BioPAX pathway converted from "Mitotic Anaphase" in the Reactome database.

Mitotic Anaphase

In anaphase, the paired chromosomes separate at the centromeres, and move to the opposite sides of the cell. The movement of the chromosomes is facilitated by a combination of kinetochore movement along the spindle microtubules and through the physical interaction of polar microtubules.

Separation of Sister Chromatids

While sister chromatids resolve in prometaphase, separating along chromosomal arms, the cohesion of sister centromeres persists until anaphase. At the anaphase onset, the anaphase promoting complex/cyclosome (APC/C) ubiquitinates PTTG1 (securin), targeting it for degradation (Hagting et al. 2002). PTTG1 acts as an inhibitor of ESPL1 (known as separin i.e. separase). Hence, PTTG1 removal initiated by APC/C, enables ESPL1 to become catalytically active (Zou et al. 1999, Waizenegger et al. 2002). ESPL1 undergoes autoleavage (Waizenegger et al. 2002) and also cleaves RAD21 subunit of centromeric cohesin (Hauf et al. 2001). RAD21 cleavage promotes dissociation of cohesin complexes from sister centromeres, leading to separation of sister chromatids. Subsequent movement of sister chromatids to opposite poles of the mitotic spindle segregates replicated chromosomes to two daughter cells (Waizenegger et al. 2000, Hauf et al. 2001, Waizenegger et al. 2002).

Authored: Orlic-Milacic, M, 2012-10-02Reviewed: Zhang, Nenggang, 2012-10-22Reviewed: Watanabe, Yoshinori, 2012-11-20Reviewed: Tanno, Yuji, 2012-11-20Edited: Matthews, L, 2012-10-05Edited: Gillespie, ME, 2012-10-05

Association of Securin with Cdc20:APC/C complex

Securin is thought to be recognized by the APC/C:Cdc20 complex through its conserved D-box sequence.

Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00

Reactome DB_ID: 174190

cytosolGO0005829

UniProt:O95997 PTTG1

PTTG1

PTTGPTTG1TUTR1EAP1FUNCTION Regulatory protein, which plays a central role in chromosome stability, in the p53/TP53 pathway, and DNA repair. Probably acts by blocking the action of key proteins. During the mitosis, it blocks Separase/ESPL1 function, preventing the proteolysis of the cohesin complex and the subsequent segregation of the chromosomes. At the onset of anaphase, it is ubiquitinated, conducting to its destruction and to the liberation of ESPL1. Its function is however not limited to a blocking activity, since it is required to activate ESPL1. Negatively regulates the transcriptional activity and related apoptosis activity of TP53. The negative regulation of TP53 may explain the strong transforming capability of the protein when it is overexpressed. May also play a role in DNA repair via its interaction with Ku, possibly by connecting DNA damage-response pathways with sister chromatid separation.SUBUNIT Interacts with RPS10 and DNAJA1 (By similarity). Interacts with the caspase-like ESPL1, and prevents its protease activity probably by covering its active site. Interacts with TP53 and blocks its activity probably by blocking its binding to DNA. Interacts with the Ku 70 kDa subunit of ds-DNA kinase. Interacts with PTTG1IP.TISSUE SPECIFICITY Expressed at low level in most tissues, except in adult testis, where it is highly expressed. Overexpressed in many patients suffering from pituitary adenomas, primary epithelial neoplasias, and esophageal cancer.DEVELOPMENTAL STAGE Low level during G1 and S phases. Peaks at M phase. During anaphase, it is degraded.DOMAIN The N-terminal destruction box (D-box) acts as a recognition signal for degradation via the ubiquitin-proteasome pathway.DOMAIN The TEK-boxes are required for 'Lys-11'-linked ubiquitination and facilitate the transfer of the first ubiquitin and ubiquitin chain nucleation. TEK-boxes may direct a catalytically competent orientation of the UBE2C/UBCH10-ubiquitin thioester with the acceptor lysine residue.PTM Phosphorylated at Ser-165 by CDK1 during mitosis.PTM Phosphorylated in vitro by ds-DNA kinase.PTM Ubiquitinated through 'Lys-11' linkage of ubiquitin moieties by the anaphase promoting complex (APC) at the onset of anaphase, conducting to its degradation. 'Lys-11'-linked ubiquitination is mediated by the E2 ligase UBE2C/UBCH10.SIMILARITY Belongs to the securin family.

Reactomehttp://www.reactome.orgHomo sapiens

NCBI Taxonomy9606UniProtO95997

Chain Coordinates

EQUAL

202

EQUAL

Reactome DB_ID: 174081

CDC20:p-APC/C [cytosol]

CDC20:p-APC/C

CDC20:Phospho-APC/C

Reactome DB_ID: 141412

UniProt:Q12834 CDC20

CDC20

CDC20FUNCTION 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 Found in a complex with CDC20, CDC27, SPATC1 and TUBG1. Interacts with NEUROD2 and SPATC1 (By similarity). Interacts with MAD2L1 and BUB1B. The phosphorylated form interacts with APC/C. Interacts with NINL. May interact with MAD2L2. Interacts with CDK5RAP2 and SIRT2. Interacts with isoform 1 of NEK2. 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.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.

UniProtQ12834

EQUAL

499

EQUAL

Reactome DB_ID: 174191

phosphorylated anaphase promoting complex (APC/C) [cytosol]

phosphorylated anaphase promoting complex (APC/C)

Reactome DB_ID: 174052

UniProt:Q8NHZ8 CDC26

CDC26

ANAPC12C9orf17CDC26FUNCTION Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains. May recruit the E2 ubiquitin-conjugating enzymes to the complex.PATHWAY Protein modification; protein ubiquitination.SUBUNIT V-shaped homodimer. Interacts with CDC16. The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5.SIMILARITY Belongs to the CDC26 family.

UniProtQ8NHZ8

EQUAL

Reactome DB_ID: 174100

UniProt:P51965 UBE2E1

UBE2E1

UBE2E1UBCH6FUNCTION Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. Catalyzes the covalent attachment of ISG15 to other proteins. Mediates the selective degradation of short-lived and abnormal proteins. In vitro also catalyzes 'Lys-48'-linked polyubiquitination.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts with RNF14.PTM ISGylation suppresses ubiquitin E2 enzyme activity.PTM Autoubiquitinated in vitro.SIMILARITY Belongs to the ubiquitin-conjugating enzyme family.

UniProtP51965

EQUAL

193

EQUAL

Reactome DB_ID: 174168

UniProt:Q9UJX5 ANAPC4

ANAPC4

ANAPC4APC4FUNCTION Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains.PATHWAY Protein modification; protein ubiquitination.SUBUNIT The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5 (PubMed:25043029, PubMed:27259151, PubMed:9469815, PubMed:26083744). In the context of the APC/C complex, directly interacts with UBE2S (PubMed:27259151).SIMILARITY Belongs to the APC4 family.

UniProtQ9UJX5

EQUAL

808

EQUAL

Reactome DB_ID: 174156

UniProt:Q13042 CDC16

CDC16

CDC16ANAPC6FUNCTION Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains.PATHWAY Protein modification; protein ubiquitination.SUBUNIT V-shaped homodimer. The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5 (PubMed:26083744, PubMed:25043029). Interacts with PPP5C and CDC20 (PubMed:9628895, PubMed:9405394). Interacts with CDC26 (PubMed:19668213).DOMAIN TPR repeats 1-7 mediate homodimerization, while the C-terminal TPR repeats bind to CDC26, burying its hydrophobic N-terminus.PTM Phosphorylated. Phosphorylation on Ser-560 occurs specifically during mitosis.SIMILARITY Belongs to the APC6/CDC16 family.

UniProtQ13042

EQUAL

620

EQUAL

Reactome DB_ID: 174189

UniProt:Q9H1A4 ANAPC1

ANAPC1

TSG24ANAPC1FUNCTION Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains.PATHWAY Protein modification; protein ubiquitination.SUBUNIT The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5.PTM Phosphorylated. Phosphorylation on Ser-355 occurs specifically during mitosis.SIMILARITY Belongs to the APC1 family.

UniProtQ9H1A4

EQUAL

1944

EQUAL

Reactome DB_ID: 6805138

UniProt:Q96DE5 ANAPC16

ANAPC16

ANAPC16C10orf104CENP-27FUNCTION Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains.PATHWAY Protein modification; protein ubiquitination.SUBUNIT The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5 (PubMed:26083744, PubMed:25043029). ANAPC16 associates with the rest of the complex independently of ANAPC2 and ANAPC11.SIMILARITY Belongs to the APC16 family.

UniProtQ96DE5

EQUAL

110

EQUAL

Reactome DB_ID: 174137

UniProt:Q9UJX2 CDC23

CDC23

CDC23ANAPC8FUNCTION Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains.PATHWAY Protein modification; protein ubiquitination.SUBUNIT The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5.PTM Phosphorylated. Phosphorylation on Thr-562 occurs specifically during mitosis.SIMILARITY Belongs to the APC8/CDC23 family.

UniProtQ9UJX2

EQUAL

597

EQUAL

Reactome DB_ID: 174073

UniProt:P30260 CDC27

CDC27

D0S1430ECDC27ANAPC3D17S978EFUNCTION Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Homodimer. The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5 (PubMed:26083744, PubMed:25043029). Interacts with RB. Interacts with FAM168B/MANI (By similarity). Interacts with MCPH1 (PubMed:22139841).PTM Phosphorylated. Phosphorylation on Ser-426 and Thr-446 occurs specifically during mitosis.SIMILARITY Belongs to the APC3/CDC27 family.

UniProtP30260

EQUAL

824

EQUAL

Reactome DB_ID: 174126

UniProt:Q9NYG5 ANAPC11

ANAPC11

HSPC214ANAPC11FUNCTION Together with the cullin protein ANAPC2, constitutes the catalytic component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains. May recruit the E2 ubiquitin-conjugating enzymes to the complex.PATHWAY Protein modification; protein ubiquitination.SUBUNIT The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5 (PubMed:26083744, PubMed:10922056, PubMed:25043029). Interacts with the cullin domain of ANAPC2 (PubMed:11739784). Interacts with UBE2D2 (PubMed:11739784).TISSUE SPECIFICITY Expressed at high levels in skeletal muscle and heart; in moderate levels in brain, kidney, and liver; and at low levels in colon, thymus, spleen, small intestine, placenta, lung and peripheral blood leukocyte.DOMAIN The RING-type zinc finger domain coordinates an additional third zinc ion.PTM Auto-ubiquitinated.SIMILARITY Belongs to the RING-box family.

UniProtQ9NYG5

EQUAL

Reactome DB_ID: 174229

UniProt:Q9UJX6 ANAPC2

ANAPC2

APC2KIAA1406ANAPC2FUNCTION Together with the RING-H2 protein ANAPC11, constitutes the catalytic component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains. 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 drives presynaptic differentiation.PATHWAY Protein modification; protein ubiquitination.SUBUNIT The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5 (PubMed:25043029, PubMed:26083744). In the context of the APC/C complex, directly interacts with UBE2C and UBE2S (PubMed:27259151). Interacts (via cullin domain) with ANAPC11 and with UBCH10 (PubMed:11739784). Interacts with NEUROD2.SIMILARITY Belongs to the cullin family.

UniProtQ9UJX6

EQUAL

822

EQUAL

Reactome DB_ID: 174236

UniProt:P51668 UBE2D1

UBE2D1

SFTUBCH5AUBE2D1UBC5AUBCH5FUNCTION Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins (PubMed:22496338). In vitro catalyzes 'Lys-48'-linked polyubiquitination (PubMed:20061386). Mediates the selective degradation of short-lived and abnormal proteins. Functions in the E6/E6-AP-induced ubiquitination of p53/TP53. Mediates ubiquitination of PEX5 and auto-ubiquitination of STUB1, TRAF6 and TRIM63/MURF1 (PubMed:18042044, PubMed:18359941). Ubiquitinates STUB1-associated HSP90AB1 in vitro (PubMed:18042044). Lacks inherent specificity for any particular lysine residue of ubiquitin (PubMed:18042044). Essential for viral activation of IRF3 (PubMed:19854139). Mediates polyubiquitination of CYP3A4 (PubMed:19103148).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Component of a E3 ubiquitin ligase complex containing UBE2D1, SIAH1, CACYBP/SIP, SKP1, APC and TBL1X. Interacts with RNF11.TISSUE SPECIFICITY Ubiquitous. Up-regulated in livers of iron-overloaded patients with hereditary hemochromatosis.PTM Autoubiquitinated in vitro.SIMILARITY Belongs to the ubiquitin-conjugating enzyme family.CAUTION PubMed:9362508 cloned and sequenced SFT which consisted of UBE2D1 last coding exon along with intronic sequences on the 5'-end of this exon. A function in iron transport has been described.

UniProtP51668

EQUAL

147

EQUAL

Reactome DB_ID: 174242

UniProt:Q9UJX3 ANAPC7

ANAPC7

ANAPC7APC7FUNCTION Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains.PATHWAY Protein modification; protein ubiquitination.SUBUNIT V-shaped homodimer. The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5 (PubMed:25043029, PubMed:26083744).SIMILARITY Belongs to the APC7 family.CAUTION It is uncertain whether Met-1 or Met-35 is the initiator.

UniProtQ9UJX3

EQUAL

599

EQUAL

Reactome DB_ID: 174142

UniProt:Q9UM13 ANAPC10

ANAPC10

APC10ANAPC10FUNCTION Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains.PATHWAY Protein modification; protein ubiquitination.SUBUNIT The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5 (PubMed:26083744, PubMed:25043029). The C-terminus of APC10 binds to CDC27/APC3 (PubMed:11524682). Interacts with PIWIL1; interaction only takes place when PIWIL1 binds piRNA.SIMILARITY Belongs to the APC10 family.

