UniProt functional annotation for Q61097



	UniProt functional annotation for Q61097

UniProt code: Q61097.

Organism: Mus musculus (Mouse).

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

Function: Part of a multiprotein signaling complex which promotes phosphorylation of Raf family members and activation of downstream MAP kinases (PubMed:10409742, PubMed:12932319, PubMed:21102438, PubMed:21441104). Independently of its kinase activity, acts as MAP2K1/MEK1 and MAP2K2/MEK2-dependent allosteric activator of BRAF; upon binding to MAP2K1/MEK1 or MAP2K2/MEK2, dimerizes with BRAF and promotes BRAF-mediated phosphorylation of MAP2K1/MEK1 and/or MAP2K2/MEK2 (By similarity). Promotes activation of MAPK1 and/or MAPK3, both in response to EGF and to cAMP (PubMed:21102438). Its kinase activity is unsure (PubMed:21441104). Some protein kinase activity has been detected in vitro, however the physiological relevance of this activity is unknown (PubMed:21441104). {ECO:0000250|UniProtKB:Q8IVT5, ECO:0000269|PubMed:10409742, ECO:0000269|PubMed:12932319, ECO:0000269|PubMed:21102438, ECO:0000269|PubMed:21441104}.

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:0000269|PubMed:21441104};

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:0000269|PubMed:21441104};

Subunit: Homodimer (By similarity). Heterodimerizes (via N-terminus) with BRAF (via N-terminus) in a MAP2K1/MEK1 or MAP2K2/MEK2-dependent manner (By similarity). Interacts with MAP2K1/MEK1 and MAP2K2/MEK2 (PubMed:10891492, PubMed:10409742, PubMed:21441104). Binding to MAP2K1/MEK1 releases the intramolecular inhibitory interaction between KSR1 N-terminus and kinase domains which is required for the subsequent RSK1 dimerization with BRAF (By similarity). Identified in a complex with AKAP13, MAP2K1 and BRAF (PubMed:21102438, PubMed:23250398). Interacts with AKAP13 and BRAF (PubMed:21102438). Interacts with RAF and MAPK/ERK, in a Ras-dependent manner (PubMed:10891492). Interacts with 14-3-3 proteins including YWHAB (PubMed:10409742, PubMed:11741534). Interacts with HSP90AA1/HSP90, YWHAE/14-3-3 and CDC37 (PubMed:10409742). The binding of 14-3-3 proteins to phosphorylated KSR1 prevents the membrane localization (PubMed:10409742). Interacts with MARK3 (PubMed:11741534). Interacts with PPP2R1A and PPP2CA (PubMed:12932319). Interacts with VRK2 (By similarity). {ECO:0000250|UniProtKB:Q8IVT5, ECO:0000269|PubMed:10409742, ECO:0000269|PubMed:10891492, ECO:0000269|PubMed:11741534, ECO:0000269|PubMed:12932319, ECO:0000269|PubMed:21102438, ECO:0000269|PubMed:21441104, ECO:0000269|PubMed:23250398}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:10409742, ECO:0000269|PubMed:11741534, ECO:0000269|PubMed:12932319, ECO:0000269|PubMed:23250398}. Membrane {ECO:0000269|PubMed:10409742}; Peripheral membrane protein {ECO:0000269|PubMed:10409742}. Cell membrane {ECO:0000269|PubMed:11741534, ECO:0000269|PubMed:12932319, ECO:0000269|PubMed:23250398}; Peripheral membrane protein {ECO:0000269|PubMed:11741534, ECO:0000269|PubMed:12932319, ECO:0000269|PubMed:23250398}. Cell projection, ruffle membrane {ECO:0000269|PubMed:23250398}. Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:Q8IVT5}. Note=In unstimulated cells, where the phosphorylated form is bound to a 14-3-3 protein, sequestration in the cytoplasm occurs. Following growth factor treatment, the protein is free for membrane translocation, and it moves from the cytoplasm to the cell periphery. {ECO:0000305|PubMed:12932319}.

Tissue specificity: Expressed in brain, spleen and testis. Isoform 1 is highly expressed spleen and weakly in testis, and isoform 2 is highly expressed in brain and weakly in testis. {ECO:0000269|PubMed:10891492}.

Domain: The protein kinase domain is predicted to be catalytically inactive. The domain is sufficient for KSR1 and KSR1-mediated MAP2K1 and MAP2K2 membrane localization. The domain is required but not sufficient for MAP kinase-mediated inhibition of ELK1 phosphorylation (PubMed:10409742). {ECO:0000255, ECO:0000269|PubMed:10409742}.

Domain: The N-terminal region mediates interaction with BRAF (PubMed:23250398). Also mediates membrane localization (PubMed:23250398). {ECO:0000269|PubMed:23250398}.

Ptm: Phosphorylated on Ser-297 and, to a higher extent, on Ser-392 by MARK3 (PubMed:11741534). Dephosphorylated on Ser-392 by PPP2CA (PubMed:12932319). Phosphorylated KSR1 is cytoplasmic and dephosphorylated KSR1 is membrane-associated (Probable). Phosphorylated by PKA at Ser-838. Phosphorylation at Ser-838 is required for cAMP- dependent activation of MAPK1 and/or MAPK3 (PubMed:21102438). {ECO:0000269|PubMed:10409742, ECO:0000269|PubMed:10891492, ECO:0000269|PubMed:11741534, ECO:0000269|PubMed:12932319, ECO:0000269|PubMed:21102438, ECO:0000305}.

