and SPBC24-SPBC25. Each subcomplex is formed by parallel interactions through the coiled-coil domains of individual subunits. Formation of a tetrameric complex is mediated by interactions between the C-terminal regions of both subunits of the NDC80/HEC1-CDCA1 subcomplex and the N-terminal regions of both subunits of the SPBC24-SPBC25 complex. The tetrameric NDC80 complex has an elongated rod-like structure with globular domains at either end. May interact with AURKB/Aurora-B. Directly interacts with CENPE; this interaction determines CENPE kinetochore localization.PTM Can be phosphorylated by AURKA and AURKB.SIMILARITY Belongs to the NUF2 family. UniProt Q9BZD4 1 EQUAL 464 EQUAL Reactome DB_ID: 375297 1 UniProt:Q8NBT2 SPC24 SPC24 SPBC24 SPC24 FUNCTION Acts as a component of the essential kinetochore-associated NDC80 complex, which is required for chromosome segregation and spindle checkpoint activity (PubMed:14738735). Required for kinetochore integrity and the organization of stable microtubule binding sites in the outer plate of the kinetochore (PubMed:14738735). The NDC80 complex synergistically enhances the affinity of the SKA1 complex for microtubules and may allow the NDC80 complex to track depolymerizing microtubules (PubMed:23085020).SUBUNIT Component of the NDC80 complex, which consists of NDC80/HEC1, CDCA1, SPBC24 and SPBC25. The NDC80 complex is formed by two subcomplexes composed of NDC80/HEC1-CDCA1 and SPBC24-SPBC25. Each subcomplex is formed by parallel interactions through the coiled-coil domains of individual subunits. Formation of a tetrameric complex is mediated by interactions between the C-terminal regions of both subunits of the NDC80/HEC1-CDCA1 subcomplex and the N-terminal regions of both subunits of the SPBC24-SPBC25 complex. The tetrameric NDC80 complex has an elongated rod-like structure with globular domains at either end.SIMILARITY Belongs to the SPC24 family. UniProt Q8NBT2 1 EQUAL 197 EQUAL Reactome DB_ID: 375307 1 UniProt:Q9HBM1 SPC25 SPC25 SPBC25 AD024 SPC25 FUNCTION Acts as a component of the essential kinetochore-associated NDC80 complex, which is required for chromosome segregation and spindle checkpoint activity (PubMed:14699129, PubMed:14738735). Required for kinetochore integrity and the organization of stable microtubule binding sites in the outer plate of the kinetochore (PubMed:14738735, PubMed:14699129). The NDC80 complex synergistically enhances the affinity of the SKA1 complex for microtubules and may allow the NDC80 complex to track depolymerizing microtubules (PubMed:23085020).SUBUNIT Component of the NDC80 complex, which consists of NDC80/HEC1, CDCA1, SPBC24 and SPBC25. The NDC80 complex is formed by two subcomplexes composed of NDC80/HEC1-CDCA1 and SPBC24-SPBC25. Each subcomplex is formed by parallel interactions through the coiled-coil domains of individual subunits. Formation of a tetrameric complex is mediated by interactions between the C-terminal regions of both subunits of the NDC80/HEC1-CDCA1 subcomplex and the N-terminal regions of both subunits of the SPBC24-SPBC25 complex. The tetrameric NDC80 complex has an elongated rod-like structure with globular domains at either end.SIMILARITY Belongs to the SPC25 family. UniProt Q9HBM1 1 EQUAL 224 EQUAL Reactome DB_ID: 375314 1 UniProt:O14777 NDC80 NDC80 KNTC2 HEC HEC1 NDC80 FUNCTION Acts as a component of the essential kinetochore-associated NDC80 complex, which is required for chromosome segregation and spindle checkpoint activity (PubMed:9315664, PubMed:12351790, PubMed:14654001, PubMed:14699129, PubMed:15062103, PubMed:15235793, PubMed:15239953, PubMed:15548592, PubMed:16732327, PubMed:30409912). Required for kinetochore integrity and the organization of stable microtubule binding sites in the outer plate of the kinetochore (PubMed:15548592, PubMed:30409912). The NDC80 complex synergistically enhances the affinity of the SKA1 complex for microtubules and may allow the NDC80 complex to track depolymerizing microtubules (PubMed:23085020). Plays a role in chromosome congression and is essential for the end-on attachment of the kinetochores to spindle microtubules (PubMed:25743205, PubMed:23891108).SUBUNIT Component of the NDC80 complex, which consists of NDC80/HEC1, CDCA1, SPBC24 and SPBC25. The NDC80 complex is formed by two subcomplexes composed of NDC80/HEC1-CDCA1 and SPBC24-SPBC25. Each subcomplex is formed by parallel interactions through the coiled-coil domains of individual subunits. Formation of a tetrameric complex is mediated by interactions between the C-terminal regions of both subunits of the NDC80/HEC1-CDCA1 subcomplex and the N-terminal regions of both subunits of the SPBC24-SPBC25 complex. The tetrameric NDC80 complex has an elongated rod-like structure with globular domains at either end. Interacts with isoform 1 of NEK2 and ZWINT specifically during mitosis. Interacts with CENPH and MIS12. May interact with AURKB, PSMC2, PSMC5 and SMC1A. May interact with RB1 during G2 phase and mitosis. Interacts with CKAP5 (PubMed:27156448). Interacts with CDT1; leading to kinetochore localization of CDT1 (PubMed:22581055).DEVELOPMENTAL STAGE Expression peaks in mitosis.PTM Phosphorylation begins in S phase of the cell cycle and peaks in mitosis. Phosphorylated by NEK2. Also phosphorylated by AURKA and AURKB.PTM Acetylated at Lys-53 and Lys-59 by KAT5 during mitosis, promoting robust kinetochore-microtubule attachment (PubMed:30409912). Deacetylated by SIRT1 (PubMed:30409912).SIMILARITY Belongs to the NDC80/HEC1 family. UniProt O14777 1 EQUAL 642 EQUAL Reactome Database ID Release 81 375444 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=375444 Reactome R-HSA-375444 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-375444.1 Reactome Database ID Release 81 377745 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=377745 Reactome R-HSA-377745 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-377745.1 Reactome DB_ID: 377888 1 UniProt:O43683 BUB1 BUB1 BUB1L BUB1 FUNCTION Serine/threonine-protein kinase that performs 2 crucial functions during mitosis: it is essential for spindle-assembly checkpoint signaling and for correct chromosome alignment. Has a key role in the assembly of checkpoint proteins at the kinetochore, being required for the subsequent localization of CENPF, BUB1B, CENPE and MAD2L1. Required for the kinetochore localization of PLK1. Required for centromeric enrichment of AUKRB in prometaphase. Plays an important role in defining SGO1 localization and thereby affects sister chromatid cohesion. Acts as a substrate for anaphase-promoting complex or cyclosome (APC/C) in complex with its activator CDH1 (APC/C-Cdh1). Necessary for ensuring proper chromosome segregation and binding to BUB3 is essential for this function. Can regulate chromosome segregation in a kinetochore-independent manner. Can phosphorylate BUB3. The BUB1-BUB3 complex plays a role in the inhibition of APC/C when spindle-assembly checkpoint is activated and inhibits the ubiquitin ligase activity of APC/C by phosphorylating its activator CDC20. This complex can also phosphorylate MAD1L1. Kinase activity is essential for inhibition of APC/CCDC20 and for chromosome alignment but does not play a major role in the spindle-assembly checkpoint activity. Mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis.ACTIVITY REGULATION Autophosphorylated when the cells enters mitosis.SUBUNIT Interacts with BUB3 and KNL1. Interacts (when phosphorylated) with PLK1. The BUB1-BUB3 complex interacts with MAD1L1.SUBUNIT (Microbial infection) Interacts with SV40 Large T antigen; this interaction induces activation of a DNA damage response and promotes p53/TP53 stabilization and phosphorylation.SUBUNIT (Microbial infection) Interacts with herpes virus 8 protein LANA1.TISSUE SPECIFICITY High expression in testis and thymus, less in colon, spleen, lung and small intestine. Expressed in fetal thymus, bone marrow, heart, liver, spleen and thymus. Expression is associated with cells/tissues with a high mitotic index.INDUCTION Inhibited by phorbol 12-myristate 13-acetate (PMA).DOMAIN The KEN box is required for its ubiquitination and degradation.DOMAIN BUB1 N-terminal domain directs kinetochore localization and binding to BUB3.PTM Upon spindle-assembly checkpoint activation it is hyperphosphorylated and its kinase activity toward CDC20 is stimulated. Phosphorylation at Thr-609 is required for interaction with PLK1, phosphorylation at this site probably creates a binding site for the POLO-box domain of PLK1, thus enhancing the PLK1-BUB1 interaction.PTM Ubiquitinated and degraded during mitotic exit by APC/C-Cdh1.