UniProtQ9UM13

EQUAL

185

EQUAL

Reactome DB_ID: 174211

UniProt:Q9UJX4 ANAPC5

ANAPC5

ANAPC5APC5FUNCTION Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains.PATHWAY Protein modification; protein ubiquitination.SUBUNIT The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5.DOMAIN The TPR repeats are six to seven residues longer than a canonical TPR motif.SIMILARITY Belongs to the APC5 family.

UniProtQ9UJX4

EQUAL

755

EQUAL

Reactome DB_ID: 174244

UniProt:O00762 UBE2C

UBE2C

UBE2CUBCH10FUNCTION Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-11'- and 'Lys-48'-linked polyubiquitination. Acts as an essential factor of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated ubiquitin ligase that controls progression through mitosis. Acts by initiating 'Lys-11'-linked polyubiquitin chains on APC/C substrates, leading to the degradation of APC/C substrates by the proteasome and promoting mitotic exit.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Component of the APC/C complex, composed of at least 14 distinct subunits that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa. Within this complex, directly interacts with ANAPC2.PTM Autoubiquitinated by the APC/C complex, leading to its degradation by the proteasome. Its degradation plays a central role in APC/C regulation, allowing cyclin-A accumulation before S phase entry. APC/C substrates inhibit the autoubiquitination of UBE2C/UBCH10 but not its E2 function, hence APC/C remaining active until its substrates have been destroyed.SIMILARITY Belongs to the ubiquitin-conjugating enzyme family.

UniProtO00762

EQUAL

179

EQUAL

Reactome DB_ID: 6805140

UniProt:P60006 ANAPC15

ANAPC15

ANAPC15C11orf51HSPC020FUNCTION Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. In the complex, plays a role in the release of the mitotic checkpoint complex (MCC) from the APC/C: not required for APC/C activity itself, but promotes the turnover of CDC20 and MCC on the APC/C, thereby participating in the responsiveness of the spindle assembly checkpoint. Also required for degradation of CDC20.SUBUNIT The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5.SIMILARITY Belongs to the APC15 family.

UniProtP60006

EQUAL

121

EQUAL

Reactome Database ID Release 69174191Database 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=174191ReactomeR-HSA-174191

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-174191.2Reactome Database ID Release 69174081Database 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=174081ReactomeR-HSA-174081

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-174081.1

Reactome DB_ID: 174212

CDC20:p-APC/C:PTTG1 [cytosol]

CDC20:p-APC/C:PTTG1

Cdc20:phosph-APC/C:Securin complex

Reactome DB_ID: 174190

EQUAL

202

EQUAL

Reactome DB_ID: 174081

Reactome Database ID Release 69174212Database 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=174212ReactomeR-HSA-174212

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-174212.1Reactome Database ID Release 69174121Database 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=174121ReactomeR-HSA-174121

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-174121.212070128Pubmed2002Human securin proteolysis is controlled by the spindle checkpoint and reveals when the APC/C switches from activation by Cdc20 to Cdh1Hagting, ADen Elzen, NVodermaier, HCWaizenegger, ICPeters, JMPines, JJ Cell Biol 157:1125-37

6.3.2.19

Ubiquitination of Securin by phospho-APC/C:Cdc20 complex

Securin is ubiquitinated by APC/C:Cdc20 (Hagting et al., 2002; Jin et al. 2008).

Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00

Reactome DB_ID: 174212

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

Ub [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityUBC(609-684) [cytosol]RPS27A(1-76) [cytosol]UBB(77-152) [cytosol]UBC(457-532) [cytosol]UBC(229-304) [cytosol]UBC(305-380) [cytosol]UBC(381-456) [cytosol]UBA52(1-76) [cytosol]UBC(153-228) [cytosol]UBC(77-152) [cytosol]UBB(153-228) [cytosol]UBC(533-608) [cytosol]UBB(1-76) [cytosol]UBC(1-76) [cytosol]

UniProtP0CG48UniProtP62979UniProtP0CG47UniProtP62987

Reactome DB_ID: 3095944

CDC20:pAPC/C:K11polyUb-PTTG1 [cytosol]

CDC20:pAPC/C:K11polyUb-PTTG1

CDC20:phospho-APC/C:K11polyUb-Securin complex

Reactome DB_ID: 174081

Reactome DB_ID: 3095943

ubiquitinylated lysine (K11polyUb [cytosol]) at unknown position

ubiquitinylated lysine [MOD:01148]

EQUAL

202

EQUAL

Reactome Database ID Release 693095944Database 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=3095944ReactomeR-HSA-3095944

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-3095944.1PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 174081

GO0004842

GO molecular function

Reactome Database ID Release 69174076Database 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=174076Reactome Database ID Release 69174144Database 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=174144ReactomeR-HSA-174144

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-174144.218485873Pubmed2008Mechanism of ubiquitin-chain formation by the human anaphase-promoting complexJin, LWilliamson, ABanerjee, SPhilipp, IRape, MCell 133:653-65GO0006511

GO biological process

Degradation of multiubiquitinated Securin

Following ubiquitination, securin is degraded by the 26S proteasome.

Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00

Reactome DB_ID: 3095944

Reactome DB_ID: 174081

Converted from EntitySet in Reactome

Reactome DB_ID: 113595

PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 68819

26S proteasome [cytosol]

26S proteasome

Reactome DB_ID: 68816

UniProt:P61289 PSME3

PSME3

PSME3FUNCTION Subunit of the 11S REG-gamma (also called PA28-gamma) proteasome regulator, a doughnut-shaped homoheptamer which associates with the proteasome. 11S REG-gamma activates the trypsin-like catalytic subunit of the proteasome but inhibits the chymotrypsin-like and postglutamyl-preferring (PGPH) subunits. Facilitates the MDM2-p53/TP53 interaction which promotes ubiquitination- and MDM2-dependent proteasomal degradation of p53/TP53, limiting its accumulation and resulting in inhibited apoptosis after DNA damage. May also be involved in cell cycle regulation. Mediates CCAR2 and CHEK2-dependent SIRT1 inhibition (PubMed:25361978).SUBUNIT Homoheptamer; the stability of the heptamer is essential for the specific activation of the trypsine-like subunit and inhibition of the chymotrypsin-like and postglutamyl-preferring (PGPH) subunits of the proteasome. Interacts with p53/TP53 and MDM2. Interacts with MAP3K3 (By similarity). Associates with the proteasome. Interacts with CCAR2. Interacts with FAM192A (via C-terminus); the interaction is direct and promotes the association of PSME3 with the 20S proteasome (PubMed:29934401). Interacts with COIL; the interaction is inhibited by FAM192A (PubMed:29934401).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus UL27.INDUCTION Up-regulated in thyroid carcinoma cells.DOMAIN The C-terminal sequences affect heptamer stability and proteasome affinity.PTM Phosphorylated by MAP3K3 (By similarity). Phosphorylation at Ser-247 promotes its association with CCAR2.PTM Acetylation at the major site Lys-195 is important for oligomerization and ability to degrade its target substrates. Deacetylated by SIRT1.SIMILARITY Belongs to the PA28 family.

UniProtP61289

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254

EQUAL

Reactome DB_ID: 8866674

UniProt:P60896 SEM1

SEM1

SEM1C7orf76SHFDG1SHFM1DSS1FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair (PubMed:15117943). Component of the TREX-2 complex (transcription and export complex 2), composed of at least ENY2, GANP, PCID2, SEM1, and either centrin CETN2 or CETN3 (PubMed:22307388). The TREX-2 complex functions in docking export-competent ribonucleoprotein particles (mRNPs) to the nuclear entrance of the nuclear pore complex (nuclear basket). TREX-2 participates in mRNA export and accurate chromatin positioning in the nucleus by tethering genes to the nuclear periphery. Binds and stabilizes BRCA2 and is thus involved in the control of R-loop-associated DNA damage and thus transcription-associated genomic instability. R-loop accumulation increases in SEM1-depleted cells.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including SEM1, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Belongs to the TREX-2 complex (transcription and export complex 2), composed of at least ENY2, GANP, PCID2, SEM1, and either centrin CETN2 or CETN3 (PubMed:22307388). Interacts with the C-terminal of BRCA2 (PubMed:10373512, PubMed:21719596).TISSUE SPECIFICITY Expressed in limb bud, craniofacial primordia and skin.SIMILARITY Belongs to the DSS1/SEM1 family.

UniProtP60896

EQUAL

Reactome DB_ID: 68765

UniProt:P28065 PSMB9

PSMB9

LMP2PSMB6iRING12PSMB9FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. Replacement of PSMB6 by PSMB9 increases the capacity of the immunoproteasome to cleave model peptides after hydrophobic and basic residues.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB6. Component of the spermatoproteasome, a form of the proteasome specifically found in testis.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.DEVELOPMENTAL STAGE Highly expressed in immature dendritic cells (at protein level).INDUCTION Up-regulated by interferon gamma (at protein level). Up-regulated by IRF1. Up-regulated by tumor necrosis factor-alpha (at protein level). Up-regulated by tetrodotoxin (TTX) in glial cells. Up-regulated in Crohn's bowel disease (CD). Up-regulated by heat shock treatment. Up-regulated by CD40L via the NFKB1 pathway in cancer cells.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.MISCELLANEOUS Encoded in the MHC class II region.MISCELLANEOUS A model for self-activation in which residue Thr-21 serves as nucleophile and Lys-53 as proton donor/acceptor has been proposed. Subunit processing of mammalian beta-subunits proceeds via a novel ordered two-step mechanism involving autocatalysis.SIMILARITY Belongs to the peptidase T1B family.

UniProtP28065

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219

EQUAL

Reactome DB_ID: 68771

UniProt:P35998 PSMC2

PSMC2

MSS1PSMC2FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC2 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC2 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with NDC80/HEC; this interaction is detected only during M phase. Interacts and SQSTM1 (PubMed:15340068). Interacts with PAAF1 (PubMed:15831487). Directly interacts with TRIM5 (PubMed:22078707).INDUCTION Expression is not cell cycle-dependent and occurs throughout the cell cycle.SIMILARITY Belongs to the AAA ATPase family.

UniProtP35998

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433

EQUAL

Reactome DB_ID: 68728

UniProt:P25788 PSMA3

PSMA3

PSMA3HC8PSC8FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Binds to the C-terminus of CDKN1A and thereby mediates its degradation. Negatively regulates the membrane trafficking of the cell-surface thromboxane A2 receptor (TBXA2R) isoform 2.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Interacts with AURKB. Interacts with CDKN1A (PubMed:11350925). Interacts with MDM2 and RB1 (PubMed:16337594). Interacts with the C-terminus of TBXA2R isoform 2 (PubMed:17499743). Interacts with DNAJB2 (PubMed:15936278).SUBUNIT (Microbial infection) Interacts with HIV-1 Tat protein.SUBUNIT (Microbial infection) Interacts with hepatitis C virus (HCV) F protein.SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus EBNA3 proteins.INDUCTION Down-regulated by antioxidants BO-653 and probucol. Up-regulated by bacterial lipopolysaccharides (LPS) and TNF.SIMILARITY Belongs to the peptidase T1A family.

UniProtP25788

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255

EQUAL

Reactome DB_ID: 68759

UniProt:Q99436 PSMB7

PSMB7

PSMB7ZFUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB7 displays a trypsin-like activity.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 Tat protein.TISSUE SPECIFICITY Expressed at a low level in colonic mucosa. Up-regulated in colorectal cancer tissues.SIMILARITY Belongs to the peptidase T1B family.

UniProtQ99436

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277

EQUAL

Reactome DB_ID: 68780

UniProt:P62195 PSMC5

PSMC5

PSMC5SUG1FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC5 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC5 and few additional components (PubMed:27428775, PubMed:27342858). Component of a complex with USP49 and RUVBL1 (PubMed:23824326). Interacts with PRPF19. Interacts with TRIM5 (PubMed:22078707). Interacts with NDC80 (PubMed:9295362, PubMed:10409732). Interacts with PAAF1 (PubMed:15831487). Interacts, in vitro, with the thyroid hormone receptor (in a thyroid hormone T3-dependent manner) and with retinoid X receptor (RXR).SIMILARITY Belongs to the AAA ATPase family.

UniProtP62195

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406

EQUAL

Reactome DB_ID: 68788

UniProt:O75832 PSMD10

PSMD10

PSMD10FUNCTION Acts as a chaperone during the assembly of the 26S proteasome, specifically of the PA700/19S regulatory complex (RC). In the initial step of the base subcomplex assembly is part of an intermediate PSMD10:PSMC4:PSMC5:PAAF1 module which probably assembles with a PSMD5:PSMC2:PSMC1:PSMD2 module. Independently of the proteasome, regulates EGF-induced AKT activation through inhibition of the RHOA/ROCK/PTEN pathway, leading to prolonged AKT activation. Plays an important role in RAS-induced tumorigenesis.FUNCTION Acts as an proto-oncoprotein by being involved in negative regulation of tumor suppressors RB1 and p53/TP53. Overexpression is leading to phosphorylation of RB1 and proteasomal degradation of RB1. Regulates CDK4-mediated phosphorylation of RB1 by competing with CDKN2A for binding with CDK4. Facilitates binding of MDM2 to p53/TP53 and the mono- and polyubiquitination of p53/TP53 by MDM2 suggesting a function in targeting the TP53:MDM2 complex to the 26S proteasome. Involved in p53-independent apoptosis. Involved in regulation of NF-kappa-B by retaining it in the cytoplasm. Binds to the NF-kappa-B component RELA and accelerates its XPO1/CRM1-mediated nuclear export.SUBUNIT Part of transient complex containing PSMD10, PSMC4, PSMC5 and PAAF1 formed during the assembly of the 26S proteasome. Stays associated throughout the assembly of the PA700/19S RC and is released upon association with the 20S core. Interacts with PSMC4. Interacts with RB1. Interacts with CDK4. Interacts with MDM2. Interacts with RELA. Associates with a CDK4:CCND2 serine/threonine kinase complex. Interacts with ARHGDIA and increases the interaction between ARHGDIA and RHOA, hence promotes ARHGDIA inactivation of RHOA and ROCK.TISSUE SPECIFICITY Tends to be up-regulated in cancer cells with RAS mutations, including lung cancers and adenocarconimas (at protein level).CAUTION Was initially identified as a genuine component of the 26S proteasome.

