Alternative titles; symbols
HGNC Approved Gene Symbol: PTK2
Cytogenetic location: 8q24.3 Genomic coordinates (GRCh38): 8:140,657,900-141,002,079 (from NCBI)
Using PCR methods with human tonsillar B cells and fetal brain cDNA libraries, Andre and Becker-Andre (1993) cloned several putative PTK2 splice variants encoding N- and C-terminally truncated PTK2 proteins. The deduced full-length protein contains at least 850 amino acids, has a central catalytic domain, and shares significant homology with chicken Ptk2. Northern blot analysis detected a 4.3-kb transcript in all tissues examined, with highest abundance in brain and lung and lowest abundance in placenta, liver, and kidney. A 2.4-kb transcript was detected in lung, placenta, and heart, and a 3.3-kb transcript was detected in brain only.
Andre and Becker-Andre (1993) described focal adhesion kinase. (See also 601212.) It concentrates in the focal adhesions that form between cells growing in the presence of extracellular matrix constituents, such as fibronectin. PTK2 contains phosphotyrosine in growing BALB/c 3T3 cells but contains little or no phosphotyrosine in cells detached by trypsinization. The tyrosine-phosphorylated state is regained within minutes when the cells are replated and anchored onto fibronectin. PTK2 appears to be a major substrate for the Rous virus-encoded oncoprotein, pp60v-src (see SRC, 190090), which transforms and confers anchorage independence on chicken embryo fibroblasts (Schaller et al., 1992). A marked increase in tyrosine phosphorylation of PTK2 is also observed after treatment of cells with cholecystokinin, bombesin, vasopressin, and endothelin. Thus, activation of PTK2 may be an important early step in cell growth and intracellular signal transduction pathways triggered in response to several neural peptides and/or to cell interactions with the extracellular matrix.
Using a yeast 2-hybrid screen, Polte and Hanks (1995) identified a Crk-associated tyrosine kinase substrate, p130Cas (BCAR1; 602941), as a Ptk2-interacting protein. Polte and Hanks (1995) demonstrated that Ptk2 and p130Cas are stably associated in mouse fibroblasts and that this interaction requires the proline-rich region of Ptk2 and the Src homology 3 domain of p130Cas. Polte and Hanks (1995) suggested that the interaction between Ptk2 and p130Cas is a key element in integrin-mediated signal transduction and that it represents a direct molecular link between the Src and Crk (164762) oncoproteins.
Hsia et al. (2003) stated that the null mutation of Fak in mice results in embryonic lethality and that Fak-null fibroblasts exhibit cell migration defects in culture. They found that viral Src (v-Src) transformation promoted integrin (see ITGA3, 605025)-stimulated motility equal to stable Fak reexpression. However, v-Src-transformed Fak-null cells failed to exhibit an invasive phenotype. Fak tyr397 phosphorylation, kinase activity, and C-terminal SH3-binding sites were required to generate the invasive cell phenotype. Cell invasion was linked to transient Fak accumulation at lamellipodia, formation of a Fak-Src-p130Cas-Dock180 (601409) signaling complex, elevated Rac (see 602048) and c-Jun N-terminal kinase (see 601158) activation, and increased matrix metalloproteinase (e.g., MMP2, 120360) expression and activity.
Torsoni et al. (2003) found that PTK2 was rapidly activated by cyclic stretch in neonatal rat ventricular myocytes and that the activation was accompanied by translocation from the perinuclear area to costamere sites in the stretched cells. Disruption of endogenous PTK2/Src signaling inhibited stretch-induced atrial natriuretic factor (ANF; 108780) gene activation. Torsoni et al. (2003) concluded that PTK2 plays an important role in the early upregulation of ANF transcription induced by mechanical stress in cardiac myocytes and may coordinate the cellular signaling machinery that controls gene expression associated with load-induced cardiac myocyte hypertrophy.
Beggs et al. (2003) found that targeted disruption of the Fak gene in mouse radial glial cells and meningeal fibroblasts in the developing dorsal forebrain resulted in local disruptions of the cortical basement membrane located between the neuroepithelium and the pia-meninges. At disruption sites, clusters of ectopic neurons invaded the marginal zone. Deletion of Fak from neurons resulted in abnormal dendrite morphology and complexity, but did not affect aberrant neuronal positioning. Beggs et al. (2003) noted that the cortical disorganization resembled lissencephaly phenotypes seen in some forms of congenital muscular dystrophy such as Walker-Warburg syndrome, now designated muscular dystrophy-dystroglycanopathy type A (see 236670).
Xie et al. (2003) found that Fak phosphorylation by Cdk5 (123831) was important for microtubule organization, nuclear movement, and neuronal migration in cultured mouse neurons. Phosphorylated Fak was enriched along a centrosome-associated microtubule fork abutting the nucleus. Overexpression of a nonphosphorylatable Fak mutant resulted in disorganization of the microtubule fork and impaired nuclear movement in vitro and a neuronal positioning defect in vivo. Xie et al. (2003) concluded that CDK5 phosphorylation of FAK is critical for neuronal migration through regulation of a microtubule fork important for nuclear translocation.
Netrin-1 (601614) plays a role in the developing nervous system by promoting both axonal outgrowth and axonal guidance in pathfinding. Liu et al. (2004), Li et al. (2004), and Ren et al. (2004) simultaneously reported a complex network of intracellular signaling downstream from netrin-1 involving the netrin receptor DCC (120470), FAK, and FYN (137025), a member of the SRC family kinases. In neurons cultured from rat cerebral cortex, Liu et al. (2004) found that netrin-1 induced tyrosine phosphorylation of FAK and FYN, and coimmunoprecipitation studies showed direct interaction of FAK and FYN with DCC. Inhibition of FYN inhibited FAK phosphorylation, and FYN mutants inhibited the attractive turning responses to netrin. Neurons lacking the FAK gene showed reduced axonal outgrowth and attractive turning responses to netrin. In cultured neurons from chick and mouse, Li et al. (2004) found that netrin increased tyrosine phosphorylation of DCC and FAK. Coimmunoprecipitation studies showed that DCC interacted directly with FAK and SRC to form a complex and that FAK and SRC cooperated to stimulate DCC phosphorylation by SRC. Li et al. (2004) suggested that phosphorylated DCC acts as a kinase-coupled receptor and that FAK and SRC act downstream of DCC in netrin signaling. Ren et al. (2004) found that inhibition of FAK phosphorylation inhibited netrin-1-induced axonal outgrowth and guidance. The authors suggested that FAK may also function as a scaffolding protein and play a role in cytoskeletal reorganization that is necessary for neurite outgrowth and turning.
Kanchanawong et al. (2010) used 3-dimensional super-resolution fluorescence microscopy to map nanoscale protein organization in focal adhesions. Their results revealed that integrins and actin are vertically separated by an approximately 40-nm focal adhesion core region consisting of multiple protein-specific strata: a membrane-apposed integrin signaling layer containing integrin cytoplasmic tails (see 193210), focal adhesion kinase, and paxillin (602505); an intermediate force-transduction layer containing talin (186745) and vinculin (193065); and an uppermost actin-regulatory layer containing zyxin (602002), vasodilator-stimulated phosphoprotein (601703), and alpha-actinin (102575). By localizing amino- and carboxy-terminally tagged talins, Kanchanawong et al. (2010) revealed talin's polarized orientation, indicative of a role in organizing the focal adhesion strata. Kanchanawong et al. (2010) concluded that their composite multilaminar protein architecture provided a molecular blueprint for understanding focal adhesion functions.
Using normal human and mouse dermal fibroblasts and mice with targeted deletion of Fak in dermal fibroblasts, Wong et al. (2012) showed that Fak was required for scar formation after wounding. Fak expression was upregulated after mechanical stretch following wounding in a mouse model of hypertrophic scar formation, and absence of Fak reduced scarring. The chemokine MCP1 (CCL2; 158105) and the MAP kinase ERK (see MAPK3, 601795), but not other MAP kinases, were required for downstream signaling and scar formation.
Tegtmeyer et al. (2011) found that knockdown of cortactin (CTTN; 164765) via small interfering RNA in a human gastric adenocarcinoma cell line inhibited cell scattering and elongation induced by infection with Helicobacter pylori (Hp). Phospho-specific antibodies to CTTN serine residues showed phosphorylation and membrane expression after Hp infection, while tyrosine residues of CTTN were dephosphorylated. Immunofluorescence analysis of uninfected cells demonstrated localization of CTTN in cytoplasm and membrane, which shifted after Hp infection to colocalization with FAK at the tip and base of cellular elongations. Interaction of CTTN with FAK required phosphorylation of either ser405 or ser418, but not both simultaneously, and involved binding of the CTTN SH3 domain with a PxxP motif, designated PR3, of FAK. Binding of CTTN phosphorylated at ser405, but not CTTN phosphorylated at ser418, to FAK increased FAK kinase activity. Tegtmeyer et al. (2011) proposed that Hp targets cortactin to protect the gastric epithelium from excessive cell lifting and to ensure sustained infection in the stomach.
Tavora et al. (2014) identified a novel molecular mechanism by which endothelial cells regulate chemosensitivity. The authors established that specific targeting of FAK in endothelial cells is sufficient to induce tumor cell sensitization to DNA-damaging therapies and thus inhibit tumor growth in mice. Tavora et al. (2014) observed that low expression of FAK in blood vessels is associated with complete remission in human lymphoma. The study showed that deletion of FAK in endothelial cells has no apparent effect on blood vessel function per se, but it does induce increased apoptosis and decreased proliferation within perivascular tumor cell compartments of doxorubicin- and radiotherapy-treated mice. Mechanistically, Tavora et al. (2014) demonstrated that endothelial cell FAK is required for DNA damage-induced NFKB (see 164011) activation in vivo and in vitro, and the production of cytokines from endothelial cells. Moreover, loss of endothelial cell FAK reduced DNA damage-induced cytokine production, thus enhancing chemosensitization of tumor cells to DNA-damaging therapies in vitro and in vivo. