UniProt functional annotation for P09217



	UniProt functional annotation for P09217

UniProt code: P09217.

Organism: Rattus norvegicus (Rat).

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

Function: Calcium- and diacylglycerol-independent serine/threonine- protein kinase that functions in phosphatidylinositol 3-kinase (PI3K) pathway and mitogen-activated protein (MAP) kinase cascade, and is involved in NF-kappa-B activation, mitogenic signaling, cell proliferation, cell polarity, inflammatory response and maintenance of long-term potentiation (LTP). Upon lipopolysaccharide (LPS) treatment in macrophages, or following mitogenic stimuli, functions downstream of PI3K to activate MAP2K1/MEK1-MAPK1/ERK2 signaling cascade independently of RAF1 activation. Required for insulin-dependent activation of AKT3, but may function as an adapter rather than a direct activator. Upon insulin treatment may act as a downstream effector of PI3K and contribute to the activation of translocation of the glucose transporter SLC2A4/GLUT4 and subsequent glucose transport in adipocytes. In EGF-induced cells, binds and activates MAP2K5/MEK5- MAPK7/ERK5 independently of its kinase activity and can activate JUN promoter through MEF2C. Through binding with SQSTM1/p62, functions in interleukin-1 signaling and activation of NF-kappa-B with the specific adapters RIPK1 and TRAF6. Participates in TNF-dependent transactivation of NF-kappa-B by phosphorylating and activating IKBKB kinase, which in turn leads to the degradation of NF-kappa-B inhibitors. In migrating astrocytes, forms a cytoplasmic complex with PARD6A and is recruited by CDC42 to function in the establishment of cell polarity along with the microtubule motor and dynein. In association with FEZ1, stimulates neuronal differentiation in PC12 cells. In the inflammatory response, is required for the T-helper 2 (Th2) differentiation process, including interleukin production, efficient activation of JAK1 and the subsequent phosphorylation and nuclear translocation of STAT6. May be involved in development of allergic airway inflammation (asthma), a process dependent on Th2 immune response. In the NF-kappa-B-mediated inflammatory response, can relieve SETD6-dependent repression of NF- kappa-B target genes by phosphorylating the RELA subunit at 'Ser-311'. Phosphorylates VAMP2 in vitro (By similarity). {ECO:0000250|UniProtKB:Q05513, ECO:0000269|PubMed:10022904, ECO:0000269|PubMed:10747026, ECO:0000269|PubMed:11158308, ECO:0000269|PubMed:11525734, ECO:0000269|PubMed:8557035, ECO:0000269|PubMed:9177193, ECO:0000269|PubMed:9374484}.

Function: [Isoform 2]: Involved in late synaptic long term potentiation phase in CA1 hippocampal cells and long term memory maintenance. {ECO:0000269|PubMed:11914719, ECO:0000269|PubMed:27498875}.

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=2.7.11.13; Evidence={ECO:0000269|PubMed:8378304};

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=2.7.11.13; Evidence={ECO:0000269|PubMed:8378304};

Activity regulation: Atypical PKCs (PRKCI and PRKCZ) exhibit an elevated basal enzymatic activity (that may be due to the interaction with SMG1 or SQSTM1) and are not regulated by diacylglycerol, phosphatidylserine, phorbol esters or calcium ions. Two specific sites, Thr-410 (activation loop of the kinase domain) and Thr-560 (turn motif), need to be phosphorylated for its full activation. Phosphatidylinositol 3,4,5-trisphosphate might be a physiological activator (Probable). Isoform 2: Constitutively active (PubMed:8378304). {ECO:0000269|PubMed:8378304, ECO:0000305}.

Subunit: Interacts with PARD6A, PARD6B and PARD6G. Part of a complex with PARD3, PARD6A or PARD6B or PARD6G and CDC42 or RAC1. Interacts with ADAP1/CENTA1 (By similarity). Forms a ternary complex with SQSTM1 and KCNAB2. Forms another ternary complex with SQSTM1 and GABRR3. Forms a complex with SQSTM1 and MAP2K5. Interacts (via the protein kinase domain) with WWC1. Forms a tripartite complex with WWC1 and DDR1, but predominantly in the absence of collagen. Component of the Par polarity complex, composed of at least phosphorylated PRKCZ, PARD3 and TIAM1. Interacts with PDPK1 (via N-terminal region). Interacts with WDFY2 (via WD repeats 1-3) (By similarity). Interacts with VAMP2 (By similarity). Forms a complex with WDFY2 and VAMP2 (By similarity). Interacts with APPL1 (By similarity). {ECO:0000250|UniProtKB:Q05513, ECO:0000269|PubMed:12431995, ECO:0000269|PubMed:12813044, ECO:0000269|PubMed:9177193}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:12431995, ECO:0000269|PubMed:8378304, ECO:0000269|PubMed:9177193}. Endosome {ECO:0000250|UniProtKB:Q05513}. Cell junction {ECO:0000250|UniProtKB:Q05513}. Membrane {ECO:0000269|PubMed:8378304}; Peripheral membrane protein {ECO:0000305}. Note=In the retina, localizes in the terminals of the rod bipolar cells (PubMed:12431995). Associated with endosomes (By similarity). Presence of KRIT1, CDH5 and RAP1B is required for its localization to the cell junction (By similarity). Colocalizes with VAMP2 and WDFY2 in intracellular vesicles (By similarity). Transiently translocates to the membrane of CA1 hippocampal cells in response to the induction of long term potentiation (PubMed:8378304). {ECO:0000250|UniProtKB:Q05513, ECO:0000269|PubMed:12431995, ECO:0000269|PubMed:8378304}.