UniProtO75832

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226

EQUAL

Reactome DB_ID: 68724

UniProt:P25786 PSMA1

PSMA1

PSMA1HC2NUPSC2PROS30FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Interacts with NOTCH3. Interacts with ZFAND1 (PubMed:29804830).INDUCTION Induced in breast cancer tissue (at protein level). Up-regulated in liver tumor tissues.SIMILARITY Belongs to the peptidase T1A family.

UniProtP25786

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263

EQUAL

Reactome DB_ID: 68762

UniProt:P28062 PSMB8

PSMB8

PSMB5iRING10Y2LMP7PSMB8FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. Replacement of PSMB5 by PSMB8 increases the capacity of the immunoproteasome to cleave model peptides after hydrophobic and basic residues. Acts as a major component of interferon gamma-induced sensitivity. Plays a key role in apoptosis via the degradation of the apoptotic inhibitor MCL1. May be involved in the inflammatory response pathway. In cancer cells, substitution of isoform 1 (E2) by isoform 2 (E1) results in immunoproteasome deficiency. Required for the differentiation of preadipocytes into adipocytes.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB5. Component of the spermatoproteasome, a form of the proteasome specifically found in testis. Directly interacts with POMP. Interacts with TAP1.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.DEVELOPMENTAL STAGE Highly expressed in immature dendritic cells (at protein level).INDUCTION Up-regulated by IFNG/IFN-gamma and IRF1 (at protein level). Up-regulated by TNF (at protein level). Up-regulated by tetrodotoxin (TTX) in glial cells. Up-regulated in Crohn's bowel disease (CD). Down-regulated by the selective inhibitor PR-957. Down-regulated in mature dendritic cells by HSV-1 infection. Up-regulated by heat shock treatment.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.SIMILARITY Belongs to the peptidase T1B family.

UniProtP28062

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276

EQUAL

Reactome DB_ID: 68814

UniProt:Q9UL46 PSME2

PSME2

PSME2FUNCTION Implicated in immunoproteasome assembly and required for efficient antigen processing. The PA28 activator complex enhances the generation of class I binding peptides by altering the cleavage pattern of the proteasome.SUBUNIT Heterodimer of PSME1 and PSME2, which forms a hexameric ring.INDUCTION By IFNG/IFN-gamma.SIMILARITY Belongs to the PA28 family.

UniProtQ9UL46

EQUAL

239

EQUAL

Reactome DB_ID: 68810

UniProt:O00233 PSMD9

PSMD9

PSMD9FUNCTION Acts as a chaperone during the assembly of the 26S proteasome, specifically of the base subcomplex of the PA700/19S regulatory complex (RC). During the base subcomplex assembly is part of an intermediate PSMD9:PSMC6:PSMC3 module, also known as modulator trimer complex; PSMD9 is released during the further base assembly process.SUBUNIT Interacts with PSMC3. Part of a transient complex (modulator) containing PSMD9, PSMC6 and PSMC3 formed during the assembly of the 26S proteasome.TISSUE SPECIFICITY Expressed in all tissues tested, highly expressed in liver and kidney.SIMILARITY Belongs to the proteasome subunit p27 family.CAUTION Was initially identified as a component of the 26S proteasome.

UniProtO00233

EQUAL

223

EQUAL

Reactome DB_ID: 947610

UniProt:Q8TAA3 PSMA8

PSMA8

PSMA7LPSMA8FUNCTION Component of the spermatoproteasome, a form of the proteasome specifically found in testis that promotes degradation of histones, thereby participating actively to the exchange of histones during spermatogenesis. The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel (By similarity). Component of the spermatoproteasome, a form of the proteasome specifically found in testis.SIMILARITY Belongs to the peptidase T1A family.

UniProtQ8TAA3

EQUAL

256

EQUAL

Reactome DB_ID: 68756

UniProt:P28072 PSMB6

PSMB6

PSMB6LMPYYFUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB6 displays a peptidylglutamyl-hydrolizing activity also termed postacidic or caspase-like activity, meaning that the peptides bond hydrolysis occurs directly after acidic residues.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 protein Tat.INDUCTION Down-regulated by IFNG/IFN-gamma (at protein level). Up-regulated in anaplastic thyroid cancer cell lines.SIMILARITY Belongs to the peptidase T1B family.

UniProtP28072

EQUAL

239

EQUAL

Reactome DB_ID: 68800

UniProt:P55036 PSMD4

PSMD4

MCB1PSMD4FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMD4 acts as an ubiquitin receptor subunit through ubiquitin-interacting motifs and selects ubiquitin-conjugates for destruction. Displays a preferred selectivity for longer polyubiquitin chains.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases and few additional components including PSMD4 (PubMed:27428775, PubMed:27342858). Interacts with NUB1 (PubMed:11585840). Interacts with SQSTM1 (PubMed:15340068). Interacts with UBQLN4 (PubMed:15280365). Interacts with UBE3A (PubMed:22645313). Interacts with UBQLN1 (via ubiquitin-like domain) (PubMed:15147878). Interacts with DDI2 (PubMed:29290612).DOMAIN The 2 UIM motifs are involved in the binding to a multi-ubiquitin chain in a cooperative way.SIMILARITY Belongs to the proteasome subunit S5A family.

UniProtP55036

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377

EQUAL

Reactome DB_ID: 68732

UniProt:P28066 PSMA5

PSMA5

PSMA5FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. PSMA5 interacts directly with the PSMG1-PSMG2 heterodimer which promotes 20S proteasome assembly.TISSUE SPECIFICITY Expressed in fetal brain (at protein level).INDUCTION Up-regulated in colon cancer cell lines. Up-regulated in fetal Down syndrome (DS) brain (at protein level). May be the target of the transcriptional activator NFE2L2.SIMILARITY Belongs to the peptidase T1A family.

UniProtP28066

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241

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Reactome DB_ID: 68741

UniProt:P40306 PSMB10

PSMB10

LMP10MECL1PSMB10FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB7. Component of the spermatoproteasome, a form of the proteasome specifically found in testis.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.DEVELOPMENTAL STAGE Highly expressed in immature dendritic cells (at protein level).INDUCTION Up-regulated by IFNG/IFN-gamma (at protein level). Up-regulated by IRF1. Up-regulated by TNF (at protein level). Up-regulated by tetrodotoxin (TTX) in glial cells. Up-regulated in Crohn's bowel disease (CD). Up-regulated by CD40L via the NFKB1 pathway in cancer cells.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.SIMILARITY Belongs to the peptidase T1B family.

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Reactome DB_ID: 68796

UniProt:Q13200 PSMD2

PSMD2

TRAP2PSMD2FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.FUNCTION Binds to the intracellular domain of tumor necrosis factor type 1 receptor. The binding domain of TRAP1 and TRAP2 resides outside the death domain of TNFR1.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases and few additional components including PSMD2 (PubMed:27428775, PubMed:27342858). Interacts with RPGRIP1L.TISSUE SPECIFICITY Found in skeletal muscle, liver, heart, brain, kidney, pancreas, lung and placenta.SIMILARITY Belongs to the proteasome subunit S2 family.

UniProtQ13200

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908

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Reactome DB_ID: 68722

UniProt:O00487 PSMD14

PSMD14

PSMD14POH1FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. The PSMD14 subunit is a metalloprotease that specifically cleaves 'Lys-63'-linked polyubiquitin chains within the complex. Plays a role in response to double-strand breaks (DSBs): acts as a regulator of non-homologous end joining (NHEJ) by cleaving 'Lys-63'-linked polyubiquitin, thereby promoting retention of JMJD2A/KDM4A on chromatin and restricting TP53BP1 accumulation. Also involved in homologous recombination repair by promoting RAD51 loading.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD4, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Within the complex, PSMD4 interacts with subunit PSMD7 through their respective MPN domain. Interacts with TXNL1 (PubMed:19349277).TISSUE SPECIFICITY Widely expressed. Highest levels in heart and skeletal muscle.SIMILARITY Belongs to the peptidase M67A family. PSMD14 subfamily.

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Reactome DB_ID: 68774

UniProt:P17980 PSMC3

PSMC3

PSMC3TBP1FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC3 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC3 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with PAAF1 (PubMed:15831487).SUBUNIT (Microbial infection) Interacts with HIV-1 Tat.PTM Sumoylated by UBE2I in response to MEKK1-mediated stimuli.SIMILARITY Belongs to the AAA ATPase family.

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439

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Reactome DB_ID: 68768

UniProt:P62191 PSMC1

PSMC1

PSMC1FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC1 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC1 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with SCA7 (PubMed:11734547). Interacts with NGLY1 (PubMed:15358861). Interacts with PAAF1 (PubMed:15831487).SIMILARITY Belongs to the AAA ATPase family.

UniProtP62191

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440

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Reactome DB_ID: 68753

UniProt:P28074 PSMB5

PSMB5

PSMB5XLMPXMB1FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB5 displays a chymotrypsin-like activity.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Directly interacts with POMP (PubMed:15944226). Interacts with ABCB1 and TAP1 (PubMed:15488952).SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.INDUCTION Down-regulated by IFNG/IFN-gamma (at protein level). Induced in breast cancer tissue. Up-regulated by sulforaphane in breast cancer cells.SIMILARITY Belongs to the peptidase T1B family.

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Reactome DB_ID: 68794

UniProt:Q9UNM6 PSMD13

PSMD13

PSMD13FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD13, a base containing 6 ATPases and few additional components.SIMILARITY Belongs to the proteasome subunit S11 family.

UniProtQ9UNM6

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376

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Reactome DB_ID: 68726

UniProt:P25787 PSMA2

PSMA2

PSMA2PSC3HC3FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.INDUCTION Down-regulated by antioxidants BO-653 and probucol. Down-regulated in response to enterovirus 71 (EV71) infection (at protein level).PTM Phosphorylated on tyrosine residues; which may be important for nuclear import.SIMILARITY Belongs to the peptidase T1A family.

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Reactome DB_ID: 68750

UniProt:P28070 PSMB4

PSMB4

PSMB4PROS26FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). SMAD1/OAZ1/PSMB4 complex mediates the degradation of the CREBBP/EP300 repressor SNIP1.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Forms a ternary complex with SMAD1 and OAZ1 before PSMB4 is incorporated into the 20S proteasome. Interacts with PRPF19 (PubMed:11571290, PubMed:12097147).SUBUNIT (Microbial infection) Interacts with HTLV-1 Tax protein.SUBUNIT (Microbial infection) Interacts with HIV-1 Nef and Tat proteins.INDUCTION Up-regulated in fibrolamellar carcinomas.SIMILARITY Belongs to the peptidase T1B family.CAUTION A report observed N-glycosylation at Asn-83 (PubMed:19139490). However, as the protein does not localize in an extracellular compartment of the cell, additional evidences are required to confirm this result.

UniProtP28070

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Reactome DB_ID: 68804

UniProt:Q15008 PSMD6

PSMD6

PSMD6KIAA0107PFAAP4FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD6, a base containing 6 ATPases and few additional components.SIMILARITY Belongs to the proteasome subunit S10 family.

UniProtQ15008

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389

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Reactome DB_ID: 68747

UniProt:P49720 PSMB3

PSMB3

PSMB3FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.INDUCTION Up-regulated in asthenozoospermic sperm.SIMILARITY Belongs to the peptidase T1B family.

UniProtP49720

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205

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Reactome DB_ID: 68786

UniProt:Q99460 PSMD1

PSMD1

PSMD1FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases and few additional components including PSMD1 (PubMed:27428775, PubMed:27342858). Interacts with ADRM1 (PubMed:16990800, PubMed:16906146). Interacts with ZFAND1 (PubMed:29804830).SIMILARITY Belongs to the proteasome subunit S1 family.

UniProtQ99460

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953

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Reactome DB_ID: 68730

UniProt:P25789 PSMA4

PSMA4

PSMA4PSC9HC9FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interaction with HTLV-1 TAX protein favors NFKB1 activation.INDUCTION Down-regulated by antioxidants BO-653 and probucol.SIMILARITY Belongs to the peptidase T1A family.

UniProtP25789

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Reactome DB_ID: 68790

UniProt:O00231 PSMD11

PSMD11

PSMD11FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. In the complex, PSMD11 is required for proteasome assembly. Plays a key role in increased proteasome activity in embryonic stem cells (ESCs): its high expression in ESCs promotes enhanced assembly of the 26S proteasome, followed by higher proteasome activity.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD11, a base containing 6 ATPases and few additional components.TISSUE SPECIFICITY Highly expressed in embryonic stem cells (ESCs). Expression decreases as ESCs differentiate.INDUCTION By FOXO4; expression in embryonic stem cells (ESCs) is mediated by FOXO4.PTM Phosphorylated by AMPK.SIMILARITY Belongs to the proteasome subunit S9 family.

UniProtO00231

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422

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Reactome DB_ID: 68798

UniProt:O43242 PSMD3

PSMD3

PSMD3FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD3, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Interacts with UBQLN1 (via ubiquitin-like domain) (PubMed:15147878).SIMILARITY Belongs to the proteasome subunit S3 family.

UniProtO43242

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534

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Reactome DB_ID: 947606

UniProt:Q14997 PSME4

PSME4

PSME4KIAA0077FUNCTION Associated component of the proteasome that specifically recognizes acetylated histones and promotes ATP- and ubiquitin-independent degradation of core histones during spermatogenesis and DNA damage response. Recognizes and binds acetylated histones via its bromodomain-like (BRDL) region and activates the proteasome by opening the gated channel for substrate entry. Binds to the core proteasome via its C-terminus, which occupies the same binding sites as the proteasomal ATPases, opening the closed structure of the proteasome via an active gating mechanism. Component of the spermatoproteasome, a form of the proteasome specifically found in testis: binds to acetylated histones and promotes degradation of histones, thereby participating actively to the exchange of histones during spermatogenesis. Also involved in DNA damage response in somatic cells, by promoting degradation of histones following DNA double-strand breaks.SUBUNIT Homodimer. Interacts with the 20S and 26S proteasomes. Component of the spermatoproteasome, a form of the proteasome specifically found in testis.DOMAIN The bromodomain-like (BRDL) region specifically recognizes and binds acetylated histones.SIMILARITY Belongs to the BLM10 family.

UniProtQ14997

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1843

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Reactome DB_ID: 68777

UniProt:P43686 PSMC4

PSMC4

TBP7PSMC4MIP224FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC4 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC4 and few additional components (PubMed:27428775,PubMed:27342858). Interacts with NR1I3. Interacts with PAAF1 (PubMed:15831487). Interacts with TRIM5 (PubMed:22078707). Interacts with ZFAND1 (PubMed:29804830).SIMILARITY Belongs to the AAA ATPase family.

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418

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Reactome DB_ID: 68812

UniProt:Q06323 PSME1

PSME1

PSME1IFI5111FUNCTION Implicated in immunoproteasome assembly and required for efficient antigen processing. The PA28 activator complex enhances the generation of class I binding peptides by altering the cleavage pattern of the proteasome.SUBUNIT Heterodimer of PSME1 and PSME2, which forms a hexameric ring. PSME1 can form homoheptamers.INDUCTION By IFNG/IFN-gamma.SIMILARITY Belongs to the PA28 family.

UniProtQ06323

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249

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Reactome DB_ID: 947607

UniProt:A5LHX3 PSMB11

PSMB11

PSMB11FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. Incorporated instead of PSMB5 or PSMB8, this unit reduces the chymotrypsin-like activity of the proteasome (By similarity). Plays a pivotal role in development of CD8-positive T cells.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Incorporated instead of PSMB5 and PSMB8.SIMILARITY Belongs to the peptidase T1B family.

UniProtA5LHX3

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300

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Reactome DB_ID: 68736

UniProt:O14818 PSMA7

PSMA7

PSMA7HSPCFUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Inhibits the transactivation function of HIF-1A under both normoxic and hypoxia-mimicking conditions. The interaction with EMAP2 increases the proteasome-mediated HIF-1A degradation under the hypoxic conditions. Plays a role in hepatitis C virus internal ribosome entry site-mediated translation. Mediates nuclear translocation of the androgen receptor (AR) and thereby enhances androgen-mediated transactivation. Promotes MAVS degradation and thereby negatively regulates MAVS-mediated innate immune response.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. PSMA7 interacts directly with the PSMG1-PSMG2 heterodimer which promotes 20S proteasome assembly (PubMed:16251969). Interacts with HIF1A. Interacts with RAB7A (PubMed:14998988). Interacts with PRKN (PubMed:15987638). Interacts with ABL1 and ABL2 (PubMed:16678104). Interacts with EMAP2 (PubMed:19362550). Interacts with MAVS (PubMed:19734229).SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.SUBUNIT (Microbial infection) Interacts with hepatitis B virus X protein (HBX).INDUCTION Down-regulated by the ribozyme Rz3'X. Up-regulated in colorectal cancer tissues.PTM Phosphorylation by ABL1 or ABL2 leads to an inhibition of proteasomal activity and cell cycle transition blocks.SIMILARITY Belongs to the peptidase T1A family.

UniProtO14818

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248

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Reactome DB_ID: 68738

UniProt:P20618 PSMB1

PSMB1

PSC5PSMB1FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Interacts with SERPINB2. Interacts with RFPL4A.SUBUNIT (Microbial infection) Interacts with HIV-1 protein Tat.SIMILARITY Belongs to the peptidase T1B family.

UniProtP20618

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241

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Reactome DB_ID: 68792

UniProt:O00232 PSMD12

PSMD12

PSMD12FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD12, a base containing 6 ATPases and few additional components.SIMILARITY Belongs to the proteasome subunit p55 family.

UniProtO00232

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456

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Reactome DB_ID: 68802

UniProt:Q16401 PSMD5

PSMD5

PSMD5KIAA0072FUNCTION Acts as a chaperone during the assembly of the 26S proteasome, specifically of the base subcomplex of the PA700/19S regulatory complex (RC). In the initial step of the base subcomplex assembly is part of an intermediate PSMD5:PSMC2:PSMC1:PSMD2 module which probably assembles with a PSMD10:PSMC4:PSMC5:PAAF1 module followed by dissociation of PSMD5.SUBUNIT Interacts with PSMC1, PSMC2, PSMD1 and PSMD6. Part of transient complex containing PSMD5, PSMC2, PSMC1 and PSMD2 formed during the assembly of the 26S proteasome.DOMAIN Rich in dileucine repeats, which have been implicated in trafficking of a variety of transmembrane proteins.SIMILARITY Belongs to the proteasome subunit S5B/HSM3 family.CAUTION Was initially identified as a genuine component of the 26S proteasome.

UniProtQ16401

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504

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Reactome DB_ID: 68783

UniProt:P62333 PSMC6

PSMC6

PSMC6SUG2FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC6 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC6 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with PAAF1 (PubMed:15831487).SIMILARITY Belongs to the AAA ATPase family.CAUTION Alternative initiation from an upstream conserved methionine cannot be fully excluded but is not experimentally supported while initiation from the displayed methionine is supported by PubMed:17323924.

UniProtP62333

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389

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Reactome DB_ID: 68808

UniProt:P48556 PSMD8

PSMD8

PSMD8FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD8, a base containing 6 ATPases and few additional components. Interacts with DDI2 (PubMed:29290612).SIMILARITY Belongs to the proteasome subunit S14 family.CAUTION It is uncertain whether Met-1 or Met-64 is the initiator.

UniProtP48556

EQUAL

350

EQUAL

Reactome DB_ID: 68806

UniProt:P51665 PSMD7

PSMD7

MOV34LPSMD7FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD7, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Within the complex, PSMD7 interacts with subunit PSMD4 through their respective MPN domain. Interacts with TRIM5 (PubMed:22078707).MISCELLANEOUS Does not bind a metal ion.SIMILARITY Belongs to the peptidase M67A family.

UniProtP51665

EQUAL

324

EQUAL

Reactome DB_ID: 68818

UniProt:Q92530 PSMF1

PSMF1

PSMF1FUNCTION Plays an important role in control of proteasome function. Inhibits the hydrolysis of protein and peptide substrates by the 20S proteasome. Also inhibits the activation of the proteasome by the proteasome regulatory proteins PA700 and PA28.SUBUNIT Monomer and homodimer. Interacts with FBXO7. Interacts with the 20S proteasome.SIMILARITY Belongs to the proteasome inhibitor PI31 family.

UniProtQ92530

EQUAL

271

EQUAL

Reactome DB_ID: 68734

UniProt:P60900 PSMA6

PSMA6

PSMA6PROS27FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Interacts with ALKBH4 (PubMed:23145062).SIMILARITY Belongs to the peptidase T1A family.

UniProtP60900

EQUAL

246

EQUAL

Reactome DB_ID: 68744

UniProt:P49721 PSMB2

PSMB2

PSMB2FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 protein Tat.INDUCTION Up-regulated in ovarian cancer cell lines.SIMILARITY Belongs to the peptidase T1B family.

UniProtP49721

EQUAL

201

EQUAL

Reactome Database ID Release 6968819Database 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=68819ReactomeR-HSA-68819

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-68819.2GO0004175

GO molecular function

Reactome Database ID Release 6968824Database 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=68824Reactome Database ID Release 69174202Database 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=174202ReactomeR-HSA-174202

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-174202.2

PTTG1 (Securin) sequesters ESPL1 (Separase)

Securin sequesters SeparaseUp to anaphase onset, ESPL1 (separase i.e. separin) forms a complex with PTTG1 (pituitary tumor-transforming gene 1) i.e. securin. PTTG1 sequesters ESPL1 and block its catalytic site, preventing it from cleaving centromeric cohesin and causing premature separation of sister chromatids (Zou et al. 1999, Waizenegger et al. 2001, Waizenegger et al. 2002). PTTG1 is overexpressed in cancer and acts as an oncogene (Zhang et al. 1999). Regulation of PTTG1 cellular level is important for chromosomal stability in human cells (Jallepalli et al. 2001).

Reactome DB_ID: 174190

EQUAL

202

EQUAL

Reactome DB_ID: 1638167

UniProt:Q14674 ESPL1

ESPL1

ESPL1KIAA0165ESP1FUNCTION Caspase-like protease, which plays a central role in the chromosome segregation by cleaving the SCC1/RAD21 subunit of the cohesin complex at the onset of anaphase. During most of the cell cycle, it is inactivated by different mechanisms.ACTIVITY REGULATION Regulated by at least two independent mechanisms. First, it is inactivated via its interaction with securin/PTTG1, which probably covers its active site. The association with PTTG1 is not only inhibitory, since PTTG1 is also required for activating it, the enzyme being inactive in cells in which PTTG1 is absent. PTTG1 degradation at anaphase, liberates it and triggers RAD21 cleavage. Second, phosphorylation at Ser-1126 inactivates it. The complete phosphorylation during mitosis, is removed when cells undergo anaphase. Activation of the enzyme at the metaphase-anaphase transition probably requires the removal of both securin and inhibitory phosphate.SUBUNIT Interacts with PTTG1. Interacts with RAD21.PTM Autocleaves. This function, which is not essential for its protease activity, is unknown.PTM Phosphorylated by CDK1. There are 8 Ser/Thr phosphorylation sites. Among them, Ser-1126 phosphorylation is the major site, which conducts to the enzyme inactivation.

UniProtQ14674

EQUAL

2120

EQUAL

Reactome DB_ID: 2467796

PTTG1:ESPL1 [cytosol]

PTTG1:ESPL1

Securin:SeparinSecurin:Separase

Reactome DB_ID: 174190

EQUAL

202

EQUAL

Reactome DB_ID: 1638167

EQUAL

2120

EQUAL

Reactome Database ID Release 692467796Database 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=2467796ReactomeR-HSA-2467796

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-2467796.1Reactome Database ID Release 692467798Database 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=2467798ReactomeR-HSA-2467798

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-2467798.112194817Pubmed2002Regulation of human separase by securin binding and autocleavageWaizenegger, IreneGiménez-Abián, Juan FWernic, DominikPeters, Jan-MichaelCurr. Biol. 12:1368-789892021Pubmed1999Structure, expression, and function of human pituitary tumor-transforming gene (PTTG)Zhang, XHorwitz, G APrezant, T RValentini, ANakashima, MBronstein, M DMelmed, SMol. Endocrinol. 13:156-6611081627Pubmed2000Two distinct pathways remove mammalian cohesin from chromosome arms in prophase and from centromeres in anaphaseWaizenegger, I CHauf, SMeinke, APeters, JMCell 103:399-41011371342Pubmed2001Securin is required for chromosomal stability in human cellsJallepalli, P VWaizenegger, I CBunz, FLanger, SSpeicher, M RPeters, JMKinzler, K WVogelstein, BLengauer, CCell 105:445-5710411507Pubmed1999Identification of a vertebrate sister-chromatid separation inhibitor involved in transformation and tumorigenesisZou, HMcGarry, TJBernal, TKirschner, Marc WScience 285:418-22

3.4

Autocleavage of ESPL1 (Separase)

Autocleavage of SeparinAfter APC/C-mediated degradation of PTTG1 (securin), ESPL1 (separin i.e. separase) is rapidly autocatalytically cleaved after arginine residues at positions 1506 and 1535. The N-terminal and C-terminal fragments remain bound to each other after cleavage. It has not been examined what happens with the short middle fragment of ESPL1, so it is annotated as a part of the autocleaved ESPL1 complex. The autocatalytic cleavage of ESPL1 is not a prerequisite for the subsequent cleavage of the cohesin subunit RAD21 (Waizenegger et al. 2002).

Reactome DB_ID: 1638167

EQUAL

2120

EQUAL

Reactome DB_ID: 2467770

ESPL1 Autocleaved [cytosol]

ESPL1 Autocleaved

Separase AutocleavedSeparin Autocleaved

Reactome DB_ID: 2467767

1536

EQUAL

2120

EQUAL

Reactome DB_ID: 2500272

1507

EQUAL

1535

EQUAL

Reactome DB_ID: 2467768

EQUAL

1506

EQUAL

Reactome Database ID Release 692467770Database 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=2467770ReactomeR-HSA-2467770

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-2467770.1PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 1638167

EQUAL

2120

EQUAL

GO0008234

GO molecular function

Reactome Database ID Release 692467764Database 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=2467764Reactome Database ID Release 692467775Database 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=2467775ReactomeR-HSA-2467775

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-2467775.1

3.4

ESPL1 (Separase) cleaves centromeric cohesin

ESPL1 (separin i.e. separase) cleaves RAD21 (SCC1) subunit of centromeric cohesin at two sites that conform to the consensus separase recognition site E-X-X-R: after arginine residue R172 and after arginine residue R450 (Hauf et al. 2001). Phosphorylation of RAD21 at the serine residue S454 by PLK1 in prometaphase facilitates ESPL1-mediated cleavage of RAD21 at the C-terminal cleavage site R450 (Hauf et al. 2005). The N-terminal and C-terminal RAD21 cleavage fragments remain bound to the rest of the cohesin complex (Deardorff et al. 2012). It is not clear whether RAD21 middle fragment also continues to be associated with cohesin.

Reactome DB_ID: 2500242

chromosome, centromeric regionGO0000775p-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: 2500251

p-RAD21-Ac-Cohesin [chromosome, centromeric region]

p-RAD21-Ac-Cohesin

Reactome DB_ID: 2466015

UniProt:Q14683 SMC1A

SMC1A

DXS423ESMC1L1KIAA0178SMC1ASB1.8SMC1FUNCTION 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.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.

UniProtQ14683

EQUAL

1233

EQUAL

Reactome DB_ID: 2468148

UniProt:Q9UQE7 SMC3

SMC3

SMC3L1CSPG6SMC3BMHBAMFUNCTION 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.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.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.

UniProtQ9UQE7

N6-acetyl-L-lysine at 105

105

EQUAL

N6-acetyl-L-lysine [MOD:00064]

N6-acetyl-L-lysine at 106

106

EQUAL

1217

EQUAL

Reactome DB_ID: 2466018

UniProt:Q8N3U4 STAG2

STAG2

STAG2SA2FUNCTION 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.SIMILARITY Belongs to the SCC3 family.

UniProtQ8N3U4

EQUAL

1231

EQUAL

Reactome DB_ID: 2466017

UniProt:Q8WVM7 STAG1

STAG1

STAG1SA1SCC3FUNCTION 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.SIMILARITY Belongs to the SCC3 family.

UniProtQ8WVM7

EQUAL

1258

EQUAL

Reactome DB_ID: 2485163

UniProt:O60216 RAD21

RAD21

RAD21HR21SCC1KIAA0078NXP1FUNCTION Double-strand-break repair protein rad21 homolog: As a member of the cohesin complex, involved in sister chromatid cohesion from the time of DNA replication in S phase to their segregation in mitosis, a function that is essential for proper chromosome segregation, post-replicative DNA repair, and the prevention of inappropriate recombination between repetitive regions (PubMed:11509732). The cohesin complex may also play a role in spindle pole assembly during mitosis (PubMed:11590136). In interphase, cohesins may function in the control of gene expression by binding to numerous sites within the genome (By similarity). May control RUNX1 gene expression (Probable). Binds to and represses APOB gene promoter (PubMed:25575569). May play a role in embryonic gut development, possibly through the regulation of enteric neuron development.FUNCTION 64-kDa C-terminal product: May promote apoptosis.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). 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).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.

UniProtO60216

O-phospho-L-serine at 454

454

EQUAL

O-phospho-L-serine [MOD:00046]

EQUAL

631

EQUAL

Reactome Database ID Release 692500251Database 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=2500251ReactomeR-HSA-2500251

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 DB_ID: 2468269

UniProt:Q96FF9 CDCA5

CDCA5

CDCA5FUNCTION 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.

UniProtQ96FF9

O-phospho-L-threonine at 159

159

EQUAL

O-phospho-L-threonine [MOD:00047]

O-phospho-L-serine at 21

EQUAL

O-phospho-L-serine at 75

EQUAL

252

EQUAL

Reactome DB_ID: 375303

Microtubule-bound kinetochore [cytosol]

Microtubule-bound kinetochore

Reactome DB_ID: 190599

Microtubule [cytosol]

Microtubule

Reactome DB_ID: 8982424

Microtubule protofilament [cytosol]

Microtubule protofilament

Reactome Database ID Release 69190599Database 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=190599ReactomeR-HSA-190599

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-190599.2

Reactome DB_ID: 375305

Kinetochore [cytosol]

Kinetochore

Reactome DB_ID: 141412

EQUAL

499

EQUAL

Reactome DB_ID: 376249

UniProt:P43034 PAFAH1B1

PAFAH1B1

MDCRLIS1MDSPAFAHAPAFAH1B1FUNCTION 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. Non-catalytic subunit of an acetylhydrolase complex which inactivates platelet-activating factor (PAF) by removing the acetyl group at the SN-2 position (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).SUBUNIT Component of cytosolic PAF-AH IB, which is composed of PAFAH1B1 (alpha), PAFAH1B2 (beta) and PAFAH1B3 (gamma) subunits. Trimer formation is not essential for the catalytic activity of the enzyme which is contributed solely by the PAFAH1B2 (beta) and PAFAH1B3 (gamma) subunits. 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 ASUN. 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.SIMILARITY Belongs to the WD repeat LIS1/nudF family.

UniProtP43034

EQUAL

410

EQUAL

Reactome DB_ID: 376229

UniProt:P49454 CENPF

CENPF

CENPFFUNCTION 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.

UniProtP49454

EQUAL

3207

EQUAL

Reactome DB_ID: 376244

UniProt:Q8WYP5 AHCTF1

AHCTF1

ELYSMSTP108AHCTF1TMBS62FUNCTION 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.SIMILARITY Belongs to the ELYS family.

UniProtQ8WYP5

EQUAL

2266

EQUAL

Reactome DB_ID: 2029145

Dynein complex [cytosol]

Dynein complex

Reactome DB_ID: 2029144

DHC dimer [cytosol]

DHC dimer

Reactome DB_ID: 380285

UniProt:Q14204 DYNC1H1

DYNC1H1

DNCH1DYHCKIAA0325DYNC1H1DNCLDNECLDHC1FUNCTION 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).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.

UniProtQ14204

EQUAL

4646

EQUAL

Reactome Database ID Release 692029144Database 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=2029144ReactomeR-HSA-2029144

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-2029144.2Converted from EntitySet in Reactome

Reactome DB_ID: 2029105

DLCs [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityDYNLL2 [cytosol]DYNLL1 [cytosol]

UniProtQ96FJ2UniProtP63167Converted from EntitySet in Reactome

Reactome DB_ID: 2029122

DLIs [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityDYNC1LI2 [cytosol]DYNC1LI1 [cytosol]

UniProtO43237UniProtQ9Y6G9Converted from EntitySet in Reactome

Reactome DB_ID: 2029119

DICs [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityDYNC1I1 [cytosol]DYNC1I2 [cytosol]

UniProtO14576UniProtQ13409Reactome Database ID Release 692029145Database 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=2029145ReactomeR-HSA-2029145

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: 376248

UniProt:Q7L7X3 TAOK1

TAOK1

MAP3K16MARKKTAOK1KIAA1361FUNCTION 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 and TESK1. 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).

UniProtQ7L7X3

EQUAL

1001

EQUAL

Reactome DB_ID: 376259

UniProt:Q8N4N8 KIF2B

KIF2B

KIF2BFUNCTION 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.

UniProtQ8N4N8

EQUAL

673

EQUAL

Reactome DB_ID: 377729

UniProt:Q14008 CKAP5

CKAP5

KIAA0097CKAP5FUNCTION 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.

UniProtQ14008

EQUAL

2032

EQUAL

Reactome DB_ID: 376230

UniProt:Q7Z460 CLASP1

CLASP1

KIAA0622MAST1CLASP1FUNCTION 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.SIMILARITY Belongs to the CLASP family.

UniProtQ7Z460

EQUAL

1538

EQUAL

Reactome DB_ID: 376256

UniProt:Q99661 KIF2C

KIF2C

KIF2CKNSL6FUNCTION 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.

UniProtQ99661

EQUAL

725

EQUAL

Reactome DB_ID: 157703

UniProt:P49792 RANBP2

RANBP2

RANBP2NUP358FUNCTION 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 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).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.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.

UniProtP49792

EQUAL

3224

EQUAL

Reactome DB_ID: 377733

UniProt:Q96EA4 SPDL1

SPDL1

SPDL1CCDC99FUNCTION 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).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).SIMILARITY Belongs to the Spindly family.

UniProtQ96EA4

EQUAL

605

EQUAL

Reactome DB_ID: 377883

Nup107-160 complex [cytosol]

Nup107-160 complex

Reactome DB_ID: 376238

UniProt:Q9BW27 NUP85

NUP85

NUP75NUP85PCNT1FUNCTION 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.

UniProtQ9BW27

EQUAL

656

EQUAL

Reactome DB_ID: 376237

UniProt:Q8NFH4 NUP37

NUP37

NUP37FUNCTION 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.

UniProtQ8NFH4

EQUAL

326

EQUAL

Reactome DB_ID: 376251

UniProt:Q8WUM0 NUP133

NUP133

NUP133FUNCTION 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.SIMILARITY Belongs to the nucleoporin Nup133 family.

UniProtQ8WUM0

EQUAL

1156

EQUAL

Reactome DB_ID: 376247

UniProt:P52948-5 NUP98

NUP98

NUP98ADAR2FUNCTION 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. 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).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 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 vesicular stomatitis virus protein M (PubMed:11106761).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 A chromosomal aberration involving NUP98 is found in a form of acute myeloid leukemia. Translocation t(7;11)(p15;p15) with HOXA9. Translocation t(11;17)(p15;p13) with PHF23.DISEASE A chromosomal aberration involving NUP98 is 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 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.

UniProtP52948-5

EQUAL

880

EQUAL

Reactome DB_ID: 376253

UniProt:Q12769 NUP160

NUP160

KIAA0197NUP120NUP160FUNCTION Involved in poly(A)+ RNA transport.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.CAUTION It is uncertain whether Met-1 or Met-35 is the initiator.

UniProtQ12769

EQUAL

1436

EQUAL

Reactome DB_ID: 376243

UniProt:Q8NFH3 NUP43

NUP43

NUP43FUNCTION 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.

UniProtQ8NFH3

EQUAL

380

EQUAL

Reactome DB_ID: 376246

UniProt:Q96EE3-1 SEH1L

SEH1L

SEH1LSEC13LSEH1FUNCTION 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.

UniProtQ96EE3-1

EQUAL

360

EQUAL

Reactome DB_ID: 376241

UniProt:P57740 NUP107

NUP107

NUP107FUNCTION 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.TISSUE SPECIFICITY Ubiquitously expressed in fetal and adult tissues.SIMILARITY Belongs to the nucleoporin Nup84/Nup107 family.

UniProtP57740

EQUAL

925

EQUAL

Reactome DB_ID: 203981

UniProt:P55735 SEC13

SEC13

SEC13SEC13L1SEC13RSEC13AD3S1231EFUNCTION 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.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.

UniProtP55735

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322

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Reactome Database ID Release 69377883Database 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=377883ReactomeR-HSA-377883

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: 376250

UniProt:Q2NKX8 ERCC6L

ERCC6L

ERCC6LPICHFUNCTION DNA helicase that acts as an essential component of the spindle assembly checkpoint. Contributes to the mitotic checkpoint by recruiting MAD2 to kinetochores and monitoring tension on centromeric chromatin (PubMed:17218258). 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.

UniProtQ2NKX8

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1250

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Reactome DB_ID: 376257

UniProt:Q9NXR1 NDE1

NDE1

NDE1NUDEFUNCTION 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.SIMILARITY Belongs to the nudE family.

UniProtQ9NXR1

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346

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Reactome DB_ID: 165539

UniProt:O14980 XPO1

XPO1

XPO1CRM1FUNCTION 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, NUPL2, 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.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.

UniProtO14980

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1071

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Reactome DB_ID: 377738

CCAN network [cytosol]

CCAN network

Reactome DB_ID: 375292

UniProt:Q03188 CENPC

CENPC

ICEN7CENPC1CENPCFUNCTION 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.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.

UniProtQ03188

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943

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Reactome DB_ID: 375295

UniProt:Q8N0S6 CENPL

CENPL

ICEN33C1orf155CENPLFUNCTION 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.

UniProtQ8N0S6

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344

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Reactome DB_ID: 375290

UniProt:Q9NSP4 CENPM

CENPM

CENPMICEN39C22orf18PANE1FUNCTION 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.

UniProtQ9NSP4

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180

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Reactome DB_ID: 375306

UniProt:Q96H22 CENPN

CENPN

ICEN32C16orf60BM-309CENPNFUNCTION 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.

UniProtQ96H22

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339

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Reactome DB_ID: 375316

UniProt:Q96BT3 CENPT

CENPT

CENPTICEN22C16orf56FUNCTION 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.

UniProtQ96BT3

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561

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Reactome DB_ID: 377884

CENP-(H,I, K) complex [cytosol]

CENP-(H,I, K) complex

Reactome DB_ID: 375296

UniProt:Q9BS16 CENPK

CENPK

ICEN37FKSG14CENPKFUNCTION 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.

UniProtQ9BS16

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269

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Reactome DB_ID: 375293

UniProt:Q92674 CENPI

CENPI

FSHPRH1CENPIICEN19LRPR1FUNCTION 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.

UniProtQ92674

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756

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Reactome DB_ID: 375294

UniProt:Q9H3R5 CENPH

CENPH

CENPHICEN35FUNCTION 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.SIMILARITY Belongs to the CENP-H/MCM16 family.

UniProtQ9H3R5

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247

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Reactome Database ID Release 69377884Database 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=377884ReactomeR-HSA-377884

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: 375310

UniProt:Q8N2Z9 CENPS

CENPS

MHF1APITD1FAAP16CENPSFUNCTION 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.

UniProtQ8N2Z9

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138

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Reactome DB_ID: 377886

CENP-O complex [cytosol]

CENP-O complex

Reactome DB_ID: 375301

UniProt:Q9BU64 CENPO

CENPO

ICEN36MCM21RCENPOFUNCTION 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.

UniProtQ9BU64

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300

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Reactome DB_ID: 375299

UniProt:Q6IPU0 CENPP

CENPP

CENPPFUNCTION 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.

UniProtQ6IPU0

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288

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Reactome DB_ID: 375298

UniProt:Q7L2Z9 CENPQ

CENPQ

C6orf139CENPQFUNCTION 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.

UniProtQ7L2Z9

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268

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Reactome DB_ID: 375315

UniProt:Q71F23 CENPU

CENPU

CENPUMLF1IPICEN24KLIP1PBIP1FUNCTION 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.

UniProtQ71F23

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418

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Reactome DB_ID: 3006405

UniProt:Q13352 ITGB3BP

ITGB3BP

NRIF3ITGB3BPCENPRFUNCTION 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.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.

UniProtQ13352

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Reactome Database ID Release 69377886Database 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=377886ReactomeR-HSA-377886

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-377886.1Reactome Database ID Release 69377738Database 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=377738ReactomeR-HSA-377738

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: 376258

UniProt:Q9GZM8 NDEL1

NDEL1

NUDELEOPAMITAP1NDEL1FUNCTION 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.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.

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Reactome DB_ID: 377736

UniProt:Q9BPU9 B9D2

B9D2

MKSR2B9D2FUNCTION 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.SIMILARITY Belongs to the B9D family.

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Reactome DB_ID: 377745

KMN network [cytosol]

KMN network

Reactome DB_ID: 375322

UniProt:Q8NG31 KNL1

KNL1

CASC5KNL1KIAA1570FUNCTION 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.

UniProtQ8NG31

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Reactome DB_ID: 375441

Mis12 complex [cytosol]

Mis12 complex

Reactome DB_ID: 375320

UniProt:Q6P1K2 PMF1

PMF1

PMF1FUNCTION 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.

UniProtQ6P1K2

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Reactome DB_ID: 375309

UniProt:Q96IY1 NSL1

NSL1

DC31MIS14DC8C1orf48NSL1FUNCTION 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.

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Reactome DB_ID: 375308

UniProt:Q9H410 DSN1

DSN1

DSN1C20orf172MIS13FUNCTION 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.

UniProtQ9H410

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Reactome DB_ID: 375313

UniProt:Q9H081 MIS12

MIS12

MIS12FUNCTION 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.

UniProtQ9H081

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Reactome Database ID Release 69375441Database 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=375441ReactomeR-HSA-375441

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: 375444

NDC80 complex [cytosol]

NDC80 complex

Reactome DB_ID: 375297

UniProt:Q8NBT2 SPC24

SPC24

SPBC24SPC24FUNCTION 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.

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Reactome DB_ID: 375314

UniProt:O14777 NDC80

NDC80

KNTC2HECHEC1NDC80FUNCTION 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). 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). 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. May also be phosphorylated by AURKA and AURKB.SIMILARITY Belongs to the NDC80/HEC1 family.

UniProtO14777

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Reactome DB_ID: 375300

UniProt:Q9BZD4 NUF2

NUF2

CDCA1NUF2NUF2RFUNCTION 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.

UniProtQ9BZD4

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Reactome DB_ID: 375307

UniProt:Q9HBM1 SPC25

SPC25

SPBC25AD024SPC25FUNCTION 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.

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Reactome Database ID Release 69375444Database 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=375444ReactomeR-HSA-375444

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-375444.1Reactome Database ID Release 69377745Database 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=377745ReactomeR-HSA-377745

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: 377879

Chromosome passenger complex [cytosol]

Chromosome passenger complex

Reactome DB_ID: 375288

UniProt:Q53HL2 CDCA8

CDCA8

CDCA8PESCRG3FUNCTION 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.

UniProtQ53HL2

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Reactome DB_ID: 50851

UniProt:O15392 BIRC5

BIRC5

API4BIRC5IAP4FUNCTION Multitasking protein that has dual roles in promoting cell proliferation and preventing apoptosis (PubMed:9859993, PubMed:21364656, PubMed:20627126). 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). 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.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.

UniProtO15392

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Reactome DB_ID: 174231

UniProt:Q96GD4 AURKB

AURKB

AIK2STK1AIM1STK12ARK2AIRK2STK5AURKBFUNCTION Serine/threonine-protein kinase 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. Involved in the bipolar attachment of spindle microtubules to kinetochores and is a key regulator for the onset of cytokinesis during mitosis. Required for central/midzone spindle assembly and cleavage furrow formation. 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. Phosphorylation of INCENP leads to increased AURKB activity. Other known AURKB substrates involved in centromeric functions and mitosis are CENPA, DES/desmin, GPAF, KIF2C, NSUN2, RACGAP1, SEPT1, VIM/vimentin, HASPIN, and histone H3. A positive feedback loop involving HASPIN and AURKB contributes to localization of CPC to centromeres. 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). A positive feedback between HASPIN and AURKB contributes to CPC localization. AURKB is also required for kinetochore localization of BUB1 and SGO1. Phosphorylation of p53/TP53 negatively regulates its transcriptional activity. 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.ACTIVITY REGULATION Activity is greatly increased when AURKB is within the CPC complex. In particular, AURKB-phosphorylated INCENP acts as an activator of AURKB. Positive feedback between HASPIN and AURKB contributes to CPC localization.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. Associates with RACGAP1 during M phase. Interacts with CDCA1, EVI5, JTB, NDC80, PSMA3, SEPT1, SIRT2 and TACC1. Interacts with SPDYC; this interaction may be required for proper localization of active, Thr-232-phosphorylated AURKB form during prometaphase and metaphase. Interacts with p53/TP53. Interacts (via the middle kinase domain) with NOC2L (via the N- and C-terminus domains). Interacts with TTC28. Interacts with RNF2/RING1B.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. Thr-232 phosphorylation is indispensable for the AURKB kinase activity.PTM Ubiquitinated by different BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complexes. Ubiquitinated by the BCR(KLHL9-KLHL13) E3 ubiquitin ligase complex, ubiquitination leads to removal from mitotic chromosomes and is required for cytokinesis. 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. Ubiquitination of AURKB by BCR(KLHL21) E3 ubiquitin ligase complex may not lead to its degradation by the proteasome.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.

UniProtQ96GD4

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Reactome DB_ID: 375311

UniProt:Q9NQS7 INCENP

INCENP

INCENPFUNCTION 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 H2AFZ (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.

UniProtQ9NQS7

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918

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Reactome Database ID Release 69377879Database 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=377879ReactomeR-HSA-377879

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: 377888

UniProt:O43683 BUB1

BUB1

BUB1LBUB1FUNCTION 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.

UniProtO43683

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1085

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Reactome DB_ID: 377885

RZZ complex [cytosol]

RZZ complex

Reactome DB_ID: 377880

UniProt:O43264 ZW10

ZW10

ZW10FUNCTION 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).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.

UniProtO43264

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779

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Reactome DB_ID: 376233

UniProt:P50748 KNTC1

KNTC1

KNTC1KIAA0166FUNCTION 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.

UniProtP50748

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2209

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Reactome DB_ID: 376234

UniProt:Q9H900 ZWILCH

ZWILCH

ZWILCHFUNCTION 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.

UniProtQ9H900

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591

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Reactome Database ID Release 69377885Database 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=377885ReactomeR-HSA-377885

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: 376254

UniProt:O95229 ZWINT

ZWINT

ZWINTFUNCTION 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.

UniProtO95229

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277

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Reactome DB_ID: 376242

UniProt:Q562F6 SGO2

SGO2

SGO2SGOL2FUNCTION 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.

UniProtQ562F6

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1265

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Reactome DB_ID: 376240

UniProt:Q15691 MAPRE1

MAPRE1

MAPRE1FUNCTION 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:28726242, PubMed:28814570). Promotes cytoplasmic microtubule nucleation and elongation (PubMed:12388762, PubMed:16109370, PubMed:19632184, PubMed:21646404, PubMed:28726242, PubMed:28814570). May be involved in spindle function by stabilizing microtubules and anchoring them at centrosomes (PubMed:12388762). 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.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).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.SIMILARITY Belongs to the MAPRE family.

UniProtQ15691

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268

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Reactome DB_ID: 376239

UniProt:Q8NI77 KIF18A

KIF18A

KIF18AOK/SW-cl.108FUNCTION 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.

UniProtQ8NI77

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898

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Reactome DB_ID: 376228

UniProt:Q96BD8 SKA1

SKA1

C18orf24SKA1FUNCTION 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.

UniProtQ96BD8

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255

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Reactome DB_ID: 376252

UniProt:O75122 CLASP2

CLASP2

KIAA0627CLASP2FUNCTION 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.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.

UniProtO75122

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1294

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Reactome DB_ID: 72361

UniProt:P42677 RPS27

RPS27

RPS27MPS1FUNCTION 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.

UniProtP42677

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Reactome DB_ID: 376232

UniProt:O00139 KIF2A

KIF2A

KNS2KIF2AKIF2FUNCTION 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.

UniProtO00139

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706

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Reactome DB_ID: 376255

UniProt:P46060 RANGAP1

RANGAP1

SDKIAA1835RANGAP1FUNCTION 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).SIMILARITY Belongs to the RNA1 family.

UniProtP46060

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587

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Reactome DB_ID: 163443

UniProt:P36873 PPP1CC

PPP1CC

PPP1CCFUNCTION 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).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).

UniProtP36873

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323

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Reactome DB_ID: 376245

UniProt:Q02224 CENPE

CENPE

CENPEFUNCTION 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.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.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.

UniProtQ02224

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2698

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Reactome DB_ID: 376227

UniProt:Q5FBB7 SGO1

SGO1

SGO1SGOL1FUNCTION 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.

UniProtQ5FBB7

EQUAL

561

EQUAL

Reactome DB_ID: 376235

UniProt:Q9P258 RCC2

RCC2

RCC2TD60KIAA1470FUNCTION 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).

UniProtQ9P258

EQUAL

522

EQUAL

Reactome DB_ID: 376231

UniProt:Q8WVK7 SKA2

SKA2

FAM33ASKA2FUNCTION 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.

UniProtQ8WVK7

EQUAL

121

EQUAL

Reactome DB_ID: 377731

UniProt:Q9Y266 NUDC

NUDC

NUDCFUNCTION Plays a role in neurogenesis and neuronal migration (By similarity). Necessary for correct formation of mitotic spindles and chromosome separation during mitosis. Necessary for cytokinesis and cell proliferation.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).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.

UniProtQ9Y266

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331

EQUAL

Reactome DB_ID: 375317

UniProt:P49450 CENPA

CENPA

CENPAFUNCTION 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 H2AFY and H2A.Z/H2AFZ (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.

UniProtP49450

EQUAL

140

EQUAL

Reactome DB_ID: 141433

UniProt:Q9Y6D9 MAD1L1

MAD1L1

MAD1TXBP181MAD1L1FUNCTION Component of the spindle-assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at the metaphase plate. May recruit MAD2L1 to unattached kinetochores. Has a role in the correct positioning of the septum. Required for anchoring MAD2L1 to the nuclear periphery. Binds to the TERT promoter and represses telomerase expression, possibly by interfering with MYC binding.SUBUNIT Homodimer. Heterodimerizes with MAD2L1 in order to form a tetrameric MAD1L1-MAD2L1 core complex (PubMed:9546394, PubMed:18981471, PubMed:22351768, PubMed:12006501). Perturbation of the original MAD1L1-MAD2L1 structure by the spindle checkpoint may decrease MAD2L1 affinity for MAD1L1. 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. Also able to interact with the BUB1/BUB3 complex (PubMed:10198256). Interacts with NEK2 (PubMed:14978040). 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).TISSUE SPECIFICITY Expressed weakly at G0/G1 and highly at late S and G2/M phase.INDUCTION Increased by p53/TP53.PTM Phosphorylated; by BUB1. Become hyperphosphorylated in late S through M phases or after mitotic spindle damage.DISEASE Defects in MAD1L1 are involved in the development and/or progression of various types of cancer.SIMILARITY Belongs to the MAD1 family.

UniProtQ9Y6D9

EQUAL

718

EQUAL

Reactome DB_ID: 196206

PP2A [cytosol]

PP2A

Converted from EntitySet in Reactome

Reactome DB_ID: 196216

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

Converted from EntitySet in Reactome

Reactome DB_ID: 165977

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: 165990

PP2A-subunit A [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 69196206Database 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=196206ReactomeR-HSA-196206

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: 375311

EQUAL

918

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Reactome DB_ID: 164603

UniProt:P53350 PLK1

PLK1

PLK1PLKFUNCTION 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).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 FOPNL 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.

UniProtP53350

EQUAL

603

EQUAL

Reactome DB_ID: 377732

UniProt:P30622 CLIP1

CLIP1

CYLN1CLIP1RSNFUNCTION 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.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).

UniProtP30622

EQUAL

1438

EQUAL

Reactome DB_ID: 377882

Mitotic checkpoint complex [cytosol]

Mitotic checkpoint complex

Reactome DB_ID: 141412

EQUAL

499

EQUAL

Reactome DB_ID: 141436

UniProt:O60566 BUB1B

BUB1B

SSK1MAD3LBUBR1BUB1BFUNCTION 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, CENPF, mitosin, PLK1 and BUB3. Part of a complex containing BUB3, CDC20 and BUB1B. Interacts with anaphase-promoting complex/cyclosome (APC/C). Interacts with KNL1. Interacts with RIPK3 (PubMed:29883609).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.

UniProtO60566

EQUAL

1050

EQUAL

Reactome DB_ID: 141416

UniProt:O43684 BUB3

BUB3

BUB3FUNCTION 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.

UniProtO43684

EQUAL

328

EQUAL

Reactome DB_ID: 141400

UniProt:Q13257 MAD2L1

MAD2L1

MAD2MAD2L1FUNCTION Component of the spindle-assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at the metaphase plate. 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.SUBUNIT Monomer and homodimer. Heterotetramer with MAD1L1. 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. Interacts with CDC20, MAD2L1BP and with ADAM17/TACE. Dimeric MAD2L1 in the closed conformation interacts with CDC20. Monomeric MAD2L1 in the open conformation does not interact with CDC20. CDC20 competes with MAD1L1 for MAD2L1 binding. Interacts with TPR. Binds to UBD (via ubiquitin-like 1 domain) during mitosis. Interacts with isoform 1 and isoform 2 of NEK2. Interacts with HSF1; this interaction occurs in mitosis (PubMed:18794143).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.

UniProtQ13257

EQUAL

205

EQUAL

Reactome Database ID Release 69377882Database 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=377882ReactomeR-HSA-377882

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-377882.1Reactome Database ID Release 69375305Database 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=375305ReactomeR-HSA-375305

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-375305.2Reactome Database ID Release 69375303Database 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=375303ReactomeR-HSA-375303

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: 2577088

UniProt:Q7Z5K2 WAPL

WAPL

WAPALFOEWAPLKIAA0261FUNCTION 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.

