BioPAX pathway converted from "PP2A-B56 dephosphorylates centromeric cohesin" in the Reactome database. 3.1.3.16 PP2A-B56 dephosphorylates centromeric cohesin PP2A-B56 dephosphorylates centromeric cohesin PLK1-mediated phosphorylation of the STAG2 subunit of centromeric cohesin (Hauf et al. 2005) is counteracted by the kinetochore PP2A phosphatase, containing the 56 kDa regulatory B subunit (PP2A-B56 i.e. PP2A-PPP2R5). PP2A-B56 is recruited to the centromeric cohesin complex by shugoshin proteins (SGOL1 and SGOL2) (Kitajima et al. 2006), which are also kinetochore constituents (Cheeseman and Desai 2008). SGOL1 localization to centromeres is sustained by the interaction with histone H2A possessing the phosphorylation of T120 which is introduced by the protein kinase BUB1, and heterochromatin protein HP1 (Kitajima et al. 2005, Kawashima et al. 2010, Yamagishi et al. 2008). Shugoshin- and PP2A-B56-regulated dephosphorylation of centromeric STAG2 ensures that the cohesin complex remains bound to centromeres throughout prometaphase and metaphase, thereby preventing premature separation of sister chromatids (Salic et al. 2004, Kitajima et al. 2004, Kitajima et al. 2005, Kitajima et al. 2006). Authored: Orlic-Milacic, M, 2012-10-02 Reviewed: Zhang, Nenggang, 2012-10-22 Reviewed: Watanabe, Yoshinori, 2012-11-20 Reviewed: Tanno, Yuji, 2012-11-20 Edited: Matthews, L, 2012-10-05 Edited: Gillespie, ME, 2012-10-05 Reactome DB_ID: 1638796 1 chromosome, centromeric region GO 0000775 p-STAG2,RAD21-Ac-Cohesin:PDS5:p-CDCA5:WAPAL:Sister Centromeres:Kinetochores:Microtubules [chromosome, centromeric region] p-STAG2,RAD21-Ac-Cohesin:PDS5:p-CDCA5:WAPAL:Sister Centromeres:Kinetochores:Microtubules Reactome DB_ID: 1638792 2 chromosome GO 0005694 Sister Centromere [chromosome] Sister Centromere Reactome http://www.reactome.org Converted from EntitySet in Reactome Reactome DB_ID: 2468261 1 PDS5 [chromosome, centromeric region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PDS5A [chromosome, centromeric region] PDS5B [chromosome, centromeric region] Homo sapiens NCBI Taxonomy 9606 UniProt Q29RF7 UniProt Q9NTI5 Reactome DB_ID: 2577088 1 UniProt:Q7Z5K2 WAPL WAPL WAPAL FOE WAPL KIAA0261 FUNCTION Regulator of sister chromatid cohesion in mitosis which negatively regulates cohesin association with chromatin. Involved in both sister chromatid cohesion during interphase and sister-chromatid resolution during early stages of mitosis. Couples DNA replication to sister chromatid cohesion. Cohesion ensures that chromosome partitioning is accurate in both meiotic and mitotic cells and plays an important role in DNA repair.SUBUNIT Interacts with the cohesin complex throughout the cell cycle; interacts with both chromatin-bound and soluble pools of the complex. Interacts with RAD21; the interaction is direct. Interacts with PDS5A; the interaction is direct, cohesin-dependent and competitive with CDCA5/SORORIN. Interacts (via FGF motifs) with PDS5B; the interaction is direct. Interacts with a SMC1 protein (SMC1A or SMC1B) and SMC3.SUBUNIT (Microbial infection) Isoform 2 interacts with Epstein-Barr virus EBNA2.TISSUE SPECIFICITY Isoform 1 is highly expressed in uterine cervix tumor. Isoform 2 is widely expressed with a high level in skeletal muscle and heart.SIMILARITY Belongs to the WAPL family. UniProt Q7Z5K2 Chain Coordinates 1 EQUAL 1190 EQUAL Reactome DB_ID: 375303 2 cytosol GO 0005829 Microtubule-bound kinetochore [cytosol] Microtubule-bound kinetochore 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 > double-stranded > splay arm > 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: 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 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 DB_ID: 2484809 1 p-STAG2,RAD21-Ac-Cohesin [chromosome, centromeric region] p-STAG2,RAD21-Ac-Cohesin Reactome DB_ID: 2466015 1 UniProt:Q14683 SMC1A SMC1A DXS423E SMC1L1 KIAA0178 SMC1A SB1.8 SMC1 FUNCTION Involved in chromosome cohesion during cell cycle and in DNA repair. Central component of cohesin complex. The cohesin complex is required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. The cohesin complex may also play a role in spindle pole assembly during mitosis. Involved in DNA repair via its interaction with BRCA1 and its related phosphorylation by ATM, or via its phosphorylation by ATR. Works as a downstream effector both in the ATM/NBS1 branch and in the ATR/MSH2 branch of S-phase checkpoint.SUBUNIT Forms a heterodimer with SMC3 in cohesin complexes (PubMed:22628566). Cohesin complexes are composed of the SMC1 (SMC1A or SMC1B) and SMC3 heterodimer attached via their SMC hinge domain, RAD21 which link them, and one STAG protein (STAG1, STAG2 or STAG3), which interacts with RAD21 (PubMed:11076961). In germ cell cohesin complexes, SMC1A is mutually exclusive with SMC1B (By similarity). Interacts with BRCA1 (PubMed:11877377). Found in a complex with CDCA5, SMC3 and RAD21, PDS5A/SCC-112 and PDS5B/APRIN (PubMed:15837422). Interacts with NDC80 (PubMed:9295362, PubMed:10409732,). Interacts with BRAT1 (PubMed:22977523). Found in a complex containing POLE and SMC3. Interacts with RPGR, STAG3 and SYCP2 (By similarity). Found in a cohesin complex with SMC3, STAG1 and RAD21 (PubMed:22628566). The SMC1A-SMC3 heterodimer interacts with the NIPBL-MAU2 heterodimer (PubMed:22628566).DOMAIN The flexible SMC hinge domain, which separates the large intramolecular coiled coil regions, allows the heterotypic interaction with the corresponding domain of SMC3, forming a V-shaped heterodimer. The two heads of the heterodimer are then connected by different ends of the cleavable RAD21 protein, forming a ring structure (By similarity).PTM Ubiquitinated by the DCX(DCAF15) complex, leading to its degradation.PTM Phosphorylated by ATM upon ionizing radiation in a NBS1-dependent manner. Phosphorylated by ATR upon DNA methylation in a MSH2/MSH6-dependent manner. Phosphorylation of Ser-957 and Ser-966 activates it and is required for S-phase checkpoint activation.MISCELLANEOUS Mutated Cornelia de Lange cell lines display genomic instability and sensitivity to ionizing radiation and interstrand cross-linking agents.SIMILARITY Belongs to the SMC family. SMC1 subfamily. UniProt Q14683 1 EQUAL 1233 EQUAL Reactome DB_ID: 2466017 1 UniProt:Q8WVM7 STAG1 STAG1 STAG1 SA1 SCC3 FUNCTION Component of cohesin complex, a complex required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. The cohesin complex may also play a role in spindle pole assembly during mitosis.SUBUNIT Cohesin complexes are composed of a heterodimer between a SMC1 protein (SMC1A or SMC1B) and SMC3, which are attached via their hinge domain, and RAD21 which link them at their heads, and one STAG protein (STAG1, STAG2 or STAG3). In cohesin complexes, STAG1 is mutually exclusive with STAG2 and STAG3 (PubMed:11076961). Interacts directly with RAD21 in cohesin complex (By similarity). Found in a cohesin complex with SMC1A, SMC3 and RAD21 (PubMed:22628566).PTM Phosphorylated by PLK1. The large dissociation of cohesin from chromosome arms during prophase is partly due to its phosphorylation (By similarity).SIMILARITY Belongs to the SCC3 family. UniProt Q8WVM7 1 EQUAL 1258 EQUAL Reactome DB_ID: 2468148 1 UniProt:Q9UQE7 SMC3 SMC3 SMC3L1 CSPG6 SMC3 BMH BAM FUNCTION Central component of cohesin, a complex required for chromosome cohesion during the cell cycle. The cohesin complex may form a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. Cohesion is coupled to DNA replication and is involved in