UniProt functional annotation for Q14289



	UniProt functional annotation for Q14289

UniProt code: Q14289.

Organism: Homo sapiens (Human).

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

Function: Non-receptor protein-tyrosine kinase that regulates reorganization of the actin cytoskeleton, cell polarization, cell migration, adhesion, spreading and bone remodeling. Plays a role in the regulation of the humoral immune response, and is required for normal levels of marginal B-cells in the spleen and normal migration of splenic B-cells. Required for normal macrophage polarization and migration towards sites of inflammation. Regulates cytoskeleton rearrangement and cell spreading in T-cells, and contributes to the regulation of T-cell responses. Promotes osteoclastic bone resorption; this requires both PTK2B/PYK2 and SRC. May inhibit differentiation and activity of osteoprogenitor cells. Functions in signaling downstream of integrin and collagen receptors, immune receptors, G-protein coupled receptors (GPCR), cytokine, chemokine and growth factor receptors, and mediates responses to cellular stress. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and of the AKT1 signaling cascade. Promotes activation of NOS3. Regulates production of the cellular messenger cGMP. Promotes activation of the MAP kinase signaling cascade, including activation of MAPK1/ERK2, MAPK3/ERK1 and MAPK8/JNK1. Promotes activation of Rho family GTPases, such as RHOA and RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Acts as a scaffold, binding to both PDPK1 and SRC, thereby allowing SRC to phosphorylate PDPK1 at 'Tyr-9, 'Tyr-373', and 'Tyr-376'. Promotes phosphorylation of NMDA receptors by SRC family members, and thereby contributes to the regulation of NMDA receptor ion channel activity and intracellular Ca(2+) levels. May also regulate potassium ion transport by phosphorylation of potassium channel subunits. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ASAP1, NPHP1, KCNA2 and SHC1. Promotes phosphorylation of ASAP2, RHOU and PXN; this requires both SRC and PTK2/PYK2. {ECO:0000269|PubMed:10022920, ECO:0000269|PubMed:12771146, ECO:0000269|PubMed:12893833, ECO:0000269|PubMed:14585963, ECO:0000269|PubMed:15050747, ECO:0000269|PubMed:15166227, ECO:0000269|PubMed:17634955, ECO:0000269|PubMed:18086875, ECO:0000269|PubMed:18339875, ECO:0000269|PubMed:18587400, ECO:0000269|PubMed:18765415, ECO:0000269|PubMed:19086031, ECO:0000269|PubMed:19207108, ECO:0000269|PubMed:19244237, ECO:0000269|PubMed:19428251, ECO:0000269|PubMed:19648005, ECO:0000269|PubMed:19880522, ECO:0000269|PubMed:20001213, ECO:0000269|PubMed:20381867, ECO:0000269|PubMed:20521079, ECO:0000269|PubMed:21357692, ECO:0000269|PubMed:21533080, ECO:0000269|PubMed:7544443, ECO:0000269|PubMed:8670418, ECO:0000269|PubMed:8849729}.

Catalytic activity: Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl- [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.2; Evidence={ECO:0000255|PROSITE-ProRule:PRU10028, ECO:0000269|PubMed:15050747, ECO:0000269|PubMed:15166227, ECO:0000269|PubMed:18339875, ECO:0000269|PubMed:18951788, ECO:0000269|PubMed:19428251, ECO:0000269|PubMed:19648005};

Activity regulation: Activated in response to stimuli that lead to increased intracellular Ca(2+) levels; this activation is indirect and may be mediated by calcium-mediated production of reactive oxygen species (ROS). Activated by autophosphorylation at Tyr-402; this creates a binding site for SRC family kinases and leads to phosphorylation at additional tyrosine residues. Phosphorylation at Tyr-402, Tyr-579 and Tyr-580 is required for optimal kinase activity. Inhibited by PF-562,271, BIRB796, PF-4618433 and by PF-431396, PF- 2318841 and their derivatives. Inhibited by sulfoximine-substituted trifluoromethylpyrimidines. Inhibited by 4-amino and 5-aryl substituted pyridinone compounds. {ECO:0000269|PubMed:18339875, ECO:0000269|PubMed:18951788, ECO:0000269|PubMed:19428251, ECO:0000269|PubMed:19648005}.

