ID:FAK2_HUMAN DESCRIPTION: RecName: Full=Protein-tyrosine kinase 2-beta; EC=2.7.10.2; AltName: Full=Calcium-dependent tyrosine kinase; Short=CADTK; AltName: Full=Calcium-regulated non-receptor proline-rich tyrosine kinase; AltName: Full=Cell adhesion kinase beta; Short=CAK-beta; Short=CAKB; AltName: Full=Focal adhesion kinase 2; Short=FADK 2; AltName: Full=Proline-rich tyrosine kinase 2; AltName: Full=Related adhesion focal tyrosine kinase; Short=RAFTK; 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. CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. 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. SUBUNIT: Homodimer, or homooligomer. Interacts with SIRPA and SH2D3C. Interacts with ARHGAP10. Interacts with DLG4 (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. INTERACTION: Q7L0Q8:RHOU; NbExp=4; IntAct=EBI-298640, EBI-1638043; 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. 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. 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. SIMILARITY: Contains 1 FERM domain. SIMILARITY: Contains 1 protein kinase domain.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
Pfam Domains: PF00069 - Protein kinase domain PF00373 - FERM central domain PF03623 - Focal adhesion targeting region PF07714 - Protein tyrosine and serine/threonine kinase PF18038 - FERM N-terminal domain
SCOP Domains: 47031 - Second domain of FERM 68993 - FAT domain of focal adhesion kinase 50729 - PH domain-like 56112 - Protein kinase-like (PK-like) 54236 - Ubiquitin-like
ModBase Predicted Comparative 3D Structure on Q14289
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Gene Ontology (GO) Annotations with Structured Vocabulary
Molecular Function: GO:0000166 nucleotide binding GO:0004672 protein kinase activity GO:0004683 calmodulin-dependent protein kinase activity GO:0004713 protein tyrosine kinase activity GO:0004715 non-membrane spanning protein tyrosine kinase activity GO:0004871 signal transducer activity GO:0004972 NMDA glutamate receptor activity GO:0005102 receptor binding GO:0005515 protein binding GO:0005524 ATP binding GO:0008022 protein C-terminus binding GO:0016301 kinase activity GO:0016740 transferase activity GO:0019899 enzyme binding GO:0031625 ubiquitin protein ligase binding GO:0043423 3-phosphoinositide-dependent protein kinase binding GO:0044877 macromolecular complex binding
Biological Process: GO:0000165 MAPK cascade GO:0000302 response to reactive oxygen species GO:0001525 angiogenesis GO:0001556 oocyte maturation GO:0001666 response to hypoxia GO:0001954 positive regulation of cell-matrix adhesion GO:0002040 sprouting angiogenesis GO:0002250 adaptive immune response GO:0002315 marginal zone B cell differentiation GO:0002376 immune system process GO:0002688 regulation of leukocyte chemotaxis GO:0006468 protein phosphorylation GO:0006915 apoptotic process GO:0006968 cellular defense response GO:0006970 response to osmotic stress GO:0007015 actin filament organization GO:0007155 cell adhesion GO:0007165 signal transduction GO:0007166 cell surface receptor signaling pathway GO:0007172 signal complex assembly GO:0007173 epidermal growth factor receptor signaling pathway GO:0007204 positive regulation of cytosolic calcium ion concentration GO:0007229 integrin-mediated signaling pathway GO:0008284 positive regulation of cell proliferation GO:0008285 negative regulation of cell proliferation GO:0008360 regulation of cell shape GO:0009612 response to mechanical stimulus GO:0009725 response to hormone GO:0009749 response to glucose GO:0010226 response to lithium ion GO:0010243 response to organonitrogen compound GO:0010595 positive regulation