UniProtQ7Z5K2

EQUAL

1190

EQUAL

Reactome DB_ID: 1638792

chromosomeGO0005694Sister Centromere [chromosome]

Sister Centromere

Converted from EntitySet in Reactome

Reactome DB_ID: 2468261

PDS5 [chromosome, centromeric region]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityPDS5B [chromosome, centromeric region]PDS5A [chromosome, centromeric region]

UniProtQ9NTI5UniProtQ29RF7Reactome Database ID Release 692500242Database 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=2500242ReactomeR-HSA-2500242

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: 2467806

Cleaved Cohesin:PDS5:p-CDCA5:WAPAL:Sister Centromeres:Kinetochores:Microtubules [chromosome, centromeric region]

Cleaved Cohesin:PDS5:p-CDCA5:WAPAL:Sister Centromeres:Kinetochores:Microtubules

Reactome DB_ID: 2467801

Cleaved Cohesin [chromosome, centromeric region]

Cleaved Cohesin

Reactome DB_ID: 2466015

EQUAL

1233

EQUAL

Reactome DB_ID: 2466018

EQUAL

1231

EQUAL

Reactome DB_ID: 2468148

N6-acetyl-L-lysine at 105

105

EQUAL

N6-acetyl-L-lysine at 106

106

EQUAL

1217

EQUAL

Reactome DB_ID: 2500296

173

EQUAL

450

EQUAL

Reactome DB_ID: 2466017

EQUAL

1258

EQUAL

Reactome DB_ID: 2467790

O-phospho-L-serine at 454

454

EQUAL

451

EQUAL

631

EQUAL

Reactome DB_ID: 2467793

EQUAL

172

EQUAL

Reactome Database ID Release 692467801Database 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=2467801ReactomeR-HSA-2467801

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-2467801.1

Reactome DB_ID: 190599

Reactome DB_ID: 2468269

O-phospho-L-threonine at 159

159

EQUAL

O-phospho-L-serine at 21

EQUAL

O-phospho-L-serine at 75

EQUAL

252

EQUAL

Reactome DB_ID: 2577088

EQUAL

1190

EQUAL

Reactome DB_ID: 1638792

Converted from EntitySet in Reactome

Reactome DB_ID: 2468261

Reactome DB_ID: 375305

Reactome Database ID Release 692467806Database 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=2467806ReactomeR-HSA-2467806

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-2467806.2PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 2467770

Reactome Database ID Release 692467772Database 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=2467772Reactome Database ID Release 692467809Database 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=2467809ReactomeR-HSA-2467809

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-2467809.111509732Pubmed2001Cohesin cleavage by separase required for anaphase and cytokinesis in human cellsHauf, SWaizenegger, ICPeters, JMScience 293:1320-315737063Pubmed2005Dissociation of cohesin from chromosome arms and loss of arm cohesion during early mitosis depends on phosphorylation of SA2Hauf, SRoitinger, EKoch, BDittrich, CMMechtler, KPeters, JMPLoS Biol 3:e6922885700Pubmed2012HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycleDeardorff, Matthew ABando, MasashigeNakato, RyuichiroWatrin, ErwanItoh, TakehikoMinamino, MasashiSaitoh, KatsuyaKomata, MakikoKatou, YukiClark, DinahCole, Kathryn EDe Baere, ElfrideDecroos, ChristopheDi Donato, NataliyaErnst, SarahFrancey, Lauren JGyftodimou, YolandaHirashima, KyotaroHullings, MelanieIshikawa, YuuichiJaulin, ChristianKaur, ManinderKiyono, TLombardi, Patrick MMagnaghi-Jaulin, LMortier, Geert RNozaki, NaohitoPetersen, Michael BSeimiya, HiroyukiSiu, Victoria MSuzuki, YutakaTakagaki, KentaroWilde, Jonathan JWillems, Patrick JPrigent, ClaudeGillessen-Kaesbach, GabrieleChristianson, DWKaiser, Frank JJackson, Laird GHirota, ToruKrantz, Ian DShirahige, KatsuhikoNature 489:313-7

Separation of sister chromatids

The cleavage of RAD21 subunit of centromeric cohesin by ESPL1 (separin i.e. separase) promotes dissociation of cohesin complexes from centromeric chromatin at the onset of anaphase, allowing for sister chromatid separation and segregation of replicated chromosomes to daughter cells (Waizenegger et al. 2000, Hauf et al. 2001, Waizenegger et al. 2002).

Reactome DB_ID: 2467806

Reactome DB_ID: 2467805

Cleaved Cohesin:PDS5:WAPAL [cytosol]

Cleaved Cohesin:PDS5:WAPAL

Converted from EntitySet in Reactome

Reactome DB_ID: 2484796

PDS5 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityPDS5A [cytosol]PDS5B [cytosol]

Reactome DB_ID: 2467802

Cleaved Cohesin [cytosol]

Cleaved Cohesin

Reactome DB_ID: 2484793

EQUAL

1258

EQUAL

Reactome DB_ID: 2484897

EQUAL

1231

EQUAL

Reactome DB_ID: 2500309

O-phospho-L-serine at 454

454

EQUAL

451

EQUAL

631

EQUAL

Reactome DB_ID: 2484798

EQUAL

1233

EQUAL

Reactome DB_ID: 2500308

173

EQUAL

450

EQUAL

Reactome DB_ID: 2484792

N6-acetyl-L-lysine at 105

105

EQUAL

N6-acetyl-L-lysine at 106

106

EQUAL

1217

EQUAL

Reactome DB_ID: 2484901

EQUAL

172

EQUAL

Reactome Database ID Release 692467802Database 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=2467802ReactomeR-HSA-2467802

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-2467802.1

Reactome DB_ID: 2484802

EQUAL

1190

EQUAL

Reactome Database ID Release 692467805Database 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=2467805ReactomeR-HSA-2467805

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-2467805.1

Reactome DB_ID: 2484902

Sister Centromere:Kinetochore:Microtubules [cytosol]

Sister Centromere:Kinetochore:Microtubules

Reactome DB_ID: 190599

Reactome DB_ID: 1638792

Reactome DB_ID: 375305

Reactome Database ID Release 692484902Database 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=2484902ReactomeR-HSA-2484902

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-2484902.1

Reactome DB_ID: 2484804

O-phospho-L-threonine at 159

159

EQUAL

O-phospho-L-serine at 21

EQUAL

O-phospho-L-serine at 75

EQUAL

252

EQUAL

Reactome Database ID Release 692467811Database 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=2467811ReactomeR-HSA-2467811

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-2467811.1

3.5.1.98

Deacetylation of cleaved cohesin

Histone deacetylase HDAC8 deacetylates SMC3 cohesin subunit. SMC3 deacetylation promotes dissociation of cleaved RAD21 fragments from other cohesin proteins and their replacement with intact RAD21, thereby allowing restoration of the cohesin complex (Deardorff et al. 2012). HDAC8 mutations, as well as mutations in NIPBL, SMC1A and SMC3, can cause Cornelia de Lang syndrome (Deardorff et al. 2012).

Reactome DB_ID: 2467805

Reactome DB_ID: 2484795

EQUAL

631

EQUAL

Reactome DB_ID: 76194

coenzyme A [ChEBI:15346]

coenzyme A

ChEBI15346

Reactome DB_ID: 2500309

O-phospho-L-serine at 454

454

EQUAL

451

EQUAL

631

EQUAL

Reactome DB_ID: 2500308

173

EQUAL

450

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 2484796

Reactome DB_ID: 2484901

EQUAL

172

EQUAL

Reactome DB_ID: 2484802

EQUAL

1190

EQUAL

Reactome DB_ID: 76183

acetyl-CoA [ChEBI:15351]

acetyl-CoA

ChEBI15351

Reactome DB_ID: 2545214

Cohesin Complex [cytosol]

Cohesin Complex

Reactome DB_ID: 2484795

EQUAL

631

EQUAL

Reactome DB_ID: 2484793

EQUAL

1258

EQUAL

Reactome DB_ID: 2484897

EQUAL

1231

EQUAL

Reactome DB_ID: 2484798

EQUAL

1233

EQUAL

Reactome DB_ID: 2545223

EQUAL

1217

EQUAL

Reactome Database ID Release 692545214Database 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=2545214ReactomeR-HSA-2545214

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-2545214.1PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Converted from EntitySet in Reactome

Reactome DB_ID: 2545205

HDAC8 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

GO0004407

GO molecular function

Reactome Database ID Release 692545204Database 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=2545204Reactome Database ID Release 692545203Database 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=2545203ReactomeR-HSA-2545203

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-2545203.1

Reactome Database ID Release 692467813Database 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=2467813ReactomeR-HSA-2467813

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-2467813.1

Nuclear Envelope Reassembly

The reassembly of the nuclear envelope (NE) around separated sister chromatids begins in late anaphase and is completed in telophase. Nuclear pore complexes (NPCs) reassemble and insert into the reforming nuclear envelope (reviewed by Guttinger et al. 2009).

Authored: Orlic-Milacic, M, 2013-01-22Reviewed: Gorjánácz, Mátyás, 2013-01-30Reviewed: Mattaj, Iain W, 2013-01-30Edited: Gillespie, ME, 2013-01-23

Initiation of Nuclear Envelope Reformation

Reassembly of the nuclear envelope is initiated at late anaphase/early telophase when BANF1 (BAF) accumulates on the decondensing chromosome mass close to the spindle ('core' region), together with EMD (emerin), TMPO (LAP2beta), LEMD3 (MAN1), LEMD2 (LEM2) and lamin A (Haraguchi et al. 2008, reviewed by Guttinger et al. 2009).

Authored: Orlic-Milacic, M, 2013-01-22Reviewed: Gorjánácz, Mátyás, 2013-01-30Reviewed: Mattaj, Iain W, 2013-01-30Edited: Gillespie, ME, 2013-01-23

ANKLE2 binds VRK1 or VRK2

ANKLE2 (LEM4) is required for nuclear envelope formation in C. elegans and its function appears to be conserved in human cells. Both human LEM4 and the C. elegans ortholog bind VRK1 (and possibly VRK2), the kinase responsible for phosphorylation of BANF1 (BAF) in mitotic prophase, and inhibit VRK1 catalytic activity (Asencio et al. 2012).

Authored: Orlic-Milacic, M, 2013-01-22Reviewed: Gorjánácz, Mátyás, 2013-01-30Reviewed: Mattaj, Iain W, 2013-01-30Edited: Gillespie, ME, 2013-01-23

Reactome DB_ID: 2529000

endoplasmic reticulum membraneGO0005789

UniProt:Q86XL3 ANKLE2

ANKLE2

ANKLE2LEM4KIAA0692FUNCTION Involved in mitotic nuclear envelope reassembly by promoting dephosphorylation of BAF/BANF1 during mitotic exit. Coordinates the control of BAF/BANF1 dephosphorylation by inhibiting VRK1 kinase and promoting dephosphorylation of BAF/BANF1 by protein phosphatase 2A (PP2A), thereby facilitating nuclear envelope assembly. It is unclear whether it acts as a real PP2A regulatory subunit or whether it is involved in recruitment of the PP2A complex. Involved in brain development (PubMed:25259927).SUBUNIT Interacts with BAF/BANF1. Interacts with protein phosphatase 2A (PP2A) components PPP2C (PPP2CA or PPP2CB) and PPP2R1A.SIMILARITY Belongs to the ANKLE2 family.

UniProtQ86XL3

EQUAL

938

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 2995386

VRK1/VRK2 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityVRK1 [cytosol]

UniProtQ99986

Reactome DB_ID: 2995385

ANKLE2:VRK1/VRK2 [endoplasmic reticulum membrane]

ANKLE2:VRK1/VRK2

LEM4:VRK1/VRK2

Reactome DB_ID: 2529000

EQUAL

938

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 2995386

Reactome Database ID Release 692995385Database 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=2995385ReactomeR-HSA-2995385

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-2995385.1Reactome Database ID Release 692995389Database 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=2995389ReactomeR-HSA-2995389

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-2995389.122770216Pubmed2012Coordination of kinase and phosphatase activities by Lem4 enables nuclear envelope reassembly during mitosisAsencio, ClaudioDavidson, Iain FSantarella-Mellwig, RachelLy-Hartig, Thi Bach NgaMall, MoritzWallenfang, Matthew RMattaj, Iain WGorjánácz, MátyásCell 150:122-35

PP2A dephosphorylates BANF1

The PP2A complex that contains the regulatory subunit B55-alpha (PPP2R2A) is the only phosphatase essential for mitotic exit (Schmitz et al. 2010). The PP2A complex is necessary for BANF1 (BAF) dephosphorylation in late mitotic anaphase. ANKLE2 (LEM4) binds the PP2A complex that contains the B55-alpha regulatory subunit and facilitates BANF1 dephosphorylation, but as ANKLE2 does not interact with BANF1 (BAF) directly, the exact mechanism has not been determined (Asencio et al. 2012).