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. BUB1 subfamily. UniProt O43683 1 EQUAL 1085 EQUAL Reactome DB_ID: 164603 1 UniProt:P53350 PLK1 PLK1 PLK1 PLK FUNCTION Serine/threonine-protein kinase that performs several important functions throughout M phase of the cell cycle, including the regulation of centrosome maturation and spindle assembly, the removal of cohesins from chromosome arms, the inactivation of anaphase-promoting complex/cyclosome (APC/C) inhibitors, and the regulation of mitotic exit and cytokinesis. Polo-like kinase proteins acts by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates BORA, BUB1B/BUBR1, CCNB1, CDC25C, CEP55, ECT2, ERCC6L, FBXO5/EMI1, FOXM1, KIF20A/MKLP2, CENPU, NEDD1, NINL, NPM1, NUDC, PKMYT1/MYT1, KIZ, PPP1R12A/MYPT1, PRC1, RACGAP1/CYK4, SGO1, STAG2/SA2, TEX14, TOPORS, p73/TP73, TPT1, WEE1 and HNRNPU. Plays a key role in centrosome functions and the assembly of bipolar spindles by phosphorylating KIZ, NEDD1 and NINL. NEDD1 phosphorylation promotes subsequent targeting of the gamma-tubulin ring complex (gTuRC) to the centrosome, an important step for spindle formation. Phosphorylation of NINL component of the centrosome leads to NINL dissociation from other centrosomal proteins. Involved in mitosis exit and cytokinesis by phosphorylating CEP55, ECT2, KIF20A/MKLP2, CENPU, PRC1 and RACGAP1. Recruited at the central spindle by phosphorylating and docking PRC1 and KIF20A/MKLP2; creates its own docking sites on PRC1 and KIF20A/MKLP2 by mediating phosphorylation of sites subsequently recognized by the POLO box domains. Phosphorylates RACGAP1, thereby creating a docking site for the Rho GTP exchange factor ECT2 that is essential for the cleavage furrow formation. Promotes the central spindle recruitment of ECT2. Plays a central role in G2/M transition of mitotic cell cycle by phosphorylating CCNB1, CDC25C, FOXM1, CENPU, PKMYT1/MYT1, PPP1R12A/MYPT1 and WEE1. Part of a regulatory circuit that promotes the activation of CDK1 by phosphorylating the positive regulator CDC25C and inhibiting the negative regulators WEE1 and PKMYT1/MYT1. Also acts by mediating phosphorylation of cyclin-B1 (CCNB1) on centrosomes in prophase. Phosphorylates FOXM1, a key mitotic transcription regulator, leading to enhance FOXM1 transcriptional activity. Involved in kinetochore functions and sister chromatid cohesion by phosphorylating BUB1B/BUBR1, FBXO5/EMI1 and STAG2/SA2. PLK1 is high on non-attached kinetochores suggesting a role of PLK1 in kinetochore attachment or in spindle assembly checkpoint (SAC) regulation. Required for kinetochore localization of BUB1B. Regulates the dissociation of cohesin from chromosomes by phosphorylating cohesin subunits such as STAG2/SA2. Phosphorylates SGO1: required for spindle pole localization of isoform 3 of SGO1 and plays a role in regulating its centriole cohesion function. Mediates phosphorylation of FBXO5/EMI1, a negative regulator of the APC/C complex during prophase, leading to FBXO5/EMI1 ubiquitination and degradation by the proteasome. Acts as a negative regulator of p53 family members: phosphorylates TOPORS, leading to inhibit the sumoylation of p53/TP53 and simultaneously enhance the ubiquitination and subsequent degradation of p53/TP53. Phosphorylates the transactivation domain of the transcription factor p73/TP73, leading to inhibit p73/TP73-mediated transcriptional activation and pro-apoptotic functions. Phosphorylates BORA, and thereby promotes the degradation of BORA. Contributes to the regulation of AURKA function. Also required for recovery after DNA damage checkpoint and entry into mitosis. Phosphorylates MISP, leading to stabilization of cortical and astral microtubule attachments required for proper spindle positioning (PubMed:8991084, PubMed:11202906, PubMed:12207013, PubMed:12447691, PubMed:12524548, PubMed:12738781, PubMed:12852856, PubMed:12939256, PubMed:14532005, PubMed:14734534, PubMed:15070733, PubMed:15148369, PubMed:15469984, PubMed:16198290, PubMed:16247472, PubMed:16980960, PubMed:17081991, PubMed:17351640, PubMed:17376779, PubMed:17617734, PubMed:18174154, PubMed:18331714, PubMed:18418051, PubMed:18477460, PubMed:18521620, PubMed:18615013, PubMed:19160488, PubMed:19351716, PubMed:19468300, PubMed:19468302, PubMed:19473992, PubMed:19509060, PubMed:19597481, PubMed:23455478, PubMed:23509069). Together with MEIKIN, acts as a regulator of kinetochore function during meiosis I: required both for mono-orientation of kinetochores on sister chromosomes and protection of centromeric cohesin from separase-mediated cleavage (By similarity). Phosphorylates CEP68 and is required for its degradation (PubMed:25503564). Regulates nuclear envelope breakdown during prophase by phosphorylating DCTN1 resulting in its localization in the nuclear envelope (PubMed:20679239). Phosphorylates the heat shock transcription factor HSF1, promoting HSF1 nuclear translocation upon heat shock (PubMed:15661742). Phosphorylates HSF1 also in the early mitotic period; this phosphorylation regulates HSF1 localization to the spindle pole, the recruitment of the SCF(BTRC) ubiquitin ligase complex induicing HSF1 degradation, and hence mitotic progression (PubMed:18794143). Regulates mitotic progression by phosphorylating RIOK2 (PubMed:21880710). Through the phosphorylation of DZIP1 regulates the localization during mitosis of the BBSome, a ciliary protein complex involved in cilium biogenesis (PubMed:27979967).ACTIVITY REGULATION Activated by phosphorylation of Thr-210 by AURKA; phosphorylation by AURKA is enhanced by BORA. Once activated, activity is stimulated by binding target proteins. Binding of target proteins has no effect on the non-activated kinase. Several inhibitors targeting PLKs are currently in development and are under investigation in a growing number of clinical trials, such as BI 2536, an ATP-competitive PLK1 inhibitor or BI 6727, a dihydropteridinone that specifically inhibits the catalytic activity of PLK1.SUBUNIT Interacts with CEP170 and EVI5. Interacts and phosphorylates ERCC6L. Interacts with FAM29A. Interacts with SLX4/BTBD12 and TTDN1. Interacts with BUB1B. Interacts (via POLO-box domain) with the phosphorylated form of BUB1, CENPU and CDC25C. Interacts with isoform 3 of SGO1. Interacts with BORA, KIF2A and AURKA. Interacts with TOPORS and CYLD. Interacts with ECT2; the interaction is stimulated upon phosphorylation of ECT2 on 'Thr-444'. Interacts with PRC1. Interacts with KIF20A/MKLP2 (when phosphorylated), leading to the recruitment at the central spindle. Interacts (via POLO box domains) with PPP1R12A/MYPT1 (when previously phosphorylated by CDK1). Part of an astrin (SPAG5)-kinastrin (SKAP) complex containing KNSTRN, SPAG5, PLK1, DYNLL1 and SGO2. Interacts with BIRC6/bruce. Interacts with CDK1-phosphorylated FRY; this interaction occurs in mitotic cells, but not in interphase cells. FRY interaction facilitates AURKA-mediated PLK1 phosphorylation. Interacts with CDK1-phosphorylated DCTN6 during mitotic prometaphase; the interaction facilitates recruitment to kinetochores. Interacts with CEP68; the interaction phosphorylates CEP68 (PubMed:25503564). Interacts (via POLO-box domain) with DCTN1 (PubMed:20679239). Interacts with CEP20 in later G1, S, G2 and M phases of the cell cycle; this interaction recruits PLK1 to centrosomes, a step required for S phase progression (PubMed:24018379). Interacts with HSF1; this interaction increases upon heat shock but does not modulate neither HSF1 homotrimerization nor DNA-binding activities (PubMed:15661742, PubMed:18794143). Interacts with HNRNPU; this interaction induces phosphorylation of HNRNPU in mitosis (PubMed:25986610). Interacts (via its N-terminus) to RIOK2 (PubMed:21880710). Interacts with KLHL22 (PubMed:24067371, PubMed:23455478).TISSUE SPECIFICITY Placenta and colon.DEVELOPMENTAL STAGE Accumulates to a maximum during the G2 and M phases, declines to a nearly undetectable level following mitosis and throughout G1 phase, and then begins to accumulate again during S phase.INDUCTION By growth-stimulating agents.DOMAIN The POLO box domains act as phosphopeptide-binding module that recognize and bind serine-[phosphothreonine/phosphoserine]-(proline/X) motifs. PLK1 recognizes and binds docking proteins that are already phosphorylated on these motifs, and then phosphorylates them. PLK1 can also create its own docking sites by mediating phosphorylation of serine-[phosphothreonine/phosphoserine]-(proline/X) motifs subsequently recognized by the POLO box domains.PTM Catalytic activity is enhanced by phosphorylation of Thr-210. Phosphorylation at Thr-210 is first detected on centrosomes in the G2 phase of the cell cycle, peaks in prometaphase and gradually disappears from centrosomes during anaphase. Dephosphorylation at Thr-210 at centrosomes is probably mediated by protein phosphatase 1C (PP1C), via interaction with PPP1R12A/MYPT1. Autophosphorylation and phosphorylation of Ser-137 may not be significant for the activation of PLK1 during mitosis, but may enhance catalytic activity during recovery after DNA damage checkpoint. Phosphorylated in vitro by STK10.PTM Ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) in anaphase and following DNA damage, leading to its degradation by the proteasome. Ubiquitination is mediated via its interaction with FZR1/CDH1. Ubiquitination and subsequent degradation prevents entry into mitosis and is essential to maintain an efficient G2 DNA damage checkpoint. Monoubiquitination at Lys-492 by the BCR(KLHL22) ubiquitin ligase complex does not lead to degradation: it promotes PLK1 dissociation from phosphoreceptor proteins and subsequent removal from kinetochores, allowing silencing of the spindle assembly checkpoint (SAC) and chromosome segregation.DISEASE Defects in PLK1 are associated with some cancers, such as gastric, thyroid or B-cell lymphomas. Expression is cancer increased in tumor tissues with a poor prognosis, suggesting a role in malignant transformations and carcinogenesis.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. CDC5/Polo subfamily. UniProt P53350 1 EQUAL 603 EQUAL Reactome DB_ID: 376229 1 UniProt:P49454 CENPF CENPF CENPF FUNCTION Required for kinetochore function and chromosome segregation in mitosis. Required for kinetochore localization of dynein, LIS1, NDE1 and NDEL1. Regulates recycling of the plasma membrane by acting as a link between recycling vesicles and the microtubule network though its association with STX4 and SNAP25. Acts as a potential inhibitor of pocket protein-mediated cellular processes during development by regulating the activity of RB proteins during cell division and proliferation. May play a regulatory or permissive role in the normal embryonic cardiomyocyte cell cycle and in promoting continued mitosis in transformed, abnormally dividing neonatal cardiomyocytes. Interaction with RB directs embryonic stem cells toward a cardiac lineage. Involved in the regulation of DNA synthesis and hence cell cycle progression, via its C-terminus. Has a potential role regulating skeletal myogenesis and in cell differentiation in embryogenesis. Involved in dendritic cell regulation of T-cell immunity against chlamydia.SUBUNIT Interacts with and STX4 (via C-terminus) (By similarity). Interacts (via N-terminus) with RBL1, RBL2 and SNAP25 (By similarity). Self-associates. Interacts with CENP-E and BUBR1 (via C-terminus). Interacts (via C-terminus) with NDE1, NDEL1 and RB1.DEVELOPMENTAL STAGE Gradually accumulates during the cell cycle, reaching peak levels in G2 and M phase, and is rapidly degraded upon completion of mitosis.PTM Hyperphosphorylated during mitosis.SIMILARITY Belongs to the centromere protein F family. UniProt P49454 1 EQUAL 3207 EQUAL Reactome DB_ID: 377731 1 UniProt:Q9Y266 NUDC NUDC NUDC FUNCTION Plays a role in neurogenesis and neuronal migration (By similarity). Necessary for correct formation of mitotic spindles and chromosome separation during mitosis (PubMed:12852857, PubMed:12679384, PubMed:25789526). Necessary for cytokinesis and cell proliferation (PubMed:12852857, PubMed:12679384).SUBUNIT Interacts with PAFAH1B1 (By similarity). Interacts with PLK1 (PubMed:12852857). Part of a complex containing PLK1, NUDC, dynein and dynactin (PubMed:12852857). Interacts with DCDC1 (PubMed:22159412). Interacts with EML4 (via WD repeats) (PubMed:25789526).TISSUE SPECIFICITY Ubiquitous. Highly expressed in fetal liver, kidney, lung and brain. Highly expressed in adult pancreas, kidney, skeletal muscle, liver, lung, placenta, prostate, brain and heart.INDUCTION Up-regulated in actively dividing hematopoietic precursor cells. Up-regulated in cultured erythroleukemia TF-1 cells by granulocyte-macrophage colony-stimulating factor. Strongly down-regulated during maturation of erythroid precursor cells.PTM Reversibly phosphorylated on serine residues during the M phase of the cell cycle. Phosphorylation on Ser-274 and Ser-326 is necessary for correct formation of mitotic spindles and chromosome separation during mitosis. Phosphorylated by PLK and other kinases.SIMILARITY Belongs to the nudC family. UniProt Q9Y266 1 EQUAL 331 EQUAL Reactome DB_ID: 376235 1 UniProt:Q9P258 RCC2 RCC2 RCC2 TD60 KIAA1470 FUNCTION Multifunctional protein that may effect its functions by regulating the activity of small GTPases, such as RAC1 and RALA (PubMed:12919680, PubMed:25074804, PubMed:26158537, PubMed:28869598). Required for normal progress through the cell cycle, both during interphase and during mitosis (PubMed:23388455, PubMed:12919680, PubMed:26158537). Required for the presence of normal levels of MAD2L1, AURKB and BIRC5 on inner centromeres during mitosis, and for normal attachment of kinetochores to mitotic spindles (PubMed:12919680, PubMed:26158537). Required for normal organization of the microtubule cytoskeleton in interphase cells (PubMed:23388455). Functions as guanine nucleotide exchange factor (GEF) for RALA (PubMed:26158537). Interferes with the activation of RAC1 by guanine nucleotide exchange factors (PubMed:25074804). Prevents accumulation of active, GTP-bound RAC1, and suppresses RAC1-mediated reorganization of the actin cytoskeleton and formation of membrane protrusions (PubMed:25074804, PubMed:28869598). Required for normal cellular responses to contacts with the extracellular matrix of adjacent cells, and for directional cell migration in response to a fibronectin gradient (in vitro) (PubMed:25074804, PubMed:28869598).SUBUNIT Interacts with RAC1 (PubMed:12919680, PubMed:25074804, PubMed:28869598). Interacts with nucleotide-free and with GDP and GTP-bound forms of RAC1, with a slight preference for GDP-bound RAC1 (PubMed:25074804). Binds preferentially to the nucleotide-free form of RAC1 (PubMed:12919680). Interacts with CORO1C (PubMed:25074804). Interacts with microtubules (PubMed:12919680).INDUCTION Induced by TP53/p53 in response to oxidative stress and DNA damage.CAUTION Its precise role in the regulation of RAC1 activity is under debate. Was originally proposed to function as a guanine nucleotide exchange factor for RAC1, but later publications indicate it attenuates RAC1 activation by guanine nucleotide exchange factors and prevents accumulation of active, GTP-bound RAC1 (PubMed:12919680, PubMed:25074804, PubMed:28869598). Conflicting results have also been reported regarding its preferential interaction with nucleotide-free RAC1, as opposed to GPD or GTP-bound RAC1 (PubMed:12919680, PubMed:25074804). UniProt Q9P258 1 EQUAL 522 EQUAL Reactome DB_ID: 376259 1 UniProt:Q8N4N8 KIF2B KIF2B KIF2B FUNCTION Plus end-directed microtubule-dependent