of endothelial cell migration GO:0010656 negative regulation of muscle cell apoptotic process GO:0010752 regulation of cGMP-mediated signaling GO:0010758 regulation of macrophage chemotaxis GO:0010976 positive regulation of neuron projection development GO:0014009 glial cell proliferation GO:0016310 phosphorylation GO:0018108 peptidyl-tyrosine phosphorylation GO:0030154 cell differentiation GO:0030155 regulation of cell adhesion GO:0030279 negative regulation of ossification GO:0030307 positive regulation of cell growth GO:0030334 regulation of cell migration GO:0030335 positive regulation of cell migration GO:0030500 regulation of bone mineralization GO:0030502 negative regulation of bone mineralization GO:0030826 regulation of cGMP biosynthetic process GO:0030838 positive regulation of actin filament polymerization GO:0031175 neuron projection development GO:0032270 positive regulation of cellular protein metabolic process GO:0032960 regulation of inositol trisphosphate biosynthetic process GO:0033209 tumor necrosis factor-mediated signaling pathway GO:0035235 ionotropic glutamate receptor signaling pathway GO:0035902 response to immobilization stress GO:0038083 peptidyl-tyrosine autophosphorylation GO:0038110 interleukin-2-mediated signaling pathway GO:0042127 regulation of cell proliferation GO:0042220 response to cocaine GO:0042493 response to drug GO:0042542 response to hydrogen peroxide GO:0042976 activation of Janus kinase activity GO:0043066 negative regulation of apoptotic process GO:0043149 stress fiber assembly GO:0043267 negative regulation of potassium ion transport GO:0043507 positive regulation of JUN kinase activity GO:0043524 negative regulation of neuron apoptotic process GO:0043534 blood vessel endothelial cell migration GO:0043552 positive regulation of phosphatidylinositol 3-kinase activity GO:0045087 innate immune response GO:0045428 regulation of nitric oxide biosynthetic process GO:0045429 positive regulation of nitric oxide biosynthetic process GO:0045453 bone resorption GO:0045471 response to ethanol GO:0045638 negative regulation of myeloid cell differentiation GO:0045727 positive regulation of translation GO:0045765 regulation of angiogenesis GO:0045766 positive regulation of angiogenesis GO:0045860 positive regulation of protein kinase activity GO:0046330 positive regulation of JNK cascade GO:0046777 protein autophosphorylation GO:0048010 vascular endothelial growth factor receptor signaling pathway GO:0048041 focal adhesion assembly GO:0048167 regulation of synaptic plasticity GO:0050731 positive regulation of peptidyl-tyrosine phosphorylation GO:0050848 regulation of calcium-mediated signaling GO:0051000 positive regulation of nitric-oxide synthase activity GO:0051279 regulation of release of sequestered calcium ion into cytosol GO:0051591 response to cAMP GO:0051592 response to calcium ion GO:0051968 positive regulation of synaptic transmission, glutamatergic GO:0060291 long-term synaptic potentiation GO:0060292 long term synaptic depression GO:0065003 macromolecular complex assembly GO:0070098 chemokine-mediated signaling pathway GO:0070374 positive regulation of ERK1 and ERK2 cascade GO:0071300 cellular response to retinoic acid GO:0071498 cellular response to fluid shear stress GO:0090630 activation of GTPase activity GO:2000058 regulation of protein ubiquitination involved in ubiquitin-dependent protein catabolic process GO:2000060 positive regulation of protein ubiquitination involved in ubiquitin-dependent protein catabolic process GO:2000114 regulation of establishment of cell polarity GO:2000249 regulation of actin cytoskeleton reorganization GO:2000310 regulation of N-methyl-D-aspartate selective glutamate receptor activity GO:2000379 positive regulation of reactive oxygen species metabolic process GO:2000463 positive regulation of excitatory postsynaptic potential GO:2000538 positive regulation of B cell chemotaxis GO:2000573 positive regulation of DNA biosynthetic process