Subunit: Homodimer, or homooligomer. Interacts with SIRPA and SH2D3C. Interacts with ARHGAP10. Interacts with DLG4 (By similarity). Interacts with KCNA2 (By similarity). Interacts with NPHP1, ASAP1, ASAP2, ARHGAP26, SKAP2 and TGFB1I1. The Tyr-402 phosphorylated form interacts with SRC (via SH2 domain) and SRC family members. Forms a signaling complex with EPHA1, LCK and phosphatidylinositol 3-kinase; upon activation by EFNA1. Interacts with GRB2 (via SH2 domain). Interacts with P53/TP53 and MDM2. Interacts with MYLK. Interacts with BCAR1. Interacts with PDPK1. Interacts (hypophosphorylated) with PXN. Interacts with RB1CC1. Interacts with RHOU. Interacts with VAV1. Interacts with LPXN and PTPN12. {ECO:0000250|UniProtKB:P70600, ECO:0000250|UniProtKB:Q9QVP9, ECO:0000269|PubMed:10022920, ECO:0000269|PubMed:10769033, ECO:0000269|PubMed:11493697, ECO:0000269|PubMed:12771146, ECO:0000269|PubMed:12893833, ECO:0000269|PubMed:14585963, ECO:0000269|PubMed:17329398, ECO:0000269|PubMed:17634955, ECO:0000269|PubMed:18086875, ECO:0000269|PubMed:18587400, ECO:0000269|PubMed:18765415, ECO:0000269|PubMed:18951788, ECO:0000269|PubMed:19086031, ECO:0000269|PubMed:19207108, ECO:0000269|PubMed:19358827, ECO:0000269|PubMed:19428251, ECO:0000269|PubMed:20521079, ECO:0000269|PubMed:21357692, ECO:0000269|PubMed:7544443, ECO:0000269|PubMed:8849729, ECO:0000269|PubMed:9422762}.

Subcellular location: Cytoplasm. Cytoplasm, perinuclear region. Cell membrane; Peripheral membrane protein; Cytoplasmic side. Cell junction, focal adhesion. Cell projection, lamellipodium. Cytoplasm, cell cortex. Nucleus. Note=Interaction with NPHP1 induces the membrane-association of the kinase. Colocalizes with integrins at the cell periphery.

Tissue specificity: Most abundant in the brain, with highest levels in amygdala and hippocampus. Low levels in kidney (at protein level). Also expressed in spleen and lymphocytes. {ECO:0000269|PubMed:7544443, ECO:0000269|PubMed:9545257}.

Ptm: Phosphorylated on tyrosine residues in response to various stimuli that elevate the intracellular calcium concentration; this activation is indirect and may be mediated by production of reactive oxygen species (ROS). Tyr-402 is the major autophosphorylation site, but other kinases can also phosphorylate Tyr-402. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Phosphorylation at Tyr-402 promotes interaction with SRC and SRC family members, leading to phosphorylation at Tyr-579; Tyr-580 and Tyr-881. Phosphorylation at Tyr-881 is important for interaction with GRB2. Phosphorylated on tyrosine residues upon activation of FGR and PKC. Recruitment by NPHP1 to cell matrix adhesions initiates Tyr-402 phosphorylation. In monocytes, adherence to substrata is required for tyrosine phosphorylation and kinase activation. Angiotensin II, thapsigargin and L-alpha- lysophosphatidic acid (LPA) also induce autophosphorylation and increase kinase activity. Phosphorylation by MYLK promotes ITGB2 activation and is thus essential to trigger neutrophil transmigration during lung injury. Dephosphorylated by PTPN12. {ECO:0000269|PubMed:11493697, ECO:0000269|PubMed:15166227, ECO:0000269|PubMed:17329398, ECO:0000269|PubMed:18587400, ECO:0000269|PubMed:19207108, ECO:0000269|PubMed:20028775, ECO:0000269|PubMed:20381867, ECO:0000269|PubMed:20521079, ECO:0000269|PubMed:9545257}.

Disease: Note=Aberrant PTK2B/PYK2 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. Elevated PTK2B/PYK2 expression is seen in gliomas, hepatocellular carcinoma, lung cancer and breast cancer.

Miscellaneous: Promotes bone resorption, and thus PTK2B/PYK2 inhibitors might be used to treat osteoporosis.

Similarity: Belongs to the protein kinase superfamily. Tyr protein kinase family. FAK subfamily. {ECO:0000255|PROSITE-ProRule:PRU00159}.

