Alternative titles; symbols
HGNC Approved Gene Symbol: PTK2B
Cytogenetic location: 8p21.2 Genomic coordinates (GRCh38): 8:27,310,506-27,459,391 (from NCBI)
Focal adhesion kinases are cytoplasmic protein-tyrosine kinases associated with focal adhesions and whose activity is induced by ligand binding to various receptors including those for integrin, growth factors, etc. FAKs are known to target paxillin (602505) and are substrates for Src family kinases (see 190090) (Calalb et al., 1995). Herzog et al. (1996) identified a gene for another focal adhesion kinase by low-stringency screening of a hippocampus cDNA library. They symbolized the gene FAK2. The FAK2 cDNA encodes a predicted 1,009-amino acid protein with 42% identity to FAK1 (600758). Northern blot analysis detected a 4.5-kb mRNA in brain, kidney, spleen, and lymphocytes.
Protein-tyrosine kinases in the central nervous system are activated in response to a variety of neurotrophic factors that control neuronal differentiation and survival via cell surface receptors. Also, protein phosphorylation is involved in membrane excitability and the function of ion channels. Lev et al. (1995) discovered a nonreceptor type protein kinase that is highly expressed in adult rat brain. The kinase, which they symbolized PYK2 (proline-rich tyrosine kinase-2), was cloned from a rat spinal cord cDNA library using degenerate PCR primers corresponding to conserved tyrosine kinase motifs of PYK1 (see Manser et al., 1993). Lev et al. (1995) cloned the human homolog from a human fetal brain cDNA library using the rat sequence as a probe. The predicted protein of 1,009 amino acids has 61% sequence identity to the FAK1 protein (PTK2; 600758).
Lev et al. (1995) showed that the PYK2 protein undergoes rapid tyrosine phosphorylation in response to various stimuli that elevate intracellular calcium concentration, such as addition of bradykinin, a neuropeptide hormone that binds to a G protein-coupled receptor and in turn stimulates phosphatidylinositol hydrolysis. PYK2 is also tyrosine phosphorylated following activation of the nicotinic acetylcholine receptor (see 100690), by membrane depolarization, and by treatment of cells with a calcium ionophore. Protein kinase C (176960) activation also induces PYK2 phosphorylation. Activation of PYK2 leads to the modulation of ion channel function and activation of the MAP kinase signaling pathway. Lev et al. (1995) proposed that PYK2 may represent an important signaling intermediate between neuropeptide activated receptors or neurotransmitters that increase calcium flux and the downstream signals that regulate neuronal activity. PYK2 may also provide a mechanism for a variety of short- and long-term calcium-dependent signaling events in the nervous system.
Matsuya et al. (1998) found specific interaction between the C-terminal region of PYK2 and HIC5 (TGFB1I1; 602353). Both proteins were tyrosine-phosphorylated in parallel in rat fibroblasts exposed to hypertonic osmotic stress or stimulated with lysophosphatidic acid.
Hepatitis B virus (HBV) causes acute and chronic infection of the liver and is also a risk factor for hepatic cancer. The virus has only 4 open reading frames, 3 of which encode the capsid, envelope, and polymerase proteins. The fourth encodes HBX, a poorly expressed protein required for viral replication (Ganem, 2001). Bouchard et al. (2001) showed that HBX induces release of calcium into the cytoplasm, presumably from mitochondria or endoplasmic reticulum. HBX expression thereby induces activation of PYK2, which activates SRC and HBV DNA replication. Inhibition of PYK2 or calcium signaling mediated by mitochondrial calcium channels could block HBV DNA replication, and enhancement of cytoplasmic calcium was able to substitute for HBX in stimulating HBV DNA replication.
In a kidney proximal epithelial cell line (OKP) incubated in acid media, Li et al. (2004) observed an increase in PYK2 phosphorylation and PYK2/SRC binding. Transfection of OKP cells with dominant-negative PYK2 or small interfering PYK2 duplex RNA blocked acid activation of sodium/hydrogen exchanger-3 (NHE3, or SLC9A3; 182307), whereas neither had an effect on glucocorticoid activation of NHE3. Dominant-negative PYK2 also blocked acid activation of SRC kinase, which is required for acid regulation of NHE3. Li et al. (2004) concluded that PYK2 is directly activated by acidic pH and that PYK2 activation is required for acid activation of SRC kinase and NHE3. Partially purified PYK2 was activated by acid in a cell-free system, leading Li et al. (2004) to suggest that PYK2 may serve as the pH sensor that initiates the acid-regulated signaling cascade involved in NHE3 regulation.
Herzog et al. (1996) assigned the FAK2 gene to chromosome 8 by PCR analysis of somatic cell hybrid DNAs and localized it to 8p22-p11.2 by fluorescence in situ hybridization.