motor required for spindle assembly and chromosome movement. Has microtubule depolymerization activity (PubMed:17538014). Plays a role in chromosome congression (PubMed:23891108).TISSUE SPECIFICITY Highest level in lung. High level in ovary, moderate levels in heart, kidney, placenta, skeletal muscle and spleen (at protein level). Pancreas and spleen express a shorter isoform (at protein level).PTM Phosphorylation at Thr-125 by PLK1 is required for activity in the correction of kinetochore-microtubules attachment errors, while phosphorylation at Ser-204 also by PLK1 is required for the kinetochore localization and activity in prometaphase.MISCELLANEOUS Osteosarcoma cells (U2OS) lacking KIF2B show disorganised often monopolar mitotic spindles, severely reduced velocity of chromosome movement and blocked cytokinesis. Bipolar mitotic spindles can be restored by simultaneous depletion of KIF2B, KIFC1 and NUMA1.SIMILARITY Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. MCAK/KIF2 subfamily. UniProt Q8N4N8 1 EQUAL 673 EQUAL Reactome DB_ID: 377883 1 Nup107-160 complex [cytosol] Nup107-160 complex Reactome DB_ID: 376246 1 UniProt:Q96EE3-1 SEH1L SEH1L SEH1L SEC13L SEH1 FUNCTION Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex is required for the assembly of a functional NPC. The Nup107-160 subcomplex is also required for normal kinetochore microtubule attachment, mitotic progression and chromosome segregation. This subunit plays a role in recruitment of the Nup107-160 subcomplex to the kinetochore.FUNCTION As a component of the GATOR subcomplex GATOR2, functions within the amino acid-sensing branch of the TORC1 signaling pathway. Indirectly activates mTORC1 and the TORC1 signaling pathway through the inhibition of the GATOR1 subcomplex (PubMed:23723238). It is negatively regulated by the upstream amino acid sensors SESN2 and CASTOR1 (PubMed:25457612, PubMed:27487210).SUBUNIT Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex includes NUP160, NUP133, NUP107, NUP98, NUP85, NUP43, NUP37, SEH1 and SEC13. The SEH1 subunit appears to be only weakly associated with the Nup107-160 subcomplex. Within the GATOR complex, component of the GATOR2 subcomplex, made of MIOS, SEC13, SEH1L, WDR24 and WDR59. The GATOR complex strongly interacts with RRAGA/RRAGC and RRAGB/RRAGC heterodimers (PubMed:17360435, PubMed:23723238). The GATOR2 complex interacts with CASTOR2 and CASTOR1; the interaction is negatively regulated by arginine (PubMed:26972053). The GATOR2 complex interacts with SESN1, SESN2 and SESN3; the interaction is negatively regulated by amino acids (PubMed:25263562, PubMed:25457612).SIMILARITY Belongs to the WD repeat SEC13 family. UniProt Q96EE3-1 1 EQUAL 360 EQUAL Reactome DB_ID: 376241 1 UniProt:P57740 NUP107 NUP107 NUP107 FUNCTION Plays a role in the nuclear pore complex (NPC) assembly and/or maintenance (PubMed:12552102, PubMed:15229283, PubMed:30179222). Required for the assembly of peripheral proteins into the NPC (PubMed:15229283, PubMed:12552102). May anchor NUP62 to the NPC (PubMed:15229283). Involved in nephrogenesis (PubMed:30179222).SUBUNIT Part of the nuclear pore complex (NPC) (PubMed:11564755, PubMed:12802065, PubMed:15229283, PubMed:26411495). Forms part of the Nup160 subcomplex in the nuclear pore which is composed of NUP160, NUP133, NUP107 and Nup96; this complex plays a role in RNA export and in tethering Nup98 and NUP153 to the nucleus (PubMed:11564755, PubMed:11684705, PubMed:26411495, PubMed:30179222). Does not interact with TPR (PubMed:12802065). Interacts with ZNF106 (By similarity).TISSUE SPECIFICITY Ubiquitously expressed in fetal and adult tissues.SIMILARITY Belongs to the nucleoporin Nup84/Nup107 family. UniProt P57740 1 EQUAL 925 EQUAL Reactome DB_ID: 376237 1 UniProt:Q8NFH4 NUP37 NUP37 NUP37 FUNCTION Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex is required for the assembly of a functional NPC. The Nup107-160 subcomplex is also required for normal kinetochore microtubule attachment, mitotic progression and chromosome segregation.SUBUNIT Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex includes NUP160, NUP133, NUP107, NUP98, NUP85, NUP43, NUP37, SEH1 and SEC13. UniProt Q8NFH4 1 EQUAL 326 EQUAL Reactome DB_ID: 376253 1 UniProt:Q12769 NUP160 NUP160 KIAA0197 NUP120 NUP160 FUNCTION Functions as a component of the nuclear pore complex (NPC) (PubMed:11564755, PubMed:11684705). Involved in poly(A)+ RNA transport.SUBUNIT Part of the nuclear pore complex (NPC) (PubMed:11564755, PubMed:11684705). Forms part of the NUP160 subcomplex in the nuclear pore which is composed of NUP160, NUP133, NUP107 and NUP96 (PubMed:11564755, PubMed:11684705). This complex plays a role in RNA export and in tethering NUP98 and NUP153 to the nucleus (PubMed:11564755, PubMed:11684705).CAUTION It is uncertain whether Met-1 or Met-35 is the initiator. UniProt Q12769 1 EQUAL 1436 EQUAL Reactome DB_ID: 376251 1 UniProt:Q8WUM0 NUP133 NUP133 NUP133 FUNCTION Involved in poly(A)+ RNA transport. Involved in nephrogenesis (PubMed:30179222).SUBUNIT Forms part of the Nup160 subcomplex in the nuclear pore which is composed of NUP160, NUP133, NUP107 and Nup96. This complex plays a role in RNA export and in tethering Nup98 and NUP153 to the nucleus.TISSUE SPECIFICITY Widely expressed in fetal and adult tissues. Expressed in the brain and kidney.SIMILARITY Belongs to the nucleoporin Nup133 family. UniProt Q8WUM0 1 EQUAL 1156 EQUAL Reactome DB_ID: 376238 1 UniProt:Q9BW27 NUP85 NUP85 NUP75 NUP85 PCNT1 FUNCTION Essential component of the nuclear pore complex (NPC) that seems to be required for NPC assembly and maintenance (PubMed:12718872). As part of the NPC Nup107-160 subcomplex plays a role in RNA export and in tethering NUP96/Nup98 and NUP153 to the nucleus (PubMed:12718872). The Nup107-160 complex seems to be required for spindle assembly during mitosis (PubMed:16807356). NUP85 is required for membrane clustering of CCL2-activated CCR2 (PubMed:15995708). Seems to be involved in CCR2-mediated chemotaxis of monocytes and may link activated CCR2 to the phosphatidyl-inositol 3-kinase-Rac-lammellipodium protrusion cascade (PubMed:15995708). Involved in nephrogenesis (PubMed:30179222).SUBUNIT Component of the nuclear pore complex (NPC) (PubMed:12196509). Component of the NPC Nup107-160 subcomplex, consisting of at least NUP107, NUP98/Nup96, NUP160, NUP133, NUP85, NUP37, NUP43 and SEC13 (PubMed:15146057). Interacts with NUP160, NUP133 and SEC13 (PubMed:12718872, PubMed:30179222). Interacts with NUP37, NUP107 and NUP43 (PubMed:15146057). Interacts with CCR2 (PubMed:15995708).SIMILARITY Belongs to the nucleoporin Nup85 family. UniProt Q9BW27 1 EQUAL 656 EQUAL Reactome DB_ID: 376243 1 UniProt:Q8NFH3 NUP43 NUP43 NUP43 FUNCTION Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex is required for the assembly of a functional NPC. The Nup107-160 subcomplex is also required for normal kinetochore microtubule attachment, mitotic progression and chromosome segregation.SUBUNIT Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex includes NUP160, NUP133, NUP107, NUP98, NUP85, NUP43, NUP37, SEH1 and SEC13. UniProt Q8NFH3 1 EQUAL 380 EQUAL Reactome DB_ID: 203981 1 UniProt:P55735 SEC13 SEC13 SEC13 SEC13L1 SEC13R SEC13A D3S1231E FUNCTION Functions as a component of the nuclear pore complex (NPC) and the COPII coat. At the endoplasmic reticulum, SEC13 is involved in the biogenesis of COPII-coated vesicles (PubMed:8972206). Required for the exit of adipsin (CFD/ADN), an adipocyte-secreted protein from the endoplasmic reticulum (By similarity).FUNCTION As a component of the GATOR subcomplex GATOR2, functions within the amino acid-sensing branch of the TORC1 signaling pathway. Indirectly activates mTORC1 and the TORC1 signaling pathway through the inhibition of the GATOR1 subcomplex (PubMed:23723238). It is negatively regulated by the upstream amino acid sensors SESN2 and CASTOR1 (PubMed:25457612, PubMed:27487210).SUBUNIT At the nuclear pore: component of the Y-shaped Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex includes NUP160, NUP133, NUP107, NUP98, NUP85, NUP43, NUP37, SEH1 and SEC13. At the COPII coat complex: interacts with SEC31A and SEC31B. Within the GATOR complex, component of the GATOR2 subcomplex, made of MIOS, SEC13, SEH1L, WDR24 and WDR59. The GATOR complex strongly interacts with RRAGA/RRAGC and RRAGB/RRAGC heterodimers (PubMed:14517296, PubMed:16495487, PubMed:16957052, PubMed:18160040, PubMed:23723238). The GATOR2 complex interacts with CASTOR2 and CASTOR1; the interaction is negatively regulated by arginine (PubMed:26972053). The GATOR2 complex interacts with SESN1, SESN2 and SESN3; the interaction is negatively regulated by amino acids (PubMed:25263562, PubMed:25457612). Interacts with SEC16A (PubMed:17428803, PubMed:19638414, PubMed:25201882). Interacts with SEC16B (PubMed:22355596).SIMILARITY Belongs to the WD repeat SEC13 family. UniProt P55735 2 EQUAL 322 EQUAL Reactome DB_ID: 376247 1 UniProt:P52948-5 NUP98 NUP98 NUP98 ADAR2 FUNCTION Plays a role in the nuclear pore complex (NPC) assembly and/or maintenance. NUP98 and NUP96 are involved in the bidirectional transport across the NPC (PubMed:33097660). May anchor NUP153 and TPR to the NPC. In cooperation with DHX9, plays a role in transcription and alternative splicing activation of a subset of genes (PubMed:28221134). Involved in the localization of DHX9 in discrete intranuclear foci (GLFG-body) (PubMed:28221134).FUNCTION (Microbial infection) Interacts with HIV-1 capsid protein P24 and nucleocapsid protein P7 and may thereby promote the integration of the virus in the host nucleus (in vitro) (PubMed:23523133). Binding affinity to HIV-1 CA-NC complexes bearing the capsid change ASN-74-ASP is reduced (in vitro) (PubMed:23523133).SUBUNIT Part of the nuclear pore complex (NPC) (PubMed:15229283, PubMed:18287282). Interacts directly with NUP96 (PubMed:12191480). Part of the Nup160 subcomplex in the nuclear pore which is composed of NUP160, NUP133, NUP107 and NUP96; this complex plays a role in RNA export and in tethering NUP98 and NUP153 to the nucleus (PubMed:11684705). Interacts with RAE1 (PubMed:10209021, PubMed:20498086). Does not interact with TPR (PubMed:11684705). Interacts with NUP88 (PubMed:30543681). Interacts directly with NUP88 and NUP214, subunits of the cytoplasmic filaments of the NPC (By similarity). Interacts (via N-terminus) with DHX9 (via DRBM, OB-fold and RGG domains); this interaction occurs in a RNA-dependent manner and stimulates DHX9-mediated ATPase activity (PubMed:28221134).SUBUNIT (Microbial infection) Interacts with HIV-1 capsid protein P24 and nucleocapsid protein P7 (in vitro); the interaction may promote the integration of the virus in the host nucleus (in vitro).SUBUNIT (Microbial infection) Interacts with vesicular stomatitis virus protein M (PubMed:11106761).SUBUNIT (Microbial infection) Interacts with SARS coronavirus-2/SARS-CoV-2 ORF6 protein; the interaction blocks STAT1 nuclear translocation, antagonizes interferon signaling and blocks mRNA nuclear export (ex vivo).SUBUNIT (Microbial infection) Interacts with SARS coronavirus/SARS-CoV ORF6 protein.DOMAIN Contains G-L-F-G repeats. The FG repeat domains in Nup98 have a direct role in the transport.PTM Isoform 1 to isoform 4 are autoproteolytically cleaved to yield Nup98 and Nup96 or Nup98 only, respectively (PubMed:10087256, PubMed:20407419, PubMed:12191480, PubMed:18287282). Cleaved Nup98 is necessary for the targeting of Nup98 to the nuclear pore and the interaction with Nup96 (PubMed:20407419, PubMed:12191480).PTM Proteolytically degraded after poliovirus (PV) infection; degradation is partial and NCP- and TPR-binding domains withstand degradation.DISEASE Chromosomal aberrations involving NUP98 have been found in acute myeloid leukemia. Translocation t(7;11)(p15;p15) with HOXA9 (PubMed:8563753). The chimera includes NUP98 intrinsic disordered regions which contribute to aberrant liquid-liquid phase separation puncta of the chimera in the nucleus. This phase-separation enhances the chimera genomic targeting and induces organization of aberrant three-dimensional chromatin structures leading to tumorous transformation (PubMed:34163069). Translocation t(11;17)(p15;p13) with PHF23 (PubMed:17287853).DISEASE A chromosomal aberration involving NUP98 has been found in M0 type acute myeloid leukemia. Translocation t(4;11)(q23;p15) with RAP1GDS1.DISEASE A chromosomal aberration involving NUP98 has been found in T-cell acute lymphocytic leukemia. Translocation t(4;11)(q23;p15) with RAP1GDS1.DISEASE A chromosomal aberration involving NUP98 has been found in M5 type acute myeloid leukemia. Translocation t(11;12)(p15;p13) with KDM5A.DISEASE Chromosomal aberrations involving NUP98 have been found in childhood acute myeloid leukemia. Translocation t(5;11)(q35;p15.5) with NSD1. Translocation t(8;11)(p11.2;p15) with WHSC1L1.DISEASE Chromosomal aberrations involving NUP98 have been found in M7 type childhood acute myeloid leukemia. Translocation t(11;12)(p15;p13) with KDM5A.DISEASE A chromosomal aberration involving NUP98 is found in a form of therapy-related myelodysplastic syndrome. Translocation t(11;20)(p15;q11) with TOP1.DISEASE A chromosomal aberration involving NUP98 is found in a form of T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(3;11)(q12.2;p15.4) with LNP1.DISEASE A chromosomal aberration involving NUP98 is associated with pediatric acute myeloid leukemia (AML) with intermediate characteristics between M2-M3 French-American-British (FAB) subtypes. Translocation t(9;11)(p22;p15) with PSIP1/LEDGF. The chimeric transcript is an in-frame fusion of NUP98 exon 8 to PSIP1/LEDGF exon 4.DISEASE A chromosomal aberration involving NUP98 has been identified in acute leukemias. Translocation t(6;11)(q24.1;p15.5) with CCDC28A. The chimeric transcript is an in-frame fusion of NUP98 exon 13 to CCDC28A exon 2. Ectopic expression of NUP98-CCDC28A in mouse promotes the proliferative capacity and self-renewal potential of hematopoietic progenitors and rapidly induced fatal myeloproliferative neoplasms and defects in the differentiation of the erythro-megakaryocytic lineage.SIMILARITY Belongs to the nucleoporin GLFG family. UniProt P52948-5 1 EQUAL 880 EQUAL Reactome Database ID Release 81 377883 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=377883 Reactome R-HSA-377883 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-377883.2 Reactome DB_ID: 376258 1 UniProt:Q9GZM8 NDEL1 NDEL1 NUDEL EOPA MITAP1 NDEL1 FUNCTION Required for organization of the cellular microtubule array and microtubule anchoring at the centrosome. May regulate microtubule organization at least in part by targeting the microtubule severing protein KATNA1 to the centrosome. Also positively regulates the activity of the minus-end directed microtubule motor protein dynein. May enhance dynein-mediated microtubule sliding by targeting dynein to the microtubule plus ends. Required for several dynein- and microtubule-dependent processes such as the maintenance of Golgi integrity, the centripetal motion of secretory vesicles and the coupling of the nucleus and centrosome. Also required during brain development for the migration of newly formed neurons from the ventricular/subventricular zone toward the cortical plate. Plays a role, together with DISC1, in the regulation of neurite outgrowth. Required for mitosis in some cell types but appears to be dispensible for mitosis in cortical neuronal progenitors, which instead requires NDE1. Facilitates the polymerization of neurofilaments from the individual subunits NEFH and NEFL. Positively regulates lysosome peripheral distribution and ruffled border formation in osteoclasts (By similarity).SUBUNIT Interacts with PLEKHM1 (via N- and C-terminus) (By similarity). Interacts with YWHAE. Interacts directly with NEFL and indirectly with NEFH. Interacts with microtubules (By similarity). Self-associates. Interacts with DISC1, dynein, dynactin, tubulin gamma, KATNA1, KATNB1, PAFAH1B1, PCM1 and PCNT. Interacts (via C-terminus) with CENPF. Interacts with ZNF365.TISSUE SPECIFICITY Expressed in brain, heart, kidney, liver, lung, pancreas, placenta