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:		Non-receptor protein-tyrosine kinase that regulates reorganization of the actin cytoskeleton, cell polarization, cell migration, adhesion, spreading and bone remodeling. Plays a role in the regulation of the humoral immune response, and is required for normal levels of marginal B-cells in the spleen and normal migration of splenic B-cells. Required for normal macrophage polarization and migration towards sites of inflammation. Regulates cytoskeleton rearrangement and cell spreading in T-cells, and contributes to the regulation of T-cell responses. Promotes osteoclastic bone resorption; this requires both PTK2B/PYK2 and SRC. May inhibit differentiation and activity of osteoprogenitor cells. Functions in signaling downstream of integrin and collagen receptors, immune receptors, G-protein coupled receptors (GPCR), cytokine, chemokine and growth factor receptors, and mediates responses to cellular stress. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and of the AKT1 signaling cascade. Promotes activation of NOS3. Regulates production of the cellular messenger cGMP. Promotes activation of the MAP kinase signaling cascade, including activation of MAPK1/ERK2, MAPK3/ERK1 and MAPK8/JNK1. Promotes activation of Rho family GTPases, such as RHOA and RAC1. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Acts as a scaffold, binding to both PDPK1 and SRC, thereby allowing SRC to phosphorylate PDPK1 at 'Tyr-9, 'Tyr-373', and 'Tyr-376'. Promotes phosphorylation of NMDA receptors by SRC family members, and thereby contributes to the regulation of NMDA receptor ion channel activity and intracellular Ca(2+) levels. May also regulate potassium ion transport by phosphorylation of potassium channel subunits. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ASAP1, NPHP1, KCNA2 and SHC1. Promotes phosphorylation of ASAP2, RHOU and PXN; this requires both SRC and PTK2/PYK2. {ECO:0000269\|PubMed:10022920, ECO:0000269\|PubMed:12771146, ECO:0000269\|PubMed:12893833, ECO:0000269\|PubMed:14585963, ECO:0000269\|PubMed:15050747, ECO:0000269\|PubMed:15166227, ECO:0000269\|PubMed:17634955, ECO:0000269\|PubMed:18086875, ECO:0000269\|PubMed:18339875, ECO:0000269\|PubMed:18587400, ECO:0000269\|PubMed:18765415, ECO:0000269\|PubMed:19086031, ECO:0000269\|PubMed:19207108, ECO:0000269\|PubMed:19244237, ECO:0000269\|PubMed:19428251, ECO:0000269\|PubMed:19648005, ECO:0000269\|PubMed:19880522, ECO:0000269\|PubMed:20001213, ECO:0000269\|PubMed:20381867, ECO:0000269\|PubMed:20521079, ECO:0000269\|PubMed:21357692, ECO:0000269\|PubMed:21533080, ECO:0000269\|PubMed:7544443, ECO:0000269\|PubMed:8670418, ECO:0000269\|PubMed:8849729}.


