UniProt functional annotation for P05132



	UniProt functional annotation for P05132

UniProt code: P05132.

Organism: Mus musculus (Mouse).

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

Function: Phosphorylates a large number of substrates in the cytoplasm and the nucleus (By similarity). Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA, SOX9 and VASP (PubMed:10805756, PubMed:19223768). Regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis (By similarity). RORA is activated by phosphorylation. Required for glucose-mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts (By similarity). Involved in chondrogenesis by mediating phosphorylation of SOX9 (PubMed:10805756). Involved in the regulation of platelets in response to thrombin and collagen; maintains circulating platelets in a resting state by phosphorylating proteins in numerous platelet inhibitory pathways when in complex with NF-kappa-B (NFKB1 and NFKB2) and I-kappa- B-alpha (NFKBIA), but thrombin and collagen disrupt these complexes and free active PRKACA stimulates platelets and leads to platelet aggregation by phosphorylating VASP. RYR2 channel activity is potentiated by phosphorylation in presence of luminal Ca(2+), leading to reduced amplitude and increased frequency of store overload-induced Ca(2+) release (SOICR) characterized by an increased rate of Ca(2+) release and propagation velocity of spontaneous Ca(2+) waves, despite reduced wave amplitude and resting cytosolic Ca(2+). PSMC5/RPT6 activation by phosphorylation stimulates proteasome. Negatively regulates tight junctions (TJs) in ovarian cancer cells via CLDN3 phosphorylation. NFKB1 phosphorylation promotes NF-kappa-B p50-p50 DNA binding. Involved in embryonic development by down-regulating the Hedgehog (Hh) signaling pathway that determines embryo pattern formation and morphogenesis (By similarity). Prevents meiosis resumption in prophase-arrested oocytes via CDC25B inactivation by phosphorylation (PubMed:19223768). May also regulate rapid eye movement (REM) sleep in the pedunculopontine tegmental (PPT) (By similarity). Phosphorylates APOBEC3G and AICDA. Phosphorylates HSF1; this phosphorylation promotes HSF1 nuclear localization and transcriptional activity upon heat shock (By similarity). {ECO:0000250|UniProtKB:P17612, ECO:0000250|UniProtKB:P27791, ECO:0000269|PubMed:10805756, ECO:0000269|PubMed:19223768}.

Function: [Isoform 2]: Phosphorylates and activates ABL1 in sperm flagellum to promote spermatozoa capacitation. {ECO:0000269|PubMed:15340140, ECO:0000269|PubMed:19560455}.

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=2.7.11.11;

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=2.7.11.11;

Activity regulation: Allosterically activated by various compounds, including ATP. Activated by cAMP; the nucleotide acts as a dynamic and allosteric activator by coupling the two lobes of apo PKA, enhancing the enzyme dynamics synchronously and priming it for catalysis. {ECO:0000269|PubMed:20890288}.

Subunit: A number of inactive tetrameric holoenzymes are produced by the combination of homo- or heterodimers of the different regulatory subunits associated with two catalytic subunits. Protein kinase A holoenzyme is comprised of two catalytic (C) and two regulatory (R) subunits which keep the enzyme in an inhibited state before activation by cyclic-AMP. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits. The cAMP-dependent protein kinase catalytic subunit binds PJA2. Both isoforms 1 and 2 forms activate cAMP-sensitive PKAI and PKAII holoenzymes by interacting with regulatory subunit (R) of PKA, PRKAR1A/PKR1 and PRKAR2A/PKR2, respectively. Interacts with NFKB1, NFKB2 and NFKBIA in platelets; these interactions are disrupted by thrombin and collagen. Binds to ABL1 in spermatozoa and with CDC25B in oocytes. Interacts with APOBEC3G and AICDA (By similarity). Interacts with RAB13; downstream effector of RAB13 involved in tight junction assembly (By similarity). Found in a complex at least composed of MROH2B isoform 2, PRKACA isoform 2 and TCP11 (PubMed:27105888). Interacts with MROH2B isoform 2 (PubMed:27105888). Interacts with HSF1 (By similarity). Isoform 2 interacts with TCP11 (PubMed:27105888). {ECO:0000250, ECO:0000250|UniProtKB:P17612, ECO:0000269|PubMed:22323819}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:18367160}. Cell membrane {ECO:0000250}. Nucleus {ECO:0000250}. Mitochondrion {ECO:0000269|PubMed:18367160}. Membrane {ECO:0000250|UniProtKB:P17612}; Lipid-anchor {ECO:0000250|UniProtKB:P17612}. Note=Translocates into the nucleus (monomeric catalytic subunit) (By similarity). The inactive holoenzyme is found in the cytoplasm. Distributed throughout the cytoplasm in meiotically incompetent oocytes. Associated to mitochondrion as meiotic competence is acquired. Aggregates around the germinal vesicles (GV) at the immature GV stage oocytes. Colocalizes with HSF1 in nuclear stress bodies (nSBs) upon heat shock (By similarity). {ECO:0000250, ECO:0000250|UniProtKB:P17612}.

