UniProt functional annotation for Q9UKT4



	UniProt functional annotation for Q9UKT4

UniProt code: Q9UKT4.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Regulator of APC activity during mitotic and meiotic cell cycle (PubMed:17485488, PubMed:17234884, PubMed:17875940, PubMed:23708001, PubMed:23708605, PubMed:16921029). During mitotic cell cycle plays a role as both substrate and inhibitor of APC-FZR1 complex (PubMed:29875408, PubMed:17485488, PubMed:17234884, PubMed:17875940, PubMed:23708001, PubMed:23708605, PubMed:16921029). During G1 phase, plays a role as substrate of APC-FZR1 complex E3 ligase (PubMed:29875408). Then switches as an inhibitor of APC-FZR1 complex during S and G2 leading to cell-cycle commitment (PubMed:29875408). As APC inhibitor, prevents the degradation of APC substrates at multiple levels: by interacting with APC and blocking access of APC substrates to the D-box coreceptor, formed by FZR1 and ANAPC10; by suppressing ubiquitin ligation and chain elongation by APC by preventing the UBE2C and UBE2S activities (PubMed:23708605, PubMed:23708001, PubMed:16921029). Plays a role in genome integrity preservation by coordinating DNA replication with mitosis through APC inhibition in interphase to stabilize CCNA2 and GMNN in order to promote mitosis and prevent rereplication and DNA damage-induced cellular senescence (PubMed:17234884, PubMed:17485488, PubMed:17875940). During oocyte maturation, plays a role in meiosis through inactivation of APC-FZR1 complex. Inhibits APC through RPS6KA2 interaction that increases FBXO5 affiniy for CDC20 leading to the metaphase arrest of the second meiotic division before fertilization (By similarity). Controls entry into the first meiotic division through inactivation of APC-FZR1 complex (By similarity). Promotes migration and osteogenic differentiation of mesenchymal stem cells (PubMed:29850565). {ECO:0000250|UniProtKB:Q7TSG3, ECO:0000269|PubMed:16921029, ECO:0000269|PubMed:17234884, ECO:0000269|PubMed:17485488, ECO:0000269|PubMed:17875940, ECO:0000269|PubMed:23708001, ECO:0000269|PubMed:23708605, ECO:0000269|PubMed:29850565, ECO:0000269|PubMed:29875408}.

Pathway: Protein modification; protein ubiquitination.

Subunit: Part of a SCF (SKP1-cullin-F-box) protein ligase complex (By similarity). Interacts with BTRC; mediates proteolysis by the SCF ubiquitin ligase complex leading to activation of APC in late mitosis and subsequent mitotic progression (PubMed:12791267). Interacts with FZR1/CDH1 and the N-terminal substrate-binding domain of CDC20; prevents APC activation (PubMed:11988738). Also interacts with EVI5 which blocks its phosphorylation by PLK1 and prevents its subsequent binding to BTRC and degradation (PubMed:16439210). Interacts simultaneously with anaphase promoting complex (APC), through at least ANAPC2, CDC23, CDC27, the APC substrate GMNN and the APC activator FZR1 (PubMed:23708001, PubMed:26083744). Interacts with UBE2S; interferes with the activity of UBE2S mainly by disrupting the dynamic electrostatic association between the C-terminal tail of UBE2S and ANAPC2 (PubMed:23708001). Interacts with RPS6KA2; cooperates to induce the metaphase arrest of early blastomeres; increases and stabilizes interaction of FBXO5 with CDC20 (By similarity). {ECO:0000250|UniProtKB:Q7TSG3, ECO:0000269|PubMed:11988738, ECO:0000269|PubMed:12791267, ECO:0000269|PubMed:16439210, ECO:0000269|PubMed:23708001, ECO:0000269|PubMed:26083744}.

Subcellular location: Nucleus {ECO:0000269|PubMed:11988738}. Cytoplasm {ECO:0000269|PubMed:11988738}. Cytoplasm, cytoskeleton, spindle {ECO:0000269|PubMed:15469984}. Note=In interphase, localizes in a punctate manner in the nucleus and cytoplasm with some perinuclear concentration (PubMed:11988738). In mitotic cells, localizes throughout the cell, particularly at the spindle (PubMed:15469984). {ECO:0000269|PubMed:11988738, ECO:0000269|PubMed:15469984}.