Catalytic activity:		Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl- [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA- COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.2; Evidence={ECO:0000255\|PROSITE-ProRule:PRU10028, ECO:0000269\|PubMed:15050747, ECO:0000269\|PubMed:15166227, ECO:0000269\|PubMed:18339875, ECO:0000269\|PubMed:18951788, ECO:0000269\|PubMed:19428251, ECO:0000269\|PubMed:19648005};
Activity regulation:		Activated in response to stimuli that lead to increased intracellular Ca(2+) levels; this activation is indirect and may be mediated by calcium-mediated production of reactive oxygen species (ROS). Activated by autophosphorylation at Tyr-402; this creates a binding site for SRC family kinases and leads to phosphorylation at additional tyrosine residues. Phosphorylation at Tyr-402, Tyr-579 and Tyr-580 is required for optimal kinase activity. Inhibited by PF-562,271, BIRB796, PF-4618433 and by PF-431396, PF- 2318841 and their derivatives. Inhibited by sulfoximine-substituted trifluoromethylpyrimidines. Inhibited by 4-amino and 5-aryl substituted pyridinone compounds. {ECO:0000269\|PubMed:18339875, ECO:0000269\|PubMed:18951788, ECO:0000269\|PubMed:19428251, ECO:0000269\|PubMed:19648005}.
Subunit:		Homodimer, or homooligomer. Interacts with SIRPA and SH2D3C. Interacts with ARHGAP10. Interacts with DLG4 (By similarity). Interacts with KCNA2 (By similarity). Interacts with NPHP1, ASAP1, ASAP2, ARHGAP26, SKAP2 and TGFB1I1. The Tyr-402 phosphorylated form interacts with SRC (via SH2 domain) and SRC family members. Forms a signaling complex with EPHA1, LCK and phosphatidylinositol 3-kinase; upon activation by EFNA1. Interacts with GRB2 (via SH2 domain). Interacts with P53/TP53 and MDM2. Interacts with MYLK. Interacts with BCAR1. Interacts with PDPK1. Interacts (hypophosphorylated) with PXN. Interacts with RB1CC1. Interacts with RHOU. Interacts with VAV1. Interacts with LPXN and PTPN12. {ECO:0000250\|UniProtKB:P70600, ECO:0000250\|UniProtKB:Q9QVP9, ECO:0000269\|PubMed:10022920, ECO:0000269\|PubMed:10769033, ECO:0000269\|PubMed:11493697, ECO:0000269\|PubMed:12771146, ECO:0000269\|PubMed:12893833, ECO:0000269\|PubMed:14585963, ECO:0000269\|PubMed:17329398, ECO:0000269\|PubMed:17634955, ECO:0000269\|PubMed:18086875, ECO:0000269\|PubMed:18587400, ECO:0000269\|PubMed:18765415, ECO:0000269\|PubMed:18951788, ECO:0000269\|PubMed:19086031, ECO:0000269\|PubMed:19207108, ECO:0000269\|PubMed:19358827, ECO:0000269\|PubMed:19428251, ECO:0000269\|PubMed:20521079, ECO:0000269\|PubMed:21357692, ECO:0000269\|PubMed:7544443, ECO:0000269\|PubMed:8849729, ECO:0000269\|PubMed:9422762}.
Subcellular location:		Cytoplasm. Cytoplasm, perinuclear region. Cell membrane; Peripheral membrane protein; Cytoplasmic side. Cell junction, focal adhesion. Cell projection, lamellipodium. Cytoplasm, cell cortex. Nucleus. Note=Interaction with NPHP1 induces the membrane-association of the kinase. Colocalizes with integrins at the cell periphery.
Tissue specificity:		Most abundant in the brain, with highest levels in amygdala and hippocampus. Low levels in kidney (at protein level). Also expressed in spleen and lymphocytes. {ECO:0000269\|PubMed:7544443, ECO:0000269\|PubMed:9545257}.
Ptm:		Phosphorylated on tyrosine residues in response to various stimuli that elevate the intracellular calcium concentration; this activation is indirect and may be mediated by production of reactive oxygen species (ROS). Tyr-402 is the major autophosphorylation site, but other kinases can also phosphorylate Tyr-402. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Phosphorylation at Tyr-402 promotes interaction with SRC and SRC family members, leading to phosphorylation at Tyr-579; Tyr-580 and Tyr-881. Phosphorylation at Tyr-881 is important for interaction with GRB2. Phosphorylated on tyrosine residues upon activation of FGR and PKC. Recruitment by NPHP1 to cell matrix adhesions initiates Tyr-402 phosphorylation. In monocytes, adherence to substrata is required for tyrosine phosphorylation and kinase activation. Angiotensin II, thapsigargin and L-alpha- lysophosphatidic acid (LPA) also induce autophosphorylation and increase kinase activity. Phosphorylation by MYLK promotes ITGB2 activation and is thus essential to trigger neutrophil transmigration during lung injury. Dephosphorylated by PTPN12. {ECO:0000269\|PubMed:11493697, ECO:0000269\|PubMed:15166227, ECO:0000269\|PubMed:17329398, ECO:0000269\|PubMed:18587400, ECO:0000269\|PubMed:19207108, ECO:0000269\|PubMed:20028775, ECO:0000269\|PubMed:20381867, ECO:0000269\|PubMed:20521079, ECO:0000269\|PubMed:9545257}.
Disease:		Note=Aberrant PTK2B/PYK2 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. Elevated PTK2B/PYK2 expression is seen in gliomas, hepatocellular carcinoma, lung cancer and breast cancer.
Miscellaneous:		Promotes bone resorption, and thus PTK2B/PYK2 inhibitors might be used to treat osteoporosis.
Similarity:		Belongs to the protein kinase superfamily. Tyr protein kinase family. FAK subfamily. {ECO:0000255\|PROSITE-ProRule:PRU00159}.