Subcellular location: [Isoform 2]: Cell projection, cilium, flagellum {ECO:0000269|PubMed:27105888}. Cytoplasmic vesicle, secretory vesicle, acrosome {ECO:0000269|PubMed:27105888}. Note=Expressed in the midpiece region of the sperm flagellum (By similarity). Colocalizes with MROH2B and TCP11 on the acrosome and tail regions in round spermatids and spermatozoa regardless of the capacitation status of the sperm (PubMed:27105888). {ECO:0000250, ECO:0000269|PubMed:27105888}.

Tissue specificity: Isoform 2 is sperm specific.

Developmental stage: Accumulates in oocytes before fertilization but fades out after fertilization. {ECO:0000269|PubMed:18367160}.

Ptm: Autophosphorylated. Phosphorylation is enhanced by vitamin K(2) (By similarity). Phosphorylated on threonine and serine residues. Phosphorylation on Thr-198 is required for full activity. {ECO:0000250, ECO:0000269|PubMed:8395513, ECO:0000269|PubMed:9707564}.

Ptm: Asn-3 is partially deaminated to Asp-3 giving rise to 2 major isoelectric variants, called CB and CA respectively.

Ptm: When myristoylated, Ser-11 is autophosphorylated probably in conjunction with deamidation of Asn-3. {ECO:0000269|PubMed:11141074, ECO:0000269|PubMed:8395513}.

Ptm: Phosphorylated at Tyr-331 by activated receptor tyrosine kinases EGFR and PDGFR; this increases catalytic efficiency. {ECO:0000269|PubMed:21866565}.

Disruption phenotype: Frequent early postnatal lethality. Survivals are runted accompanied with mature sperm exhibiting defective forward motility. {ECO:0000269|PubMed:11875122}.

Similarity: Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. cAMP subfamily. {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:		Phosphorylates a large number of substrates in the cytoplasm and the nucleus (By similarity). Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA, SOX9 and VASP (PubMed:10805756, PubMed:19223768). Regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis (By similarity). RORA is activated by phosphorylation. Required for glucose-mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts (By similarity). Involved in chondrogenesis by mediating phosphorylation of SOX9 (PubMed:10805756). Involved in the regulation of platelets in response to thrombin and collagen; maintains circulating platelets in a resting state by phosphorylating proteins in numerous platelet inhibitory pathways when in complex with NF-kappa-B (NFKB1 and NFKB2) and I-kappa- B-alpha (NFKBIA), but thrombin and collagen disrupt these complexes and free active PRKACA stimulates platelets and leads to platelet aggregation by phosphorylating VASP. RYR2 channel activity is potentiated by phosphorylation in presence of luminal Ca(2+), leading to reduced amplitude and increased frequency of store overload-induced Ca(2+) release (SOICR) characterized by an increased rate of Ca(2+) release and propagation velocity of spontaneous Ca(2+) waves, despite reduced wave amplitude and resting cytosolic Ca(2+). PSMC5/RPT6 activation by phosphorylation stimulates proteasome. Negatively regulates tight junctions (TJs) in ovarian cancer cells via CLDN3 phosphorylation. NFKB1 phosphorylation promotes NF-kappa-B p50-p50 DNA binding. Involved in embryonic development by down-regulating the Hedgehog (Hh) signaling pathway that determines embryo pattern formation and morphogenesis (By similarity). Prevents meiosis resumption in prophase-arrested oocytes via CDC25B inactivation by phosphorylation (PubMed:19223768). May also regulate rapid eye movement (REM) sleep in the pedunculopontine tegmental (PPT) (By similarity). Phosphorylates APOBEC3G and AICDA. Phosphorylates HSF1; this phosphorylation promotes HSF1 nuclear localization and transcriptional activity upon heat shock (By similarity). {ECO:0000250\|UniProtKB:P17612, ECO:0000250\|UniProtKB:P27791, ECO:0000269\|PubMed:10805756, ECO:0000269\|PubMed:19223768}.