S80542 - Homo sapiens related adhesion focal tyrosine kinase (RAFTK) mRNA, complete cds. BC036651 - Homo sapiens PTK2B protein tyrosine kinase 2 beta, mRNA (cDNA clone MGC:26516 IMAGE:4824966), complete cds. D45853 - Homo sapiens CAK beta mRNA for cell adhesion kinase beta, partial cds. U43522 - Human cell adhesion kinase beta (CAKbeta) mRNA, complete cds. BC042599 - Homo sapiens PTK2B protein tyrosine kinase 2 beta, mRNA (cDNA clone MGC:17184 IMAGE:4343040), complete cds. L49207 - Homo sapiens (clone B6a) focal adhesion kinase (FAK2) mRNA, complete cds. AB209085 - Homo sapiens mRNA for PTK2B protein tyrosine kinase 2 beta isoform a variant protein. U33284 - Human protein tyrosine kinase PYK2 mRNA, complete cds. AB527606 - Synthetic construct DNA, clone: pF1KB8561, Homo sapiens PTK2B gene for PTK2B protein tyrosine kinase 2 beta, without stop codon, in Flexi system. JD503734 - Sequence 484758 from Patent EP1572962. JD404110 - Sequence 385134 from Patent EP1572962. JD293698 - Sequence 274722 from Patent EP1572962. JD243382 - Sequence 224406 from Patent EP1572962. AY429564 - Homo sapiens PTK2Bv_2 mRNA sequence; alternatively spliced. JD024243 - Sequence 5267 from Patent EP1572962. JD031338 - Sequence 12362 from Patent EP1572962. AK128371 - Homo sapiens cDNA FLJ46514 fis, clone THYMU3032798, highly similar to Focal adhesion kinase 2 (EC 2.7.1.112). DQ590775 - Homo sapiens piRNA piR-57887, complete sequence. JD399975 - Sequence 380999 from Patent EP1572962. JD157069 - Sequence 138093 from Patent EP1572962. JD170346 - Sequence 151370 from Patent EP1572962. JD054818 - Sequence 35842 from Patent EP1572962. JD445980 - Sequence 427004 from Patent EP1572962. JD483893 - Sequence 464917 from Patent EP1572962. JD424087 - Sequence 405111 from Patent EP1572962. JD537140 - Sequence 518164 from Patent EP1572962. JD275883 - Sequence 256907 from Patent EP1572962. JD386483 - Sequence 367507 from Patent EP1572962. JD276731 - Sequence 257755 from Patent EP1572962. JD203271 - Sequence 184295 from Patent EP1572962. JD040723 - Sequence 21747 from Patent EP1572962. JD369594 - Sequence 350618 from Patent EP1572962. JD310943 - Sequence 291967 from Patent EP1572962. JD550644 - Sequence 531668 from Patent EP1572962. JD176094 - Sequence 157118 from Patent EP1572962. JD240909 - Sequence 221933 from Patent EP1572962.
Biochemical and Signaling Pathways
BioCarta from NCI Cancer Genome Anatomy Project h_Ccr5Pathway - Pertussis toxin-insensitive CCR5 Signaling in Macrophage h_pyk2Pathway - Links between Pyk2 and Map Kinases h_metPathway - Signaling of Hepatocyte Growth Factor Receptor h_nkcellsPathway - Ras-Independent pathway in NK cell-mediated cytotoxicity h_cxcr4Pathway - CXCR4 Signaling Pathway h_il7Pathway - IL-7 Signal Transduction h_Par1Pathway - Thrombin signaling and protease-activated receptors h_achPathway - Role of nicotinic acetylcholine receptors in the regulation of apoptosis h_At1rPathway - Angiotensin II mediated activation of JNK Pathway via Pyk2 dependent signaling h_HBxPathway - Calcium Signaling by HBx of Hepatitis B virus h_biopeptidesPathway - Bioactive Peptide Induced Signaling Pathway h_ionPathway - Ion Channel and Phorbal Esters Signaling Pathway
Reactome (by CSHL, EBI, and GO)
Protein Q14289 (Reactome details) participates in the following event(s):
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
