UniProt functional annotation for P97477



	UniProt functional annotation for P97477

UniProt code: P97477.

Organism: Mus musculus (Mouse).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.

Function: Mitotic serine/threonine kinase that contributes to the regulation of cell cycle progression. Associates with the centrosome and the spindle microtubules during mitosis and plays a critical role in various mitotic events including the establishment of mitotic spindle, centrosome duplication, centrosome separation as well as maturation, chromosomal alignment, spindle assembly checkpoint, and cytokinesis. Required for normal spindle positioning during mitosis and for the localization of NUMA1 and DCTN1 to the cell cortex during metaphase (By similarity). Required for initial activation of CDK1 at centrosomes. Phosphorylates numerous target proteins, including ARHGEF2, BORA, BRCA1, CDC25B, DLGP5, HDAC6, KIF2A, LATS2, NDEL1, PARD3, PPP1R2, PLK1, RASSF1, TACC3, p53/TP53 and TPX2. Regulates KIF2A tubulin depolymerase activity. Required for normal axon formation. Plays a role in microtubule remodeling during neurite extension. Important for microtubule formation and/or stabilization. Also acts as a key regulatory component of the p53/TP53 pathway, and particularly the checkpoint-response pathways critical for oncogenic transformation of cells, by phosphorylating and destabilizing p53/TP53. Phosphorylates its own inhibitors, the protein phosphatase type 1 (PP1) isoforms, to inhibit their activity. Necessary for proper cilia disassembly prior to mitosis. Regulates protein levels of the anti-apoptosis protein BIRC5 by suppressing the expression of the SCF(FBXL7) E3 ubiquitin-protein ligase substrate adapter FBXL7 through the phosphorylation of the transcription factor FOXP1 (By similarity). {ECO:0000250|UniProtKB:O14965, ECO:0000269|PubMed:19075002, ECO:0000269|PubMed:19668197, ECO:0000269|PubMed:20643351, ECO:0000269|PubMed:9245792}.

Catalytic activity: Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000250|UniProtKB:O14965};

Catalytic activity: Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000250|UniProtKB:O14965};

Activity regulation: Activation of CDK1, appears to be an upstream event of AURKA activation (By similarity). Phosphatase inhibitor-2 (PPP1R2) and TPX2 act also as activators (By similarity). Inactivated by the G2 checkpoint (By similarity). Inhibited by GADD45A and p53/TP53, and through dephosphorylation by protein phosphatase type 1 (PP1) (By similarity). MLN8054 is also a potent and selective inhibitor (By similarity). Activated during the early phase of cilia disassembly in the presence of PIFO (By similarity). Inhibited by the small molecule inhibitor VX-680 (By similarity). {ECO:0000250|UniProtKB:O14965}.

Subunit: Interacts with CPEB1, JTB, TACC1, TPX2, PPP2CA, as well as with the protein phosphatase type 1 (PP1) isoforms PPP1CA, PPP1CB and PPP1CC (By similarity). Interacts also with its substrates ARHGEF2, BORA, KIF2A, PARD3, and p53/TP53 (By similarity). Interaction with BORA promotes phosphorylation of PLK1 (By similarity). Interacts with GADD45A, competing with its oligomerization (By similarity). Interacts with FBXL7 and PIFO (PubMed:20643351, PubMed:22306998). Interacts (via C-terminus) with AUNIP (via C-terminus) (By similarity). Identified in a complex with AUNIP and NIN (By similarity). Interacts with SIRT2 (By similarity). Interacts with FRY; this interaction facilitates AURKA- mediated PLK1 phosphorylation (PubMed:22753416). Interacts with MYCN; interaction is phospho-independent and triggers AURKA activation; AURKA competes with FBXW7 for binding to unphosphorylated MYCN but not for binding to phosphorylated MYCN (By similarity). Interacts with HNRNPU (By similarity). Interacts with AAAS (By similarity). Interacts with KLHL18 and CUL3 (By similarity). Interacts with FOXP1 (By similarity). {ECO:0000250|UniProtKB:O14965, ECO:0000269|PubMed:18579375, ECO:0000269|PubMed:18678489, ECO:0000269|PubMed:20643351, ECO:0000269|PubMed:22306998, ECO:0000269|PubMed:22753416}.

Subcellular location: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000269|PubMed:19668197, ECO:0000269|PubMed:20643351}. Cytoplasm, cytoskeleton, spindle pole {ECO:0000269|PubMed:19075002, ECO:0000269|PubMed:9245792}. Cytoplasm, cytoskeleton, cilium basal body {ECO:0000269|PubMed:23807208}. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole {ECO:0000269|PubMed:23807208}. Cell projection, neuron projection {ECO:0000269|PubMed:19668197}. Note=Localizes on centrosomes in interphase cells and at each spindle pole in mitosis (PubMed:9245792). Associates with both the pericentriolar material (PCM) and centrioles (By similarity). Colocalized with SIRT2 at centrosome (By similarity). Detected at the neurite hillock in developing neurons (PubMed:19668197). The localization to the spindle poles is regulated by AAAS (By similarity). {ECO:0000250|UniProtKB:O14965, ECO:0000269|PubMed:19668197, ECO:0000269|PubMed:9245792}.

Tissue specificity: Detected in embryonic neurons in dorsal root ganglia and brain cortex (at protein level). Highly expressed in testis, in about one third of the seminiferous tubules. Expression is restricted to specific spermatocytes nearing completion of prophase, with levels falling off on transition to elongated spermatids. Highly expressed in the ovary, expression in the oocyte starts around the transition to large growing follicle. Abundant expression is seen in the proliferating granulosa and thecal cells of the growing follicle, and in the young corpus luteum. Very weakly expressed in spleen and intestine. {ECO:0000269|PubMed:19668197, ECO:0000269|PubMed:9245792}.

Developmental stage: At 7.5-9.5 dpc expressed evenly all over the embryo. At later stages, expression is mainly restricted to proliferating zones. The highest levels of expression at mid-embryonic development (13.5 dpc) were observed in the liver, lung, kidney and back (trapezius) muscle and all regions in active proliferation.

Induction: expression is cell cycle regulated and peaks at phase G2/M. {ECO:0000269|PubMed:9245792}.

Ptm: Activated by phosphorylation at Thr-279; this brings about a change in the conformation of the activation segment (By similarity). Phosphorylation at Thr-279 varies during the cell cycle and is highest during M phase (By similarity). Autophosphorylated at Thr-279 upon TPX2 binding (By similarity). Thr-279 can be phosphorylated by several kinases, including PAK and PKA (By similarity). Protein phosphatase type 1 (PP1) binds AURKA and inhibits its activity by dephosphorylating Thr-279 during mitosis (By similarity). Phosphorylation at Ser-333 decreases the kinase activity (By similarity). PPP2CA controls degradation by dephosphorylating Ser-52 at the end of mitosis (By similarity). {ECO:0000250|UniProtKB:O14965}.

Ptm: Ubiquitinated by the anaphase-promoting complex (APC), leading to its degradation by the proteasome (By similarity). Ubiquitinated by CHFR, leading to its degradation by the proteasome (PubMed:15793587). Ubiquitinated by the E3 ubiquitin-protein ligase complex SCF(FBXL7) during mitosis, leading to its degradation by the proteasome (PubMed:22306998). {ECO:0000250|UniProtKB:O14965, ECO:0000269|PubMed:15793587, ECO:0000269|PubMed:22306998}.

Disruption phenotype: Death at the blastocyst stage due to mitotic defects and failure of cell proliferation. {ECO:0000269|PubMed:19075002}.

Miscellaneous: Centrosome amplification can occur when the cycles are uncoupled, and this amplification is associated with cancer and with an increase in the levels of chromosomal instability.

Miscellaneous: [Isoform 2]: May be less abundant or less stable. {ECO:0000305}.

Similarity: Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. Aurora subfamily. {ECO:0000255|PROSITE- ProRule:PRU00159}.

Sequence caution: Sequence=BAC39557.1; Type=Frameshift; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Mus musculus (Mouse).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.