and skeletal muscle.DEVELOPMENTAL STAGE Expression peaks in mitosis.PTM Phosphorylated in mitosis. Can be phosphorylated by CDK1, CDK5 and MAPK1. Phosphorylation by CDK5 promotes interaction with KATNA1 and YWHAE.PTM Palmitoylation at Cys-273 reduces affinity for dynein.SIMILARITY Belongs to the nudE family.CAUTION Was originally thought to function as an oligopeptidase (NUDEL-oligopeptidase or endooligopeptidase A) which could regulate peptide levels relevant to brain function. UniProt Q9GZM8 1 EQUAL 345 EQUAL Reactome DB_ID: 376248 1 UniProt:Q7L7X3 TAOK1 TAOK1 MAP3K16 MARKK TAOK1 KIAA1361 FUNCTION Serine/threonine-protein kinase involved in various processes such as p38/MAPK14 stress-activated MAPK cascade, DNA damage response and regulation of cytoskeleton stability. Phosphorylates MAP2K3, MAP2K6 and MARK2. Acts as an activator of the p38/MAPK14 stress-activated MAPK cascade by mediating phosphorylation and subsequent activation of the upstream MAP2K3 and MAP2K6 kinases. Involved in G-protein coupled receptor signaling to p38/MAPK14. In response to DNA damage, involved in the G2/M transition DNA damage checkpoint by activating the p38/MAPK14 stress-activated MAPK cascade, probably by mediating phosphorylation of MAP2K3 and MAP2K6. Acts as a regulator of cytoskeleton stability by phosphorylating 'Thr-208' of MARK2, leading to activate MARK2 kinase activity and subsequent phosphorylation and detachment of MAPT/TAU from microtubules. Also acts as a regulator of apoptosis: regulates apoptotic morphological changes, including cell contraction, membrane blebbing and apoptotic bodies formation via activation of the MAPK8/JNK cascade.ACTIVITY REGULATION Serine/threonine-protein kinase activity is inhibited by SPRED1.SUBUNIT Self-associates. Interacts with MAP2K3 (By similarity). Interacts with SPRED1 (By similarity). Interacts with TESK1; the interaction inhibits TAOK1 kinase activity (By similarity). Interacts with MAP3K7.TISSUE SPECIFICITY Highly expressed in the testis, and to a lower extent also expressed in brain, placenta, colon and skeletal muscle.INDUCTION In response to DNA damage.PTM Proteolytically processed by caspase-3 (CASP3).PTM Autophosphorylated (By similarity). Phosphorylated by ATM in response to DNA damage. Phosphorylated by LRRK2.SIMILARITY Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily.CAUTION Was initially thought to play a role in the spindle checkpoint (PubMed:17417629). However, it was later shown that it is not the case and that phenotypes initially observed are the cause of the siRNA used that has an off-target effect resulting in MAD2L1 inhibition (PubMed:19904549 and PubMed:20162290). UniProt Q7L7X3 1 EQUAL 1001 EQUAL Reactome DB_ID: 163443 1 UniProt:P36873 PPP1CC PPP1CC PPP1CC FUNCTION Protein phosphatase that associates with over 200 regulatory proteins to form highly specific holoenzymes which dephosphorylate hundreds of biological targets. Protein phosphatase 1 (PP1) is essential for cell division, and participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis. Dephosphorylates RPS6KB1. Involved in regulation of ionic conductances and long-term synaptic plasticity. May play an important role in dephosphorylating substrates such as the postsynaptic density-associated Ca(2+)/calmodulin dependent protein kinase II. Component of the PTW/PP1 phosphatase complex, which plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase. In balance with CSNK1D and CSNK1E, determines the circadian period length, through the regulation of the speed and rhythmicity of PER1 and PER2 phosphorylation. May dephosphorylate CSNK1D and CSNK1E. Dephosphorylates the 'Ser-418' residue of FOXP3 in regulatory T-cells (Treg) from patients with rheumatoid arthritis, thereby inactivating FOXP3 and rendering Treg cells functionally defective (PubMed:23396208).ACTIVITY REGULATION Inactivated by binding to URI1. The phosphatase activity of the PPP1R15A-PP1 complex toward EIF2S1 is specifically inhibited by Salubrinal, a drug that protects cells from endoplasmic reticulum stress.SUBUNIT PP1 comprises a catalytic subunit, PPP1CA, PPP1CB or PPP1CC, which is folded into its native form by inhibitor 2 and glycogen synthetase kinase 3, and then complexed to one or several targeting or regulatory subunits. PPP1R12A, PPP1R12B and PPP1R12C mediate binding to myosin. PPP1R3A (in skeletal muscle), PPP1R3B (in liver), PPP1R3C, PPP1R3D and PPP1R3F (in brain) mediate binding to glycogen. Interacts with cyanobacterial toxin microcystin; disulfide-linked. Interacts with PPP1R3B and PPP1R7. Isoform 2 interacts with SPZ1 (By similarity). Interacts with CDCA2. PPP1R15A and PPP1R15B mediate binding to EIF2S1. Part of a complex containing PPP1R15B, PP1 and NCK1/2. Interacts with IKFZ1; the interaction targets PPP1CC to pericentromeric heterochromatin, dephosphorylates IKAROS, stabilizes it and prevents it from degradation. Interacts with PPP1R42; the interaction is direct (By similarity). Interacts with NOM1 and PPP1R8. Component of the PTW/PP1 phosphatase complex, composed of PPP1R10/PNUTS, TOX4, WDR82, and PPP1CA or PPP1CB or PPP1CC. Interacts with PPP1R8. Interacts with isoform 1 and isoform 4 NEK2. Interacts with URI1; the interaction is phosphorylation-dependent and occurs in a growth factor-dependent manner. Interacts with FOXP3. Interacts with TMEM225 (via RVxF motif) (By similarity). Interacts with MKI67 (PubMed:24867636). Interacts with RRP1B; this targets PPP1CC to the nucleolus (PubMed:20926688). Interacts with PPP1R2B (PubMed:23506001). Found in a complex with PPP1CA, PPP1CC, SHC1 and PEAK1 (PubMed:23846654). Interacts with DYNLT4 (PubMed:23789093).INDUCTION Up-regulated in synovial fluid mononuclear cells and peripheral blood mononuclear cells from patients with rheumatoid arthritis.PTM Phosphorylated by NEK2.MISCELLANEOUS Microcystin toxin is bound to Cys-273 through a thioether bond.SIMILARITY Belongs to the PPP phosphatase family. PP-1 subfamily.CAUTION Was originally thought to be part of the MLL5-L complex, at least composed of KMT2E, STK38, PPP1CA, PPP1CB, PPP1CC, HCFC1, ACTB and OGT (PubMed:19377461). However, the corresponding article has been retracted (PubMed:24336203). UniProt P36873 2 EQUAL 323 EQUAL Reactome DB_ID: 376257 1 UniProt:Q9NXR1 NDE1 NDE1 NDE1 NUDE FUNCTION Required for centrosome duplication and formation and function of the mitotic spindle. Essential for the development of the cerebral cortex. May regulate the production of neurons by controlling the orientation of the mitotic spindle during division of cortical neuronal progenitors of the proliferative ventricular zone of the brain. Orientation of the division plane perpendicular to the layers of the cortex gives rise to two proliferative neuronal progenitors whereas parallel orientation of the division plane yields one proliferative neuronal progenitor and a post-mitotic neuron. A premature shift towards a neuronal fate within the progenitor population may result in an overall reduction in the final number of neurons and an increase in the number of neurons in the deeper layers of the cortex.SUBUNIT Self-associates. Interacts with CNTRL, LIS1, dynein, SLMAP and TCP1 (By similarity). Interacts with CENPF, dynactin, tubulin gamma, PAFAH1B1, PCM1 and PCNT. Interacts with ZNF365.TISSUE SPECIFICITY Expressed in the neuroepithelium throughout the developing brain, including the cerebral cortex and cerebellum.PTM Phosphorylated in mitosis. Phosphorylated in vitro by CDC2. Phosphorylation at Thr-246 is essential for the G2/M transition (By similarity).SIMILARITY Belongs to the nudE family. UniProt Q9NXR1 1 EQUAL 346 EQUAL Reactome Database ID Release 81 375305 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=375305 Reactome R-HSA-375305 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-375305.2 Reactome DB_ID: 5666139 1 DIAPH2-2 [cytosol] DIAPH2-2 DIAPH2-2 dimer Reactome DB_ID: 5666137 2 UniProt:O60879-2 DIAPH2 DIAPH2 DIAPH2 DIA FUNCTION Could be involved in oogenesis. Involved in the regulation of endosome dynamics. Implicated in a novel signal transduction pathway, in which isoform 3 and CSK are sequentially activated by RHOD to regulate the motility of early endosomes through interactions with the actin cytoskeleton.SUBUNIT Isoform 3 interacts with RHOD in the GTP-bound form.TISSUE SPECIFICITY Expressed in testis, ovary, small intestine, prostate, lung, liver, kidney and leukocytes.DEVELOPMENTAL STAGE Expressed from E16 in ovary and testis and during P6-P16 during differentiation of ovarian follicles.DOMAIN The DAD domain regulates activation via by an autoinhibitory interaction with the GBD/FH3 domain. This autoinhibition is released upon competitive binding of an activated GTPase. The release of DAD allows the FH2 domain to then nucleate and elongate nonbranched actin filaments (By similarity).SIMILARITY Belongs to the formin homology family. Diaphanous subfamily. UniProt O60879-2 1 EQUAL 1096 EQUAL Reactome Database ID Release 81 5666139 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666139 Reactome R-HSA-5666139 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666139.1 Reactome DB_ID: 5666123 1 CDC42:GTP [cytosol] CDC42:GTP Reactome DB_ID: 29438 1 Reactome DB_ID: 442630 1 1 EQUAL 188 EQUAL Reactome Database ID Release 81 5666123 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666123 Reactome R-HSA-5666123 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666123.1 Reactome DB_ID: 5666131 1 Kinetochore:CDC42:GTP:DIAPH2-2 [cytosol] Kinetochore:CDC42:GTP:DIAPH2-2 Reactome DB_ID: 375305 1 Reactome DB_ID: 5666139 1 Reactome DB_ID: 5666123 1 Reactome Database ID Release 81 5666131 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666131 Reactome R-HSA-5666131 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666131.1 Reactome Database ID Release 81 5666129 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666129 Reactome R-HSA-5666129 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666129.1 15085137 Pubmed 2004 Cdc42 and mDia3 regulate microtubule attachment to kinetochores Yasuda, Shingo Oceguera-Yanez, Fabian Kato, Takayuki Okamoto, Muneo Yonemura, Shigenobu Terada, Yasuhiko Ishizaki, Toshimasa Narumiya, Shuh Nature 428:767-71 2.7.11.1 AURKB phosphorylates DIAPH2-2 at kinetochores AURKB phosphorylates DIAPH2-2 at kinetochores Aurora kinase B (AURKB), which is part of the kinetochore, phosphorylates DIAPH2-2 (DIA-12C, mDia3) on serine residue S196 in the FH3 (DID) domain and probably on several other residues in the FH3 and FH2 domains. AURKB-mediated phosphorylation of DIAPH2-2 is necessary for the regulation of microtubule binding to kinetochores by the CDC42:GTP:DIAPH2-2 complex (Cheng et al. 2011). Authored: Orlic-Milacic, Marija, 2014-10-24 Authored: Rivero Crespo, Francisco, 2014-12-26 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 5666131 1 Reactome DB_ID: 113592 1 Reactome DB_ID: 29370 1 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 Reactome DB_ID: 5666161 1 Kinetochore:CDC42:GTP:p-S196-DIAPH2-2 [cytosol] Kinetochore:CDC42:GTP:p-S196-DIAPH2-2 Reactome DB_ID: 375305 1 Reactome DB_ID: 5666159 1 p-S196-DIAPH2-2 [cytosol] p-S196-DIAPH2-2 p-S196-DIAPH2-2 dimer Reactome DB_ID: 5666162 2 O-phospho-L-serine at 196 196 EQUAL O-phospho-L-serine [MOD:00046] 1 EQUAL 1096 EQUAL Reactome Database ID Release 81 5666159 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666159 Reactome R-HSA-5666159 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666159.1 Reactome DB_ID: 5666123 1 Reactome Database ID Release 81 5666161 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666161 Reactome R-HSA-5666161 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666161.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 5666131 GO 0004674 GO molecular function Reactome Database ID Release 81 5666157 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666157 Reactome Database ID Release 81 5666160 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666160 Reactome R-HSA-5666160 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666160.2 21397845 Pubmed 2011 Aurora B regulates formin mDia3 in achieving metaphase chromosome alignment Cheng, Lina Zhang, Jiayin Ahmad, Sana Rozier, Lorene Yu, Haiqian Deng, Haiteng Mao, Yinghui Dev. Cell 20:342-52 Kinetochore capture of astral microtubules is positively regulated by CDC42:GTP:p-S196-DIAPH2-2 Kinetochore capture of astral microtubules is positively regulated by CDC42:GTP:p-S196-DIAPH2-2 The recruitment of DIAPH2-2 (DIA-12C, mDia3) to kinetochores by activated CDC42 (CDC42:GTP) and DIAPH2-2 phosphorylation by AURKB positively regulates the attachment of microtubules to kinetochores (Yasuda et al. 2004, Cheng et al. 2011).<p>The human kinetochore, is a complex proteinaceous structure that assembles on centromeric DNA and mediates the association of mitotic chromosomes with spindle microtubules in prometaphase. The molecular composition of the human kinetochore is reviewed in detail in Cheeseman et al., 2008. This complex structure is composed of numerous protein complexes and networks including: the constitutive centromere-associated network (CCAN) containing several sub-networks such as (CENP-H, I, K), (CENP-50/U, O, P, Q, R), the KMN network (containing KNL1, the Mis12 complex, and the Ndc80 complex), the chromosomal passenger complex, the mitotic checkpoint complex, the nucleoporin 107-160 complex and the RZZ complex. <br>At prometaphase, following breakdown of the nuclear envelope, the kinetochores of condensed chromosomes begin to interact with spindle microtubules. In humans, 15-20 microtubules are bound to each kinetochore (McEwen et al., 2001), and the attachment of 15 microtubules to the kinetochore is shown in this reaction. Recently, it was found that the core kinetochore-microtubule attachment site is within the KMN network and is likely to be formed by two closely apposed low-affinity microtubule-binding sites, one in the Ndc80 complex and a second in KNL1 (Cheeseman et al., 2006). Authored: Matthews, L, 2008-08-24 03:27:07 Reviewed: Cheeseman, IM, 2008-09-02 04:22:10 Reviewed: Rivero Crespo, Francisco, 2014-12-26 Edited: Matthews, L, 2008-08-24 03:27:07 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 375305 1 Reactome DB_ID: 190599 15 Microtubule [cytosol] Microtubule Reactome DB_ID: 8982424 13 Microtubule protofilament [cytosol] Microtubule protofilament Reactome Database ID Release 81 190599 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=190599 Reactome R-HSA-190599 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-190599.2 Reactome DB_ID: 375303 1 Microtubule-bound kinetochore [cytosol] Microtubule-bound kinetochore Reactome DB_ID: 375305 1 Reactome DB_ID: 190599 15 Reactome Database ID Release 81 375303 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=375303 Reactome R-HSA-375303 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-375303.1 Reactome Database ID Release 81 5666169 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666169 Reactome R-HSA-5666169 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666169.4 17030981 Pubmed 2006 Mapping the assembly pathways that specify formation of the trilaminar kinetochore plates in human cells Liu, ST Rattner, JB Jablonski, SA Yen, Tim J Cell Biol 175:41-53 18097444 Pubmed 2008 Molecular architecture of the kinetochore-microtubule interface Cheeseman, IM Desai, A Nat Rev Mol Cell Biol 9:33-46 17129783 Pubmed 2006 The conserved KMN network constitutes the core microtubule-binding site of the kinetochore Cheeseman, IM Chappie, JS Wilson-Kubalek, EM Desai, A Cell 127:983-97 16622419 Pubmed 2006 The human CENP-A centromeric nucleosome-associated complex Foltz, DR Jansen, LE Black, BE Bailey, AO Yates, JR 3rd Cleveland, DW Nat Cell Biol 8:458-69 16622420 Pubmed 2006 The CENP-H-I complex is required for the efficient incorporation of newly synthesized CENP-A into centromeres Okada, M Cheeseman, IM Hori, T Okawa, K McLeod, IX Yates, JR 3rd Desai, A Fukagawa, T Nat Cell Biol 8:446-57 ACTIVATION Reactome Database ID Release 81 5666165 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5666165 Reactome R-HSA-5666165 