DNA repair. The cohesin complex plays also an important role in spindle pole assembly during mitosis and in chromosomes movement.SUBUNIT Forms a heterodimer with SMC1A or SMC1B in cohesin complexes (PubMed:22628566). Cohesin complexes are composed of the SMC1 (SMC1A or SMC1B) and SMC3 heterodimer attached via their SMC hinge domain, RAD21 which link them, and one STAG protein (STAG1, STAG2 or STAG3), which interacts with RAD21. Also found in meiosis-specific cohesin complexes (PubMed:11076961). Found in a complex with SMC1A, CDCA5 and RAD21, PDS5A/SCC-112 and PDS5B/APRIN (PubMed:15837422). Interacts with NUMA1, and forms a ternary complex with KIF3B and KIFAP3, suggesting a function in tethering the chromosomes to the spindle pole and in chromosome movement (PubMed:9506951, PubMed:11590136). Interacts with PDS5A and WAPL; regulated by SMC3 acetylation (PubMed:19907496). Interacts (via SMC hinge domain) with KIAA1328 (via N- and C-terminal domains) (PubMed:15656913). Interacts with DDX11 (PubMed:17105772). Found in a cohesin complex with SMC1A, STAG1 and RAD21 (PubMed:22628566). The SMC1A-SMC3 heterodimer interacts with the NIPBL-MAU2 heterodimer (PubMed:22628566). Interacts with MXI1, MXD3, MXD4, SYCP2, RPGR and STAG3 (By similarity). Interacts with the NuRD complex component HDAC2; the interaction is direct (PubMed:12198550).DOMAIN The flexible SMC hinge domain, which separates the large intramolecular coiled coil regions, allows the heterotypic interaction with the corresponding domain of SMC1A or SMC1B, forming a V-shaped heterodimer. The two heads of the heterodimer are then connected by different ends of the cleavable RAD21 protein, forming a ring structure (By similarity).PTM Ubiquitinated by the DCX(DCAF15) complex, leading to its degradation.PTM Phosphorylated at Ser-1083 in a SPO11-dependent manner.PTM Acetylation at Lys-105 and Lys-106 by ESCO1 is important for genome stability and S phase sister chromatid cohesion. Regulated by DSCC1, it is required for processive DNA synthesis, coupling sister chromatid cohesion establishment during S phase to DNA replication. Deacetylation by HDAC8, regulates release of the cohesin complex from chromatin.MISCELLANEOUS Mutated Cornelia de Lange cell lines display genomic instability and sensitivity to ionizing radiation and interstrand cross-linking agents.SIMILARITY Belongs to the SMC family. SMC3 subfamily.CAUTION Was originally isolated as a proteoglycan protein (explaining its name). Although not excluded, such secreted function is not clear. UniProt Q9UQE7 N6-acetyl-L-lysine at 105 105 EQUAL N6-acetyl-L-lysine [MOD:00064] N6-acetyl-L-lysine at 106 106 EQUAL 1 EQUAL 1217 EQUAL Reactome DB_ID: 2485163 1 UniProt:O60216 RAD21 RAD21 RAD21 HR21 SCC1 KIAA0078 NXP1 SUBUNIT Component of the cohesin complex, which consists of an SMC1A/B and SMC3 heterodimer core and 2 non-Smc subunits RAD21 and STAG1/SA1, STAG2/SA2 or STAG3/SA3 (PubMed:10931856, PubMed:11590136, PubMed:22628566, PubMed:25575569). Interacts (via N-terminus) with SMC1A; the interaction is direct (PubMed:12198550). The cohesin complex interacts with NUMA1 (PubMed:11590136). The cohesin complex also interacts with CDCA5, PDS5A and PDS5B; this interaction might regulate the ability of the cohesin complex to mediate sister chromatid cohesion (PubMed:15837422). The interaction with PDS5B is direct and is stimulated by STAG1/SA1 (PubMed:19696148). The cohesin complex interacts with the cohesin loading complex subunits NIPBL/Scc2 (via HEAT repeats) and MAU2/Scc4 (PubMed:22628566). The cohesin complex interacts with DDX11/ChIR1 (PubMed:17105772). Directly interacts with WAPL; this interaction is stimulated by STAG1/SA1 (PubMed:19696148). Interacts with the ISWI chromatin remodeling complex component SMARCA5; the interaction is direct (PubMed:12198550). Interacts with the NuRD complex component CHD4; the interaction is direct (PubMed:12198550).TISSUE SPECIFICITY Expressed in the gut (at protein level).DEVELOPMENTAL STAGE Regulated in a cell cycle-dependent manner: expression increases in late S phase and reaches maximum in G2 at the nucleotide level (PubMed:8812457). Not regulated during the cell cycle (at protein level) (PubMed:11073952).DOMAIN The C-terminal part associates with the head of SMC1A, while the N-terminal part binds to the head of SMC3.PTM Cleaved by separase/ESPL1 at the onset of anaphase; this cleavage is required for sister chromatid separation and cytokinesis (PubMed:11509732). Cleaved by caspase-3/CASP3 or caspase-7/CASP7 at the beginning of apoptosis (PubMed:12417729, PubMed:11875078).PTM Phosphorylated; becomes hyperphosphorylated in M phase of cell cycle. The large dissociation of cohesin from chromosome arms during prophase may be partly due to its phosphorylation by PLK1.SIMILARITY Belongs to the rad21 family. UniProt O60216 O-phospho-L-serine at 454 454 EQUAL O-phospho-L-serine [MOD:00046] 1 EQUAL 631 EQUAL Reactome DB_ID: 2466013 1 UniProt:Q8N3U4 STAG2 STAG2 STAG2 SA2 FUNCTION Component of cohesin complex, a complex required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. The cohesin complex may also play a role in spindle pole assembly during mitosis.SUBUNIT Interacts directly with RAD21 in cohesin complex. Cohesin complexes are composed of a heterodimer between a SMC1 protein (SMC1A or SMC1B) and SMC3, which are attached via their hinge domain, and RAD21 which link them at their heads, and one STAG protein (STAG1, STAG2 or STAG3). In cohesin complexes, STAG2 is mutually exclusive with STAG1 and STAG3.PTM Phosphorylated by PLK1. The large dissociation of cohesin from chromosome arms during prophase is partly due to its phosphorylation (By similarity).SIMILARITY Belongs to the SCC3 family.CAUTION Variants MKMS 743-TRP--PHE-1231 DEL and HPE13 1033-ARG--PHE-1231 DEL were previously described; however, the corresponding paper has been retracted as Case 1's sex was incorrectly reported invalidating the conclusions. UniProt Q8N3U4 phosphorylated residue at unknown position phosphorylated residue [MOD:00696] 1 EQUAL 1231 EQUAL Reactome Database ID Release 81 2484809 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=2484809 Reactome R-HSA-2484809 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-2484809.1 Reactome DB_ID: 2468269 1 UniProt:Q96FF9 CDCA5 CDCA5 CDCA5 FUNCTION Regulator of sister chromatid cohesion in mitosis stabilizing cohesin complex association with chromatin. May antagonize the action of WAPL which stimulates cohesin dissociation from chromatin. Cohesion ensures that chromosome partitioning is accurate in both meiotic and mitotic cells and plays an important role in DNA repair. Required for efficient DNA double-stranded break repair.SUBUNIT Interacts with the APC/C complex (By similarity). Interacts with the chromatin-bound cohesin complex; the interaction is indirect, occurs after DNA replication and requires acetylation of the cohesin component SMC3. Interacts (via the FGF motif) with PDS5A and PDS5B; the interaction is direct and prevents the interaction of PDS5A with WAPL.DOMAIN The KEN box is required for the association with the APC/C complex.PTM Phosphorylated. Phosphorylation, as cells enter mitosis, disrupts the interaction with PDS5A and relieves the inhibition of WAPL by CDCA5.PTM Ubiquitinated by the APC/C complex in G1, leading to its degradation.MISCELLANEOUS Named sororin after the Latin word 'soror', which means 'sister', because of its critical role in sister chromatid cohesion.SIMILARITY Belongs to the sororin family. UniProt