Function:		Mitotic serine/threonine kinase that contributes to the regulation of cell cycle progression. Associates with the centrosome and the spindle microtubules during mitosis and plays a critical role in various mitotic events including the establishment of mitotic spindle, centrosome duplication, centrosome separation as well as maturation, chromosomal alignment, spindle assembly checkpoint, and cytokinesis. Required for normal spindle positioning during mitosis and for the localization of NUMA1 and DCTN1 to the cell cortex during metaphase (By similarity). Required for initial activation of CDK1 at centrosomes. Phosphorylates numerous target proteins, including ARHGEF2, BORA, BRCA1, CDC25B, DLGP5, HDAC6, KIF2A, LATS2, NDEL1, PARD3, PPP1R2, PLK1, RASSF1, TACC3, p53/TP53 and TPX2. Regulates KIF2A tubulin depolymerase activity. Required for normal axon formation. Plays a role in microtubule remodeling during neurite extension. Important for microtubule formation and/or stabilization. Also acts as a key regulatory component of the p53/TP53 pathway, and particularly the checkpoint-response pathways critical for oncogenic transformation of cells, by phosphorylating and destabilizing p53/TP53. Phosphorylates its own inhibitors, the protein phosphatase type 1 (PP1) isoforms, to inhibit their activity. Necessary for proper cilia disassembly prior to mitosis. Regulates protein levels of the anti-apoptosis protein BIRC5 by suppressing the expression of the SCF(FBXL7) E3 ubiquitin-protein ligase substrate adapter FBXL7 through the phosphorylation of the transcription factor FOXP1 (By similarity). {ECO:0000250\|UniProtKB:O14965, ECO:0000269\|PubMed:19075002, ECO:0000269\|PubMed:19668197, ECO:0000269\|PubMed:20643351, ECO:0000269\|PubMed:9245792}.


Catalytic activity:		Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl- [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA- COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000250\|UniProtKB:O14965};
Catalytic activity:		Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L- threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000250\|UniProtKB:O14965};
Activity regulation:		Activation of CDK1, appears to be an upstream event of AURKA activation (By similarity). Phosphatase inhibitor-2 (PPP1R2) and TPX2 act also as activators (By similarity). Inactivated by the G2 checkpoint (By similarity). Inhibited by GADD45A and p53/TP53, and through dephosphorylation by protein phosphatase type 1 (PP1) (By similarity). MLN8054 is also a potent and selective inhibitor (By similarity). Activated during the early phase of cilia disassembly in the presence of PIFO (By similarity). Inhibited by the small molecule inhibitor VX-680 (By similarity). {ECO:0000250\|UniProtKB:O14965}.
Subunit:		Interacts with CPEB1, JTB, TACC1, TPX2, PPP2CA, as well as with the protein phosphatase type 1 (PP1) isoforms PPP1CA, PPP1CB and PPP1CC (By similarity). Interacts also with its substrates ARHGEF2, BORA, KIF2A, PARD3, and p53/TP53 (By similarity). Interaction with BORA promotes phosphorylation of PLK1 (By similarity). Interacts with GADD45A, competing with its oligomerization (By similarity). Interacts with FBXL7 and PIFO (PubMed:20643351, PubMed:22306998). Interacts (via C-terminus) with AUNIP (via C-terminus) (By similarity). Identified in a complex with AUNIP and NIN (By similarity). Interacts with SIRT2 (By similarity). Interacts with FRY; this interaction facilitates AURKA- mediated PLK1 phosphorylation (PubMed:22753416). Interacts with MYCN; interaction is phospho-independent and triggers AURKA activation; AURKA competes with FBXW7 for binding to unphosphorylated MYCN but not for binding to phosphorylated MYCN (By similarity). Interacts with HNRNPU (By similarity). Interacts with AAAS (By similarity). Interacts with KLHL18 and CUL3 (By similarity). Interacts with FOXP1 (By similarity). {ECO:0000250\|UniProtKB:O14965, ECO:0000269\|PubMed:18579375, ECO:0000269\|PubMed:18678489, ECO:0000269\|PubMed:20643351, ECO:0000269\|PubMed:22306998, ECO:0000269\|PubMed:22753416}.
Subcellular location:		Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000269\|PubMed:19668197, ECO:0000269\|PubMed:20643351}. Cytoplasm, cytoskeleton, spindle pole {ECO:0000269\|PubMed:19075002, ECO:0000269\|PubMed:9245792}. Cytoplasm, cytoskeleton, cilium basal body {ECO:0000269\|PubMed:23807208}. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole {ECO:0000269\|PubMed:23807208}. Cell projection, neuron projection {ECO:0000269\|PubMed:19668197}. Note=Localizes on centrosomes in interphase cells and at each spindle pole in mitosis (PubMed:9245792). Associates with both the pericentriolar material (PCM) and centrioles (By similarity). Colocalized with SIRT2 at centrosome (By similarity). Detected at the neurite hillock in developing neurons (PubMed:19668197). The localization to the spindle poles is regulated by AAAS (By similarity). {ECO:0000250\|UniProtKB:O14965, ECO:0000269\|PubMed:19668197, ECO:0000269\|PubMed:9245792}.
Tissue specificity:		Detected in embryonic neurons in dorsal root ganglia and brain cortex (at protein level). Highly expressed in testis, in about one third of the seminiferous tubules. Expression is restricted to specific spermatocytes nearing completion of prophase, with levels falling off on transition to elongated spermatids. Highly expressed in the ovary, expression in the oocyte starts around the transition to large growing follicle. Abundant expression is seen in the proliferating granulosa and thecal cells of the growing follicle, and in the young corpus luteum. Very weakly expressed in spleen and intestine. {ECO:0000269\|PubMed:19668197, ECO:0000269\|PubMed:9245792}.
Developmental stage:		At 7.5-9.5 dpc expressed evenly all over the embryo. At later stages, expression is mainly restricted to proliferating zones. The highest levels of expression at mid-embryonic development (13.5 dpc) were observed in the liver, lung, kidney and back (trapezius) muscle and all regions in active proliferation.
Induction:		expression is cell cycle regulated and peaks at phase G2/M. {ECO:0000269\|PubMed:9245792}.
Ptm:		Activated by phosphorylation at Thr-279; this brings about a change in the conformation of the activation segment (By similarity). Phosphorylation at Thr-279 varies during the cell cycle and is highest during M phase (By similarity). Autophosphorylated at Thr-279 upon TPX2 binding (By similarity). Thr-279 can be phosphorylated by several kinases, including PAK and PKA (By similarity). Protein phosphatase type 1 (PP1) binds AURKA and inhibits its activity by dephosphorylating Thr-279 during mitosis (By similarity). Phosphorylation at Ser-333 decreases the kinase activity (By similarity). PPP2CA controls degradation by dephosphorylating Ser-52 at the end of mitosis (By similarity). {ECO:0000250\|UniProtKB:O14965}.
Ptm:		Ubiquitinated by the anaphase-promoting complex (APC), leading to its degradation by the proteasome (By similarity). Ubiquitinated by CHFR, leading to its degradation by the proteasome (PubMed:15793587). Ubiquitinated by the E3 ubiquitin-protein ligase complex SCF(FBXL7) during mitosis, leading to its degradation by the proteasome (PubMed:22306998). {ECO:0000250\|UniProtKB:O14965, ECO:0000269\|PubMed:15793587, ECO:0000269\|PubMed:22306998}.
Disruption phenotype:		Death at the blastocyst stage due to mitotic defects and failure of cell proliferation. {ECO:0000269\|PubMed:19075002}.
Miscellaneous:		Centrosome amplification can occur when the cycles are uncoupled, and this amplification is associated with cancer and with an increase in the levels of chromosomal instability.
Miscellaneous:		[Isoform 2]: May be less abundant or less stable. {ECO:0000305}.
Similarity:		Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. Aurora subfamily. {ECO:0000255\|PROSITE- ProRule:PRU00159}.
Sequence caution:		Sequence=BAC39557.1; Type=Frameshift; Evidence={ECO:0000305};