Developmental stage: Accumulates in late G1 phase, levels rise during S phase and drop in early mitosis. {ECO:0000269|PubMed:11988738}.

Induction: Up-regulated at 7 days after osteogenic induction (PubMed:29850565). Down-regulated in late G2 phase or mitosis (PubMed:17485488). Down-regulated in G2 phase after DNA damage in a CDKN1A-dependent manner (PubMed:19211842). Down-regulated in G1 phase when APC-FZR1 complex is active and accumulates at the G1-S transition, coincident with the inactivation of APC-FZR1 complex (PubMed:29875408). At the G1-S transition, transcriptionally induced by the E2F transcription factor (PubMed:11988738). {ECO:0000269|PubMed:11988738, ECO:0000269|PubMed:17485488, ECO:0000269|PubMed:19211842, ECO:0000269|PubMed:29850565, ECO:0000269|PubMed:29875408}.

Ptm: Phosphorylation by CDK2 and subsequently by PLK1 triggers degradation during early mitosis through ubiquitin-mediated proteolysis by the SCF ubiquitin ligase complex containing the F-box protein BTRC. This degradation is necessary for the activation of APC in late mitosis and subsequent mitotic progression (PubMed:12791267, PubMed:15469984). Phosphorylated by RPS6KA2; increases and stabilizes interaction with CDC20 (By similarity). {ECO:0000250|UniProtKB:Q7TSG3, ECO:0000269|PubMed:12791267, ECO:0000269|PubMed:15469984}.

Ptm: Ubiquitinated by the SCF(BTRC) complex following phosphorylation by PLK1 (PubMed:15469984). Undergoes both 'Lys-11' and 'Lys-48'-linked polyubiquitination by APC-FZR1 complex leading to degradation by proteasome during G1 phase (PubMed:29875408). Degraded through the SCF(BTRC) complex; degradation occurs during oocyte maturation, between germinal vesicle breakdown (GVBD) and meiosis I, and is required for the meiosis I-meiosis II transition (By similarity). {ECO:0000250|UniProtKB:Q7TSG3, ECO:0000269|PubMed:15469984, ECO:0000269|PubMed:29875408}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Regulator of APC activity during mitotic and meiotic cell cycle (PubMed:17485488, PubMed:17234884, PubMed:17875940, PubMed:23708001, PubMed:23708605, PubMed:16921029). During mitotic cell cycle plays a role as both substrate and inhibitor of APC-FZR1 complex (PubMed:29875408, PubMed:17485488, PubMed:17234884, PubMed:17875940, PubMed:23708001, PubMed:23708605, PubMed:16921029). During G1 phase, plays a role as substrate of APC-FZR1 complex E3 ligase (PubMed:29875408). Then switches as an inhibitor of APC-FZR1 complex during S and G2 leading to cell-cycle commitment (PubMed:29875408). As APC inhibitor, prevents the degradation of APC substrates at multiple levels: by interacting with APC and blocking access of APC substrates to the D-box coreceptor, formed by FZR1 and ANAPC10; by suppressing ubiquitin ligation and chain elongation by APC by preventing the UBE2C and UBE2S activities (PubMed:23708605, PubMed:23708001, PubMed:16921029). Plays a role in genome integrity preservation by coordinating DNA replication with mitosis through APC inhibition in interphase to stabilize CCNA2 and GMNN in order to promote mitosis and prevent rereplication and DNA damage-induced cellular senescence (PubMed:17234884, PubMed:17485488, PubMed:17875940). During oocyte maturation, plays a role in meiosis through inactivation of APC-FZR1 complex. Inhibits APC through RPS6KA2 interaction that increases FBXO5 affiniy for CDC20 leading to the metaphase arrest of the second meiotic division before fertilization (By similarity). Controls entry into the first meiotic division through inactivation of APC-FZR1 complex (By similarity). Promotes migration and osteogenic differentiation of mesenchymal stem cells (PubMed:29850565). {ECO:0000250\|UniProtKB:Q7TSG3, ECO:0000269\|PubMed:16921029, ECO:0000269\|PubMed:17234884, ECO:0000269\|PubMed:17485488, ECO:0000269\|PubMed:17875940, ECO:0000269\|PubMed:23708001, ECO:0000269\|PubMed:23708605, ECO:0000269\|PubMed:29850565, ECO:0000269\|PubMed:29875408}.