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5666165.1 Reactome DB_ID: 5666161 DAAM1 recruits GTP-bound RHOA DAAM1 recruits GTP-bound RHOA Activated DAAM1 recruits RHOA to the DVL complex in a WNT-dependent manner. Activated DAAM1 is able to bind to RHOA in both the GDP and GTP bound form in vitro, but displays higher affinity for GTP-bound RHOA (Habas et al, 2001; Liu et al, 2007). Studies in Xenopus have identified a DVL-associated weak guanine exchange factor (WGEF) that promotes the exchange of GDP for GTP on RHOA and is required for WNT-PCP signaling (Tanegashima et al, 2008). Evidence suggests that a similar GEF activity is associated with the DVL-DAAM1-RHOA complex in human cells, but the protein has not been definitively identified (Habas et al, 2001; Liu et al, 2007). GTP-bound RHOA relieves the auto-inhibition of RHO-associated kinases, allowing them to dimerize and effect changes to cytoskeletal organization (reviewed in Amano et al, 2010; Lai et al, 2009). DAAM1 may also play a more direct role in regulating the cytoskeleton in response to WNT signaling, since FH domains have been shown to bind actin directly to nucleate linear actin cables (Sagot et al, 2002; Watanabe and Higashida, 2004). Authored: Rothfels, K, 2013-06-28 Reviewed: Kikuchi, Akira, 2013-11-12 Reviewed: Rivero Crespo, Francisco, 2014-12-26 Edited: Matthews, L, 2013-10-07 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 3858472 1 ppDVL:DAAM1 [cytosol] ppDVL:DAAM1 Reactome DB_ID: 351052 1 UniProt:Q9Y4D1 DAAM1 DAAM1 KIAA0666 DAAM1 FUNCTION Binds to disheveled (Dvl) and Rho, and mediates Wnt-induced Dvl-Rho complex formation. May play a role as a scaffolding protein to recruit Rho-GDP and Rho-GEF, thereby enhancing Rho-GTP formation. Can direct nucleation and elongation of new actin filaments. Involved in building functional cilia (PubMed:16630611, PubMed:17482208). Involved in the organization of the subapical actin network in multiciliated epithelial cells (By similarity). Together with DAAM2, required for myocardial maturation and sarcomere assembly (By similarity).SUBUNIT Homodimer. Interacts with CIP4, FNBP1 and FNBP1L. Interacts with the SH3 domains of Abl, BTK, endophilin, spectrin and SRC. Binds specifically to GTP-bound CDC42 and RHOA. Interacts with INTU; INTU mediates the indirect interaction between DAAM1 and NPHP4.TISSUE SPECIFICITY Expressed in all tissues examined.DOMAIN The C-terminal DAD domain may participate in intramolecular interactions with the N-terminus.DOMAIN The DAD domain regulates activation via by an autoinhibitory interaction with the GBD/FH3 domain. This autoinhibition is released upon competitive binding of an activated GTPase. The release of DAD allows the FH2 domain to then nucleate and elongate nonbranched actin filaments (By similarity).SIMILARITY Belongs to the formin homology family. UniProt Q9Y4D1 1 EQUAL 1078 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 3858467 1 pp-DVL [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity pp-DVL2 [cytosol] UniProt O14641 Reactome Database ID Release 81 3858472 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3858472 Reactome R-HSA-3858472 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3858472.1 Reactome DB_ID: 3858473 1 RHOA:GTP:Mg2+ [cytosol] RHOA:GTP:Mg2+ Reactome DB_ID: 29438 1 Reactome DB_ID: 194866 1 1 EQUAL 190 EQUAL Reactome DB_ID: 29926 1 magnesium(2+) [ChEBI:18420] magnesium(2+) ChEBI 18420 Reactome Database ID Release 81 3858473 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3858473 Reactome R-HSA-3858473 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3858473.1 Reactome DB_ID: 3858474 1 ppDVL:DAAM1:RHOA:GTP [cytosol] ppDVL:DAAM1:RHOA:GTP Reactome DB_ID: 3858472 1 Reactome DB_ID: 3858473 1 Reactome Database ID Release 81 3858474 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3858474 Reactome R-HSA-3858474 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3858474.1 Reactome Database ID Release 81 3858495 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3858495 Reactome R-HSA-3858495 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3858495.1 18162551 Pubmed 2008 Mechanism of activation of the Formin protein Daam1 Liu, Wei Sato, Akira Khadka, Deepak Bharti, Ritu Diaz, Hector Runnels, Loren W Habas, Raymond Proc Natl Acad Sci U S A 105:210-5 19365405 Pubmed 2009 Wnt/Fz signaling and the cytoskeleton: potential roles in tumorigenesis Lai, Shih-Lei Chien, Andy J Moon, Randall T Cell Res. 19:532-45 15501440 Pubmed 2004 Formins: processive cappers of growing actin filaments Watanabe, Naoki Higashida, Chiharu Exp. Cell Res. 301:16-22 11779461 Pubmed 2001 Wnt/Frizzled activation of Rho regulates vertebrate gastrulation and requires a novel Formin homology protein Daam1 Habas, Raymond Kato, Yoichi He, Xi Cell 107:843-54 12134165 Pubmed 2002 An actin nucleation mechanism mediated by Bni1 and profilin Sagot, Isabelle Rodal, Avital A Moseley, James Goode, Bruce L Pellman, David Nat. Cell Biol. 4:626-31 18256687 Pubmed 2008 WGEF activates Rho in the Wnt-PCP pathway and controls convergent extension in Xenopus gastrulation Tanegashima, Kosuke Zhao, Hui Dawid, Igor B EMBO J. 27:606-17 20803696 Pubmed 2010 Rho-kinase/ROCK: A key regulator of the cytoskeleton and cell polarity Amano, Mutsuki Nakayama, Masanori Kaibuchi, Kozo Cytoskeleton (Hoboken) 67:545-54 ppDVL binds DAAM1 ppDVL binds DAAM1 DAAM1 (Dishevelled-associated activator of morphogenesis) is a formin-homology protein that was identified in a yeast two-hybrid screen for interactors with the DVL PDZ domain (Habas et al, 2001). FH proteins play a well-characterized role in regulating cytoskeletal reorganization (reviewed in Aspenstrom, 2010). DAAM1 contains an N-terminal GTPase binding domain (GBD), two central proline-rich FH domains and a C-terminal diaphanous autoinhibitory domain (DAD). In the absence of a WNT signal, DAAM1 exists in an autoinhibited conformation mediated by an intramolecular interaction between the DBD and DAD regions (Habas et al, 2001; Liu et al, 2007). Upon WNT signaling, a direct interaction between the DAD of DAAM1 and the PDZ domain of DVL relieves the autoinhibition. In the activated conformation, DAAM1 may undergo FH-dependent oligomerization and had been shown to recruit RHOA in a GBD-dependent manner (Habas et al, 2001; Liu et al, 2007). Authored: Rothfels, K, 2013-06-28 Reviewed: Kikuchi, Akira, 2013-11-12 Reviewed: Rivero Crespo, Francisco, 2014-12-26 Edited: Matthews, L, 2013-10-07 Edited: Orlic-Milacic, Marija, 2015-02-02 Reactome DB_ID: 351052 1 1 EQUAL 1078 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 3858467 1 Reactome DB_ID: 3858472 1 Reactome Database ID Release 81 3858489 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3858489 Reactome R-HSA-3858489 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3858489.2 19589360 Pubmed 2010 Formin-binding proteins: modulators of formin-dependent actin polymerization Aspenström, Pontus Biochim. Biophys. Acta 1803:174-82 Reactome Database ID Release 81 5663220 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5663220 Reactome R-HSA-5663220 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5663220.1 12906795 Pubmed 2003 The mouse Formin mDia1 is a potent actin nucleation factor regulated by autoinhibition Li, Fang Higgs, Henry N Curr. Biol. 13:1335-40 16472745 Pubmed 2006 Structure of the autoinhibitory switch in formin mDia1 Nezami, Azin G Poy, Florence Eck, Michael J Structure 14:257-63 9497258 Pubmed 1998 A human homologue of the Drosophila melanogaster diaphanous gene is disrupted in a patient with premature ovarian failure: evidence for conserved function in oogenesis and implications for human sterility Bione, S Sala, C Manzini, C Arrigo, G Zuffardi, O Banfi, S Borsani, G Jonveaux, P Philippe, C Zuccotti, M Ballabio, A Toniolo, D Am. J. Hum. Genet. 62:533-41 20233848 Pubmed 2010 The small GTPase Rif is an alternative trigger for the formation of actin stress fibers in epithelial cells Fan, Lifei Pellegrin, Stephanie Scott, Alice Mellor, Harry J. Cell. Sci. 123:1247-52