Q96FF9 O-phospho-L-threonine at 159 159 EQUAL O-phospho-L-threonine [MOD:00047] O-phospho-L-serine at 21 21 EQUAL O-phospho-L-serine at 75 75 EQUAL 1 EQUAL 252 EQUAL Reactome Database ID Release 81 1638796 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=1638796 Reactome R-HSA-1638796 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-1638796.2 Reactome DB_ID: 29356 1 water [ChEBI:15377] water ChEBI 15377 Reactome DB_ID: 2500242 1 p-RAD21-Ac-Cohesin:PDS5:p-CDCA5:WAPAL:Sister Centromeres:Kinetochores:Microtubules [chromosome, centromeric region] p-RAD21-Ac-Cohesin:PDS5:p-CDCA5:WAPAL:Sister Centromeres:Kinetochores:Microtubules Reactome DB_ID: 1638792 2 Converted from EntitySet in Reactome Reactome DB_ID: 2468261 1 Reactome DB_ID: 2577088 1 1 EQUAL 1190 EQUAL Reactome DB_ID: 375303 2 Reactome DB_ID: 2468269 1 O-phospho-L-threonine at 159 159 EQUAL O-phospho-L-serine at 21 21 EQUAL O-phospho-L-serine at 75 75 EQUAL 1 EQUAL 252 EQUAL Reactome DB_ID: 2500251 1 p-RAD21-Ac-Cohesin [chromosome, centromeric region] p-RAD21-Ac-Cohesin Reactome DB_ID: 2466015 1 1 EQUAL 1233 EQUAL Reactome DB_ID: 2466017 1 1 EQUAL 1258 EQUAL Reactome DB_ID: 2466018 1 1 EQUAL 1231 EQUAL Reactome DB_ID: 2468148 1 N6-acetyl-L-lysine at 105 105 EQUAL N6-acetyl-L-lysine at 106 106 EQUAL 1 EQUAL 1217 EQUAL Reactome DB_ID: 2485163 1 O-phospho-L-serine at 454 454 EQUAL 1 EQUAL 631 EQUAL Reactome Database ID Release 81 2500251 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=2500251 Reactome R-HSA-2500251 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-2500251.1 Reactome Database ID Release 81 2500242 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=2500242 Reactome R-HSA-2500242 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-2500242.2 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 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 1638796 GO 0004722 GO molecular function Reactome Database ID Release 81 1638806 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=1638806 Reactome Database ID Release 81 1638821 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=1638821 Reactome R-HSA-1638821 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-1638821.1 15737063 Pubmed 2005 Dissociation of cohesin from chromosome arms and loss of arm cohesion during early mitosis depends on phosphorylation of SA2 Hauf, S Roitinger, E Koch, B Dittrich, CM Mechtler, K Peters, JM PLoS Biol 3:e69 18097444 Pubmed 2008 Molecular architecture of the kinetochore-microtubule interface Cheeseman, IM Desai, A Nat Rev Mol Cell Biol 9:33-46 15339662 Pubmed 2004 Vertebrate shugoshin links sister centromere cohesion and kinetochore microtubule stability in mitosis Salic, Adrian Waters, Jennifer C Mitchison, Timothy J Cell 118:567-78 19965387 Pubmed 2010 Phosphorylation of H2A by Bub1 prevents chromosomal instability through localizing shugoshin Kawashima, Shigehiro A Yamagishi, Yuya Honda, Takashi Ishiguro, K Watanabe, Yoshinori Science 327:172-7 15723797 Pubmed 2005 Human Bub1 defines the persistent cohesion site along the mitotic chromosome by affecting Shugoshin localization Kitajima, Tomoya S Hauf, Silke Ohsugi, Miho Yamamoto, Tadashi Watanabe, Yoshinori Curr. Biol. 15:353-9 16541025 Pubmed 2006 Shugoshin collaborates with protein phosphatase 2A to protect cohesin Kitajima, TS Sakuno, T Ishiguro, K Iemura, S Natsume, T Kawashima, SA Watanabe, Yoshinori Nature 441:46-52 14730319 Pubmed 2004 The conserved kinetochore protein shugoshin protects centromeric cohesion during meiosis Kitajima, Tomoya S Kawashima, Shigehiro A Watanabe, Yoshinori Nature 427:510-7 18716626 Pubmed 2008 Heterochromatin links to centromeric protection by recruiting shugoshin Yamagishi, Yuya Sakuno, T Shimura, Mari Watanabe, Yoshinori Nature 455:251-5