Pathway:		Protein modification; protein ubiquitination.
Subunit:		Part of a SCF (SKP1-cullin-F-box) protein ligase complex (By similarity). Interacts with BTRC; mediates proteolysis by the SCF ubiquitin ligase complex leading to activation of APC in late mitosis and subsequent mitotic progression (PubMed:12791267). Interacts with FZR1/CDH1 and the N-terminal substrate-binding domain of CDC20; prevents APC activation (PubMed:11988738). Also interacts with EVI5 which blocks its phosphorylation by PLK1 and prevents its subsequent binding to BTRC and degradation (PubMed:16439210). Interacts simultaneously with anaphase promoting complex (APC), through at least ANAPC2, CDC23, CDC27, the APC substrate GMNN and the APC activator FZR1 (PubMed:23708001, PubMed:26083744). Interacts with UBE2S; interferes with the activity of UBE2S mainly by disrupting the dynamic electrostatic association between the C-terminal tail of UBE2S and ANAPC2 (PubMed:23708001). Interacts with RPS6KA2; cooperates to induce the metaphase arrest of early blastomeres; increases and stabilizes interaction of FBXO5 with CDC20 (By similarity). {ECO:0000250\|UniProtKB:Q7TSG3, ECO:0000269\|PubMed:11988738, ECO:0000269\|PubMed:12791267, ECO:0000269\|PubMed:16439210, ECO:0000269\|PubMed:23708001, ECO:0000269\|PubMed:26083744}.
Subcellular location:		Nucleus {ECO:0000269\|PubMed:11988738}. Cytoplasm {ECO:0000269\|PubMed:11988738}. Cytoplasm, cytoskeleton, spindle {ECO:0000269\|PubMed:15469984}. Note=In interphase, localizes in a punctate manner in the nucleus and cytoplasm with some perinuclear concentration (PubMed:11988738). In mitotic cells, localizes throughout the cell, particularly at the spindle (PubMed:15469984). {ECO:0000269\|PubMed:11988738, ECO:0000269\|PubMed:15469984}.
Developmental stage:		Accumulates in late G1 phase, levels rise during S phase and drop in early mitosis. {ECO:0000269\|PubMed:11988738}.
Induction:		Up-regulated at 7 days after osteogenic induction (PubMed:29850565). Down-regulated in late G2 phase or mitosis (PubMed:17485488). Down-regulated in G2 phase after DNA damage in a CDKN1A-dependent manner (PubMed:19211842). Down-regulated in G1 phase when APC-FZR1 complex is active and accumulates at the G1-S transition, coincident with the inactivation of APC-FZR1 complex (PubMed:29875408). At the G1-S transition, transcriptionally induced by the E2F transcription factor (PubMed:11988738). {ECO:0000269\|PubMed:11988738, ECO:0000269\|PubMed:17485488, ECO:0000269\|PubMed:19211842, ECO:0000269\|PubMed:29850565, ECO:0000269\|PubMed:29875408}.
Ptm:		Phosphorylation by CDK2 and subsequently by PLK1 triggers degradation during early mitosis through ubiquitin-mediated proteolysis by the SCF ubiquitin ligase complex containing the F-box protein BTRC. This degradation is necessary for the activation of APC in late mitosis and subsequent mitotic progression (PubMed:12791267, PubMed:15469984). Phosphorylated by RPS6KA2; increases and stabilizes interaction with CDC20 (By similarity). {ECO:0000250\|UniProtKB:Q7TSG3, ECO:0000269\|PubMed:12791267, ECO:0000269\|PubMed:15469984}.
Ptm:		Ubiquitinated by the SCF(BTRC) complex following phosphorylation by PLK1 (PubMed:15469984). Undergoes both 'Lys-11' and 'Lys-48'-linked polyubiquitination by APC-FZR1 complex leading to degradation by proteasome during G1 phase (PubMed:29875408). Degraded through the SCF(BTRC) complex; degradation occurs during oocyte maturation, between germinal vesicle breakdown (GVBD) and meiosis I, and is required for the meiosis I-meiosis II transition (By similarity). {ECO:0000250\|UniProtKB:Q7TSG3, ECO:0000269\|PubMed:15469984, ECO:0000269\|PubMed:29875408}.