Subcellular location: [Isoform 2]: Cytoplasm {ECO:0000269|PubMed:8378304}.

Tissue specificity: Isoform 1: In brain, expressed in hippocampus, neocortex and cerebellum (at protein level) (PubMed:8378304, PubMed:12857744). Also expressed in lung, liver, kidney, testis and to a lesser extent in pancreas, intestine and skin (at protein level) (PubMed:12857744). Isoform 2: Specifically expressed in brain where it localizes to the hippocampus, neocortex and cerebellum (at protein level) (PubMed:8378304, PubMed:12857744, PubMed:27498875). {ECO:0000269|PubMed:12857744, ECO:0000269|PubMed:27498875, ECO:0000269|PubMed:8378304}.

Induction: [Isoform 2]: Induced during synaptic long term potentiation. {ECO:0000269|PubMed:12857744, ECO:0000269|PubMed:27498875, ECO:0000269|PubMed:8378304}.

Domain: The PB1 domain mediate mutually exclusive interactions with SQSTM1 and PARD6B. {ECO:0000250}.

Domain: The C1 domain does not bind the diacylglycerol (DAG). {ECO:0000269|PubMed:9177193}.

Ptm: CDH5 is required for its phosphorylation at Thr-410. Phosphorylated by protein kinase PDPK1; phosphorylation is inhibited by the apoptotic C-terminal cleavage product of PKN2. Phosphorylation at Thr-410 by PI3K activates the kinase (By similarity). {ECO:0000250}.

Disruption phenotype: [Isoform 2]: RNAi-mediated knockdown in the dorsal hippocampus impairs the late phase of long-term potentiation and the establishment of long term memory. Formation of short term memory is not affected. {ECO:0000269|PubMed:27498875}.

Miscellaneous: [Isoform 2]: Produced by alternative promoter usage. {ECO:0000269|PubMed:12857744}.

Similarity: Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. PKC subfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Rattus norvegicus (Rat).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Rattus.



Function:		Calcium- and diacylglycerol-independent serine/threonine- protein kinase that functions in phosphatidylinositol 3-kinase (PI3K) pathway and mitogen-activated protein (MAP) kinase cascade, and is involved in NF-kappa-B activation, mitogenic signaling, cell proliferation, cell polarity, inflammatory response and maintenance of long-term potentiation (LTP). Upon lipopolysaccharide (LPS) treatment in macrophages, or following mitogenic stimuli, functions downstream of PI3K to activate MAP2K1/MEK1-MAPK1/ERK2 signaling cascade independently of RAF1 activation. Required for insulin-dependent activation of AKT3, but may function as an adapter rather than a direct activator. Upon insulin treatment may act as a downstream effector of PI3K and contribute to the activation of translocation of the glucose transporter SLC2A4/GLUT4 and subsequent glucose transport in adipocytes. In EGF-induced cells, binds and activates MAP2K5/MEK5- MAPK7/ERK5 independently of its kinase activity and can activate JUN promoter through MEF2C. Through binding with SQSTM1/p62, functions in interleukin-1 signaling and activation of NF-kappa-B with the specific adapters RIPK1 and TRAF6. Participates in TNF-dependent transactivation of NF-kappa-B by phosphorylating and activating IKBKB kinase, which in turn leads to the degradation of NF-kappa-B inhibitors. In migrating astrocytes, forms a cytoplasmic complex with PARD6A and is recruited by CDC42 to function in the establishment of cell polarity along with the microtubule motor and dynein. In association with FEZ1, stimulates neuronal differentiation in PC12 cells. In the inflammatory response, is required for the T-helper 2 (Th2) differentiation process, including interleukin production, efficient activation of JAK1 and the subsequent phosphorylation and nuclear translocation of STAT6. May be involved in development of allergic airway inflammation (asthma), a process dependent on Th2 immune response. In the NF-kappa-B-mediated inflammatory response, can relieve SETD6-dependent repression of NF- kappa-B target genes by phosphorylating the RELA subunit at 'Ser-311'. Phosphorylates VAMP2 in vitro (By similarity). {ECO:0000250\|UniProtKB:Q05513, ECO:0000269\|PubMed:10022904, ECO:0000269\|PubMed:10747026, ECO:0000269\|PubMed:11158308, ECO:0000269\|PubMed:11525734, ECO:0000269\|PubMed:8557035, ECO:0000269\|PubMed:9177193, ECO:0000269\|PubMed:9374484}.



