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MGP001030

UniProt Annotations

Entry Information

Gene Name	protein tyrosine kinase 2 beta
Protein Entry	FAK2_HUMAN
UniProt ID	Q14289
Species	Human

Comments

Comment type	Description
Alternative Products	Event=Alternative splicing; Named isoforms=2; Name=1; IsoId=Q14289-1; Sequence=Displayed; Name=2; Synonyms=PYK2H; IsoId=Q14289-2; Sequence=VSP_004981;
Catalytic Activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. {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}.
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.
Enzyme 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}.
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}.
Interaction	Q7L0Q8:RHOU; NbExp=4; IntAct=EBI-298640, EBI-1638043; P12931:SRC; NbExp=3; IntAct=EBI-298640, EBI-621482;
Miscellaneous	Promotes bone resorption, and thus PTK2B/PYK2 inhibitors might be used to treat osteoporosis.
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:18088087, ECO:0000269\|PubMed:18587400, ECO:0000269\|PubMed:18691976, ECO:0000269\|PubMed:19207108, ECO:0000269\|PubMed:19369195, ECO:0000269\|PubMed:20028775, ECO:0000269\|PubMed:20381867, ECO:0000269\|PubMed:20521079, ECO:0000269\|PubMed:9545257}.
Similarity	Belongs to the protein kinase superfamily. Tyr protein kinase family. FAK subfamily. {ECO:0000255\|PROSITE- ProRule:PRU00159}.
Similarity	Contains 1 FERM domain. {ECO:0000255\|PROSITE- ProRule:PRU00084}.
Similarity	Contains 1 protein kinase domain. {ECO:0000255\|PROSITE-ProRule:PRU00159}.
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.
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}.
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}.