Similarity: Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. {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:		Part of a multiprotein signaling complex which promotes phosphorylation of Raf family members and activation of downstream MAP kinases (PubMed:10409742, PubMed:12932319, PubMed:21102438, PubMed:21441104). Independently of its kinase activity, acts as MAP2K1/MEK1 and MAP2K2/MEK2-dependent allosteric activator of BRAF; upon binding to MAP2K1/MEK1 or MAP2K2/MEK2, dimerizes with BRAF and promotes BRAF-mediated phosphorylation of MAP2K1/MEK1 and/or MAP2K2/MEK2 (By similarity). Promotes activation of MAPK1 and/or MAPK3, both in response to EGF and to cAMP (PubMed:21102438). Its kinase activity is unsure (PubMed:21441104). Some protein kinase activity has been detected in vitro, however the physiological relevance of this activity is unknown (PubMed:21441104). {ECO:0000250\|UniProtKB:Q8IVT5, ECO:0000269\|PubMed:10409742, ECO:0000269\|PubMed:12932319, ECO:0000269\|PubMed:21102438, ECO:0000269\|PubMed:21441104}.


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:0000269\|PubMed:21441104};
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:0000269\|PubMed:21441104};
Subunit:		Homodimer (By similarity). Heterodimerizes (via N-terminus) with BRAF (via N-terminus) in a MAP2K1/MEK1 or MAP2K2/MEK2-dependent manner (By similarity). Interacts with MAP2K1/MEK1 and MAP2K2/MEK2 (PubMed:10891492, PubMed:10409742, PubMed:21441104). Binding to MAP2K1/MEK1 releases the intramolecular inhibitory interaction between KSR1 N-terminus and kinase domains which is required for the subsequent RSK1 dimerization with BRAF (By similarity). Identified in a complex with AKAP13, MAP2K1 and BRAF (PubMed:21102438, PubMed:23250398). Interacts with AKAP13 and BRAF (PubMed:21102438). Interacts with RAF and MAPK/ERK, in a Ras-dependent manner (PubMed:10891492). Interacts with 14-3-3 proteins including YWHAB (PubMed:10409742, PubMed:11741534). Interacts with HSP90AA1/HSP90, YWHAE/14-3-3 and CDC37 (PubMed:10409742). The binding of 14-3-3 proteins to phosphorylated KSR1 prevents the membrane localization (PubMed:10409742). Interacts with MARK3 (PubMed:11741534). Interacts with PPP2R1A and PPP2CA (PubMed:12932319). Interacts with VRK2 (By similarity). {ECO:0000250\|UniProtKB:Q8IVT5, ECO:0000269\|PubMed:10409742, ECO:0000269\|PubMed:10891492, ECO:0000269\|PubMed:11741534, ECO:0000269\|PubMed:12932319, ECO:0000269\|PubMed:21102438, ECO:0000269\|PubMed:21441104, ECO:0000269\|PubMed:23250398}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:10409742, ECO:0000269\|PubMed:11741534, ECO:0000269\|PubMed:12932319, ECO:0000269\|PubMed:23250398}. Membrane {ECO:0000269\|PubMed:10409742}; Peripheral membrane protein {ECO:0000269\|PubMed:10409742}. Cell membrane {ECO:0000269\|PubMed:11741534, ECO:0000269\|PubMed:12932319, ECO:0000269\|PubMed:23250398}; Peripheral membrane protein {ECO:0000269\|PubMed:11741534, ECO:0000269\|PubMed:12932319, ECO:0000269\|PubMed:23250398}. Cell projection, ruffle membrane {ECO:0000269\|PubMed:23250398}. Endoplasmic reticulum membrane {ECO:0000250\|UniProtKB:Q8IVT5}. Note=In unstimulated cells, where the phosphorylated form is bound to a 14-3-3 protein, sequestration in the cytoplasm occurs. Following growth factor treatment, the protein is free for membrane translocation, and it moves from the cytoplasm to the cell periphery. {ECO:0000305\|PubMed:12932319}.
Tissue specificity:		Expressed in brain, spleen and testis. Isoform 1 is highly expressed spleen and weakly in testis, and isoform 2 is highly expressed in brain and weakly in testis. {ECO:0000269\|PubMed:10891492}.
Domain:		The protein kinase domain is predicted to be catalytically inactive. The domain is sufficient for KSR1 and KSR1-mediated MAP2K1 and MAP2K2 membrane localization. The domain is required but not sufficient for MAP kinase-mediated inhibition of ELK1 phosphorylation (PubMed:10409742). {ECO:0000255, ECO:0000269\|PubMed:10409742}.
Domain:		The N-terminal region mediates interaction with BRAF (PubMed:23250398). Also mediates membrane localization (PubMed:23250398). {ECO:0000269\|PubMed:23250398}.
Ptm:		Phosphorylated on Ser-297 and, to a higher extent, on Ser-392 by MARK3 (PubMed:11741534). Dephosphorylated on Ser-392 by PPP2CA (PubMed:12932319). Phosphorylated KSR1 is cytoplasmic and dephosphorylated KSR1 is membrane-associated (Probable). Phosphorylated by PKA at Ser-838. Phosphorylation at Ser-838 is required for cAMP- dependent activation of MAPK1 and/or MAPK3 (PubMed:21102438). {ECO:0000269\|PubMed:10409742, ECO:0000269\|PubMed:10891492, ECO:0000269\|PubMed:11741534, ECO:0000269\|PubMed:12932319, ECO:0000269\|PubMed:21102438, ECO:0000305}.
Similarity:		Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. {ECO:0000305}.