Authored: Orlic-Milacic, M, 2013-01-22Reviewed: Gorjánácz, Mátyás, 2013-01-30Reviewed: Mattaj, Iain W, 2013-01-30Edited: Gillespie, ME, 2013-01-23

Reactome DB_ID: 29356

water [ChEBI:15377]

water

ChEBI15377

Reactome DB_ID: 2995380

p-T2,T3,S4-BANF1 [cytosol]

p-T2,T3,S4-BANF1

p-T2,T3,S4-BANF1 homodimerp-T2,T3,S4-BAF

Reactome DB_ID: 2995375

UniProt:O75531 BANF1

BANF1

BAFBANF1BCRG1FUNCTION Plays fundamental roles in nuclear assembly, chromatin organization, gene expression and gonad development. May potently compress chromatin structure and be involved in membrane recruitment and chromatin decondensation during nuclear assembly. Contains 2 non-specific dsDNA-binding sites which may promote DNA cross-bridging.FUNCTION (Microbial infection) Exploited by retroviruses for inhibiting self-destructing autointegration of retroviral DNA, thereby promoting integration of viral DNA into the host chromosome. EMD and BAF are cooperative cofactors of HIV-1 infection. Association of EMD with the viral DNA requires the presence of BAF and viral integrase. The association of viral DNA with chromatin requires the presence of BAF and EMD.FUNCTION (Microbial infection) In case of poxvirus infection, has an antiviral activity by blocking viral DNA replication.SUBUNIT Homodimer (PubMed:16337940, PubMed:22399800). Heterodimerizes with BAFL (PubMed:16337940). Interacts with ANKLE2/LEM4, leading to decreased phosphorylation by VRK1 and promoting dephosphorylation by protein phosphatase 2A (PP2A) (PubMed:22770216). Binds non-specifically to double-stranded DNA, and is found as a hexamer or dodecamer upon DNA binding. Binds to LEM domain-containing nuclear proteins such as LEMD3/MAN1, TMPO/LAP2 and EMD (emerin) (PubMed:11792822, PubMed:15681850). Interacts with ANKLE1 (via LEM domain); the interaction may favor BANF1 dimerization (PubMed:22399800). Interacts with CRX and LMNA (lamin-A). Binds linker histone H1.1 and core histones H3 (PubMed:16203725).SUBUNIT (Microbial infection) Interacts with HIV-1 pre-integration complex in cytoplasm by binding to viral matrix protein and Gag polyprotein.TISSUE SPECIFICITY Widely expressed. Expressed in colon, brain, heart, kidney, liver, lung, ovary, pancreas, placenta, prostate, skeletal muscle, small intestine, spleen and testis. Not detected in thymus and peripheral blood leukocytes.DOMAIN Has a helix-hairpin-helix (HhH) structural motif conserved among proteins that bind non-specifically to DNA.DOMAIN LEM domain proteins bind centrally on the BAF dimer.PTM Ser-4 is the major site of phosphorylation as compared to Thr-2 and Thr-3. Phosphorylation on Thr-2; Thr-3 and Ser-4 disrupts its ability to bind DNA and reduces its ability to bind LEM domain-containing proteins. Non phosphorylated BAF seems to enhance binding between EMD and LMNA. Dephosphorylated by protein phosphatase 2A (PP2A) following interaction with ANKLE2/LEM4 during mitotic exit, leading to mitotic nuclear envelope reassembly.PTM (Microbial infection) Phosphorylated at the N-terminus by vaccinia virus (VacV) B1 kinase, leading to BANF1 relocalization to the cytoplasm, loss of dimerization and impaired DNA binding activity (PubMed:24600006, PubMed:16495336). Hyperphosphorylation is linked to the loss of ability to suppress vaccinia virus replication (PubMed:24600006).SIMILARITY Belongs to the BAF family.

UniProtO75531

O-phospho-L-threonine at 2

EQUAL

O-phospho-L-threonine at 3

EQUAL

O-phospho-L-serine at 4

EQUAL

Reactome Database ID Release 692995380Database 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=2995380ReactomeR-HSA-2995380

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-2995380.1

Reactome DB_ID: 2995377

BANF1 [cytosol]

BANF1

BANF1 homodimer

Reactome DB_ID: 175371

EQUAL

Reactome Database ID Release 692995377Database 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=2995377ReactomeR-HSA-2995377

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-2995377.1

Reactome DB_ID: 29372

phosphate(3-) [ChEBI:18367]

phosphate(3-)

ChEBI18367PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 377182

PP2A (Aalpha:B55alpha:Calpha) [cytosol]

PP2A (Aalpha:B55alpha:Calpha)

Reactome DB_ID: 165971

UniProt:P67775 PPP2CA

PPP2CA

PPP2CAFUNCTION PP2A is the major phosphatase for microtubule-associated proteins (MAPs). PP2A can modulate the activity of phosphorylase B kinase casein kinase 2, mitogen-stimulated S6 kinase, and MAP-2 kinase. Cooperates with SGO2 to protect centromeric cohesin from separase-mediated cleavage in oocytes specifically during meiosis I (By similarity). Can dephosphorylate SV40 large T antigen and p53/TP53. Activates RAF1 by dephosphorylating it at 'Ser-259'.SUBUNIT PP2A consists of a common heterodimeric core enzyme, composed of PPP2CA a 36 kDa catalytic subunit (subunit C) and PPP2R1A a 65 kDa constant regulatory subunit (PR65 or subunit A), that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules. Interacts with NXN; the interaction is direct (By similarity). Interacts with KCTD20 (By similarity). Interacts with BTBD10 (By similarity). Interacts with TP53, SGO1 and SGO2. Interacts with AXIN1; the interaction dephosphorylates AXIN1. Interacts with PIM3; this interaction promotes dephosphorylation, ubiquitination and proteasomal degradation of PIM3. Interacts with RAF1. Interaction with IGBP1 protects unassembled PPP2CA from degradative ubiquitination. Interacts with GSK3B (via C2 domain). Interacts with MFHAS1; retains PPP2CA into the cytoplasm and excludes it from the nucleus (PubMed:28609714). Interacts with FAM122A (PubMed:27588481). Interacts with ADCY8; interaction is phosphatase activity-dependent; antagonizes interaction between ADCY8 and calmodulin (PubMed:16258073). Interacts with CRTC3 (when phosphorylated at 'Ser-391') (PubMed:30611118).PTM Reversibly methyl esterified on Leu-309 by leucine carboxyl methyltransferase 1 (LCMT1) and protein phosphatase methylesterase 1 (PPME1). Carboxyl methylation influences the affinity of the catalytic subunit for the different regulatory subunits, thereby modulating the PP2A holoenzyme's substrate specificity, enzyme activity and cellular localization.PTM Phosphorylation of either threonine (by autophosphorylation-activated protein kinase) or tyrosine results in inactivation of the phosphatase. Auto-dephosphorylation has been suggested as a mechanism for reactivation.PTM Polyubiquitinated, leading to its degradation by the proteasome.SIMILARITY Belongs to the PPP phosphatase family. PP-1 subfamily.

UniProtP67775

EQUAL

309

EQUAL

Reactome DB_ID: 377253

UniProt:P63151 PPP2R2A

PPP2R2A

PPP2R2AFUNCTION The B regulatory subunit might modulate substrate selectivity and catalytic activity, and also might direct the localization of the catalytic enzyme to a particular subcellular compartment.SUBUNIT Found in a complex with at least ARL2, PPP2CB, PPP2R1A, PPP2R2A, PPP2R5E and TBCD (By similarity). PP2A consists of a common heterodimeric core enzyme, composed of a 36 kDa catalytic subunit (subunit C) and a 65 kDa constant regulatory subunit (PR65 or subunit A), that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules (By similarity). Interacts with TP53 (PubMed:17245430). Interacts with IER5 (PubMed:25816751). Interacts with MFHAS1; the interaction is direct (PubMed:28609714). Interacts with FAM122A (PubMed:27588481). Interacts with CRTC3 (PubMed:30611118).TISSUE SPECIFICITY Expressed in all tissues examined.SIMILARITY Belongs to the phosphatase 2A regulatory subunit B family.

UniProtP63151

EQUAL

447

EQUAL

Reactome DB_ID: 165982

UniProt:P30153 PPP2R1A

PPP2R1A

PPP2R1AFUNCTION The PR65 subunit of protein phosphatase 2A serves as a scaffolding molecule to coordinate the assembly of the catalytic subunit and a variable regulatory B subunit. Upon interaction with GNA12 promotes dephosphorylation of microtubule associated protein TAU/MAPT (PubMed:15525651). Required for proper chromosome segregation and for centromeric localization of SGO1 in mitosis (PubMed:16580887).SUBUNIT Found in a complex with at least ARL2, PPP2CB, PPP2R1A, PPP2R2A, PPP2R5E and TBCD (By similarity). Interacts with FOXO1; the interaction dephosphorylates FOXO1 on AKT-mediated phosphorylation sites (By similarity). PP2A consists of a common heterodimeric core enzyme, composed of PPP2CA a 36 kDa catalytic subunit (subunit C) and PPP2R1A a 65 kDa constant regulatory subunit (PR65 or subunit A), that associates with a variety of regulatory subunits. Proteins that associate with the core dimer include three families of regulatory subunits B (the R2/B/PR55/B55, R3/B''/PR72/PR130/PR59 and R5/B'/B56 families), the 48 kDa variable regulatory subunit, viral proteins, and cell signaling molecules. Interacts with IPO9 (PubMed:12670497). Interacts with TP53 and SGO1 (PubMed:17245430, PubMed:16580887). Interacts with PLA2G16; this interaction might decrease PP2A activity (PubMed:17374643). Interacts with CTTNBP2NL (PubMed:18782753). Interacts with GNA12; the interaction promotes protein phosphatase 2A activation causing dephosphorylation of MAPT (PubMed:15525651). Interacts with CIP2A; this interaction stabilizes CIP2A (PubMed:28174209). Interacts with FAM122A (PubMed:27588481). Interacts with ADCY8; antagonizes interaction between ADCY8 and calmodulin (By similarity). Interacts with CRTC3 (when phosphorylated at 'Ser-391') (PubMed:30611118).DOMAIN Each HEAT repeat appears to consist of two alpha helices joined by a hydrophilic region, the intrarepeat loop. The repeat units may be arranged laterally to form a rod-like structure.SIMILARITY Belongs to the phosphatase 2A regulatory subunit A family.

UniProtP30153

EQUAL

589

EQUAL

Reactome Database ID Release 69377182Database 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=377182ReactomeR-HSA-377182

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-377182.1GO0004722

GO molecular function

Reactome Database ID Release 69376970Database 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=376970Reactome Database ID Release 692995388Database 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=2995388ReactomeR-HSA-2995388

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-2995388.420711181Pubmed2010Live-cell imaging RNAi screen identifies PP2A-B55alpha and importin-beta1 as key mitotic exit regulators in human cellsSchmitz, Michael H AHeld, MichaelJanssens, VeerleHutchins, James R AHudecz, OttoIvanova, ElitsaGoris, JozefTrinkle-Mulcahy, LauraLamond, Angus IPoser, InaHyman, Anthony AMechtler, KarlPeters, Jan-MichaelGerlich, Daniel WNat. Cell Biol. 12:886-93

ACTIVATION

Reactome Database ID Release 692995374Database 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=2995374ReactomeR-HSA-2995374

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-2995374.1

Reactome DB_ID: 2529000

EQUAL

938

EQUAL

BANF1 binds chromatin, EMD/TMPO/LEMD3/LEMD2 and lamins

In late anaphase/early telophase, dephosphorylated BANF1 (BAF) accumulates at a specialized region of the separated chromosome mass, close to the spindle. This region is known as the 'core' and is the central region of the assembling nuclear rim. At the 'core', BANF1 (BAF) binds chromatin, LEM-domain proteins of the inner nuclear membrane (EMD i.e. emerin, TMPO i.e. LAP2beta, LEMD3 i.e. MAN1, LEMD2 i.e. LEM2) and lamins, which initiates the reassembly of the nuclear envelope around separated sister chromatids. LEM-domain proteins and lamin A accumulate at the 'core' in a BANF1-dependent manner (Haraguchi et al. 2001, Haraguchi et al. 2008, Asencio et al. 2012).

Authored: Orlic-Milacic, M, 2013-01-22Reviewed: Gorjánácz, Mátyás, 2013-01-30Reviewed: Mattaj, Iain W, 2013-01-30Edited: Gillespie, ME, 2013-01-23

Converted from EntitySet in Reactome

Reactome DB_ID: 2537690

Chromatin [chromosome]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: 2995373

Lamin dimers [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: 2993892

nuclear envelopeGO0005635

EMD/ TMPO/ LEMD3/ LEMD2 [nuclear envelope]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityEMD [nuclear envelope]

UniProtP50402

Reactome DB_ID: 2995377

Reactome DB_ID: 2993900

EMD/TMPO/LEMD3/LEMD2:Lamin filaments:BANF1:Chromatin [nuclear envelope]

EMD/TMPO/LEMD3/LEMD2:Lamin filaments:BANF1:Chromatin

Reactome DB_ID: 2993914

nucleoplasmGO0005654BANF1 [nucleoplasm]

BANF1

BANF1 homodimer

Reactome DB_ID: 175030

EQUAL

Reactome Database ID Release 692993914Database 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=2993914ReactomeR-HSA-2993914

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-2993914.1Converted from EntitySet in Reactome

Reactome DB_ID: 2537690

Converted from EntitySet in Reactome

Reactome DB_ID: 2993892

Reactome DB_ID: 5228493

Lamin filaments [nucleoplasm]

Lamin filaments

Reactome Database ID Release 692993900Database 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=2993900ReactomeR-HSA-2993900

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-2993900.1Reactome Database ID Release 692995376Database 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=2995376ReactomeR-HSA-2995376

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-2995376.118628300Pubmed2008Live cell imaging and electron microscopy reveal dynamic processes of BAF-directed nuclear envelope assemblyHaraguchi, TokukoKojidani, TomokoKoujin, TakakoShimi, TakeshiOsakada, HirokoMori, ChieYamamoto, AHiraoka, YasushiJ. Cell. Sci. 121:2540-5411792822Pubmed2001BAF is required for emerin assembly into the reforming nuclear envelopeHaraguchi, TKoujin, TSegura-Totten, MLee, K KMatsuoka, YYoneda, YWilson, K LHiraoka, YJ. Cell. Sci. 114:4575-85

Reactome Database ID Release 692995383Database 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=2995383ReactomeR-HSA-2995383

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-2995383.319234477Pubmed2009Orchestrating nuclear envelope disassembly and reassembly during mitosisGüttinger, StephanLaurell, EvaKutay, UlrikeNat. Rev. Mol. Cell Biol. 10:178-91

Reactome Database ID Release 692995410Database 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=2995410ReactomeR-HSA-2995410

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-2995410.2GO0007084

GO biological process

Reactome Database ID Release 6968882Database 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=68882ReactomeR-HSA-68882

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-68882.2GO0000090

GO biological process