Function:		[Isoform 2]: Involved in late synaptic long term potentiation phase in CA1 hippocampal cells and long term memory maintenance. {ECO:0000269\|PubMed:11914719, ECO:0000269\|PubMed:27498875}.


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=2.7.11.13; Evidence={ECO:0000269\|PubMed:8378304};
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=2.7.11.13; Evidence={ECO:0000269\|PubMed:8378304};
Activity regulation:		Atypical PKCs (PRKCI and PRKCZ) exhibit an elevated basal enzymatic activity (that may be due to the interaction with SMG1 or SQSTM1) and are not regulated by diacylglycerol, phosphatidylserine, phorbol esters or calcium ions. Two specific sites, Thr-410 (activation loop of the kinase domain) and Thr-560 (turn motif), need to be phosphorylated for its full activation. Phosphatidylinositol 3,4,5-trisphosphate might be a physiological activator (Probable). Isoform 2: Constitutively active (PubMed:8378304). {ECO:0000269\|PubMed:8378304, ECO:0000305}.
Subunit:		Interacts with PARD6A, PARD6B and PARD6G. Part of a complex with PARD3, PARD6A or PARD6B or PARD6G and CDC42 or RAC1. Interacts with ADAP1/CENTA1 (By similarity). Forms a ternary complex with SQSTM1 and KCNAB2. Forms another ternary complex with SQSTM1 and GABRR3. Forms a complex with SQSTM1 and MAP2K5. Interacts (via the protein kinase domain) with WWC1. Forms a tripartite complex with WWC1 and DDR1, but predominantly in the absence of collagen. Component of the Par polarity complex, composed of at least phosphorylated PRKCZ, PARD3 and TIAM1. Interacts with PDPK1 (via N-terminal region). Interacts with WDFY2 (via WD repeats 1-3) (By similarity). Interacts with VAMP2 (By similarity). Forms a complex with WDFY2 and VAMP2 (By similarity). Interacts with APPL1 (By similarity). {ECO:0000250\|UniProtKB:Q05513, ECO:0000269\|PubMed:12431995, ECO:0000269\|PubMed:12813044, ECO:0000269\|PubMed:9177193}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:12431995, ECO:0000269\|PubMed:8378304, ECO:0000269\|PubMed:9177193}. Endosome {ECO:0000250\|UniProtKB:Q05513}. Cell junction {ECO:0000250\|UniProtKB:Q05513}. Membrane {ECO:0000269\|PubMed:8378304}; Peripheral membrane protein {ECO:0000305}. Note=In the retina, localizes in the terminals of the rod bipolar cells (PubMed:12431995). Associated with endosomes (By similarity). Presence of KRIT1, CDH5 and RAP1B is required for its localization to the cell junction (By similarity). Colocalizes with VAMP2 and WDFY2 in intracellular vesicles (By similarity). Transiently translocates to the membrane of CA1 hippocampal cells in response to the induction of long term potentiation (PubMed:8378304). {ECO:0000250\|UniProtKB:Q05513, ECO:0000269\|PubMed:12431995, ECO:0000269\|PubMed:8378304}.
Subcellular location:		[Isoform 2]: Cytoplasm {ECO:0000269\|PubMed:8378304}.
Tissue specificity:		Isoform 1: In brain, expressed in hippocampus, neocortex and cerebellum (at protein level) (PubMed:8378304, PubMed:12857744). Also expressed in lung, liver, kidney, testis and to a lesser extent in pancreas, intestine and skin (at protein level) (PubMed:12857744). Isoform 2: Specifically expressed in brain where it localizes to the hippocampus, neocortex and cerebellum (at protein level) (PubMed:8378304, PubMed:12857744, PubMed:27498875). {ECO:0000269\|PubMed:12857744, ECO:0000269\|PubMed:27498875, ECO:0000269\|PubMed:8378304}.
Induction:		[Isoform 2]: Induced during synaptic long term potentiation. {ECO:0000269\|PubMed:12857744, ECO:0000269\|PubMed:27498875, ECO:0000269\|PubMed:8378304}.
Domain:		The PB1 domain mediate mutually exclusive interactions with SQSTM1 and PARD6B. {ECO:0000250}.
Domain:		The C1 domain does not bind the diacylglycerol (DAG). {ECO:0000269\|PubMed:9177193}.
Ptm:		CDH5 is required for its phosphorylation at Thr-410. Phosphorylated by protein kinase PDPK1; phosphorylation is inhibited by the apoptotic C-terminal cleavage product of PKN2. Phosphorylation at Thr-410 by PI3K activates the kinase (By similarity). {ECO:0000250}.
Disruption phenotype:		[Isoform 2]: RNAi-mediated knockdown in the dorsal hippocampus impairs the late phase of long-term potentiation and the establishment of long term memory. Formation of short term memory is not affected. {ECO:0000269\|PubMed:27498875}.
Miscellaneous:		[Isoform 2]: Produced by alternative promoter usage. {ECO:0000269\|PubMed:12857744}.
Similarity:		Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. PKC subfamily. {ECO:0000305}.