Function:		[Isoform 2]: Phosphorylates and activates ABL1 in sperm flagellum to promote spermatozoa capacitation. {ECO:0000269\|PubMed:15340140, ECO:0000269\|PubMed:19560455}.


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=2.7.11.11;
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=2.7.11.11;
Activity regulation:		Allosterically activated by various compounds, including ATP. Activated by cAMP; the nucleotide acts as a dynamic and allosteric activator by coupling the two lobes of apo PKA, enhancing the enzyme dynamics synchronously and priming it for catalysis. {ECO:0000269\|PubMed:20890288}.
Subunit:		A number of inactive tetrameric holoenzymes are produced by the combination of homo- or heterodimers of the different regulatory subunits associated with two catalytic subunits. Protein kinase A holoenzyme is comprised of two catalytic (C) and two regulatory (R) subunits which keep the enzyme in an inhibited state before activation by cyclic-AMP. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits. The cAMP-dependent protein kinase catalytic subunit binds PJA2. Both isoforms 1 and 2 forms activate cAMP-sensitive PKAI and PKAII holoenzymes by interacting with regulatory subunit (R) of PKA, PRKAR1A/PKR1 and PRKAR2A/PKR2, respectively. Interacts with NFKB1, NFKB2 and NFKBIA in platelets; these interactions are disrupted by thrombin and collagen. Binds to ABL1 in spermatozoa and with CDC25B in oocytes. Interacts with APOBEC3G and AICDA (By similarity). Interacts with RAB13; downstream effector of RAB13 involved in tight junction assembly (By similarity). Found in a complex at least composed of MROH2B isoform 2, PRKACA isoform 2 and TCP11 (PubMed:27105888). Interacts with MROH2B isoform 2 (PubMed:27105888). Interacts with HSF1 (By similarity). Isoform 2 interacts with TCP11 (PubMed:27105888). {ECO:0000250, ECO:0000250\|UniProtKB:P17612, ECO:0000269\|PubMed:22323819}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:18367160}. Cell membrane {ECO:0000250}. Nucleus {ECO:0000250}. Mitochondrion {ECO:0000269\|PubMed:18367160}. Membrane {ECO:0000250\|UniProtKB:P17612}; Lipid-anchor {ECO:0000250\|UniProtKB:P17612}. Note=Translocates into the nucleus (monomeric catalytic subunit) (By similarity). The inactive holoenzyme is found in the cytoplasm. Distributed throughout the cytoplasm in meiotically incompetent oocytes. Associated to mitochondrion as meiotic competence is acquired. Aggregates around the germinal vesicles (GV) at the immature GV stage oocytes. Colocalizes with HSF1 in nuclear stress bodies (nSBs) upon heat shock (By similarity). {ECO:0000250, ECO:0000250\|UniProtKB:P17612}.
Subcellular location:		[Isoform 2]: Cell projection, cilium, flagellum {ECO:0000269\|PubMed:27105888}. Cytoplasmic vesicle, secretory vesicle, acrosome {ECO:0000269\|PubMed:27105888}. Note=Expressed in the midpiece region of the sperm flagellum (By similarity). Colocalizes with MROH2B and TCP11 on the acrosome and tail regions in round spermatids and spermatozoa regardless of the capacitation status of the sperm (PubMed:27105888). {ECO:0000250, ECO:0000269\|PubMed:27105888}.
Tissue specificity:		Isoform 2 is sperm specific.
Developmental stage:		Accumulates in oocytes before fertilization but fades out after fertilization. {ECO:0000269\|PubMed:18367160}.
Ptm:		Autophosphorylated. Phosphorylation is enhanced by vitamin K(2) (By similarity). Phosphorylated on threonine and serine residues. Phosphorylation on Thr-198 is required for full activity. {ECO:0000250, ECO:0000269\|PubMed:8395513, ECO:0000269\|PubMed:9707564}.
Ptm:		Asn-3 is partially deaminated to Asp-3 giving rise to 2 major isoelectric variants, called CB and CA respectively.
Ptm:		When myristoylated, Ser-11 is autophosphorylated probably in conjunction with deamidation of Asn-3. {ECO:0000269\|PubMed:11141074, ECO:0000269\|PubMed:8395513}.
Ptm:		Phosphorylated at Tyr-331 by activated receptor tyrosine kinases EGFR and PDGFR; this increases catalytic efficiency. {ECO:0000269\|PubMed:21866565}.
Disruption phenotype:		Frequent early postnatal lethality. Survivals are runted accompanied with mature sperm exhibiting defective forward motility. {ECO:0000269\|PubMed:11875122}.
Similarity:		Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. cAMP subfamily. {ECO:0000305}.