Buckbinder et al. (2007) found that Pyk2-null mice were normal in appearance and body weight, but they had increased bone mass and improved bone microstructure. Mouse bone marrow cultures showed that Pyk2 deficiency enhanced differentiation and activity of osteoprogenitor cells, as did expression of PYK2-specific short hairpin RNA or dominant interfering proteins in human mesenchymal stem cells. Daily administration of a small molecule Pyk2 inhibitor increased bone formation and protected against bone loss in ovariectomized rats, an established preclinical model of postmenopausal osteoporosis.
Using Pyk2 -/- mice, Kamen et al. (2011) showed that Pyk2 was required for integrin-mediated degranulation responses in polymorphonuclear neutrophils (PMNs), but not in adhesion-induced cell spreading or activation of superoxide production. Pyk2-deficient PMNs also displayed reduced migration on fibrinogen (see 134820)-coated surfaces and reduced paxillin and Vav (VAV1; 164875) phosphorylation after integrin ligation. Clearance of Staphylococcus aureus skin abscesses was poor in Pyk2 -/- mice. The response to soluble agonists, however, was normal. Kamen et al. (2011) concluded that PYK2 is involved in regulating adhesion-mediated release of PMN granule contents.
Bouchard, M. J., Wang, L.-H., Schneider, R. J. Calcium signaling by HBx protein in hepatitis B virus DNA replication. Science 294: 2376-2378, 2001. [PubMed: 11743208] [Full Text: https://doi.org/10.1126/science.294.5550.2376]
Buckbinder, L., Crawford, D. T., Qi, H., Ke, H. Z., Olson, L. M., Long, K. R., Bonnette, P. C., Baumann, A. P., Hambor, J. E., Grasser, W. A., III, Pan, L. C., Owen, T. A., and 11 others. Proline-rich tyrosine kinase 2 regulates osteoprogenitor cells and bone formation, and offers an anabolic treatment approach for osteoporosis. Proc. Nat. Acad. Sci. 104: 10619-10624, 2007. [PubMed: 17537919] [Full Text: https://doi.org/10.1073/pnas.0701421104]
Calalb, M. B., Polte, T. R., Hanks, S. K. Tyrosine phosphorylation of focal adhesion kinase at sites in the catalytic domain regulates kinase activity: a role for Src family kinases. Molec. Cell. Biol. 15: 954-963, 1995. [PubMed: 7529876] [Full Text: https://doi.org/10.1128/MCB.15.2.954]
Ganem, D. The X files--one step closer to closure. Science 294: 2299-2300, 2001. [PubMed: 11743185] [Full Text: https://doi.org/10.1126/science.1067850]
Herzog, H., Nicholl, J., Hort, Y. J., Sutherland, G. R., Shine, J. Molecular cloning and assignment of FAK2, a novel human focal adhesion kinase, to 8p11.2-p22 by nonisotopic in situ hybridization. Genomics 32: 484-486, 1996. [PubMed: 8838818] [Full Text: https://doi.org/10.1006/geno.1996.0149]
Kamen, L. A., Schlessinger, J., Lowell, C. A. Pyk2 is required for neutrophil degranulation and host defense responses to bacterial infection. J. Immun. 186: 1656-1665, 2011. [PubMed: 21187437] [Full Text: https://doi.org/10.4049/jimmunol.1002093]
Lev, S., Moreno, H., Martinez, R., Canoll, P., Peles, E., Musacchio, J. M., Plowman, G. D., Rudy, B., Schlessinger, J. Protein tyrosine kinase PYK2 involved in Ca(2+)-induced regulation of ion channel and MAP kinase functions. Nature 376: 737-745, 1995. [PubMed: 7544443] [Full Text: https://doi.org/10.1038/376737a0]
Li, S., Sato, S., Yang, X., Preisig, P. A., Alpern, R. J. Pyk2 activation is integral to acid stimulation of sodium/hydrogen exchanger 3. J. Clin. Invest. 114: 1782-1789, 2004. [PubMed: 15599403] [Full Text: https://doi.org/10.1172/JCI18046]
Manser, E., Leung, T., Salihuddin, H., Tan, L., Lim, L. A non-receptor tyrosine kinase that inhibits the GTPase activity of p21(cdc42). Nature 363: 364-367, 1993. [PubMed: 8497321] [Full Text: https://doi.org/10.1038/363364a0]
Matsuya, M., Sasaki, H., Aoto, H., Mitaka, T., Nagura, K., Ohba, T., Ishino, M., Takahashi, S., Suzuki, R., Sasaki, T. Cell adhesion kinase beta forms a complex with a new member, Hic-5, of proteins localized at focal adhesions. J. Biol. Chem. 273: 1003-1014, 1998. [PubMed: 9422762] [Full Text: https://doi.org/10.1074/jbc.273.2.1003]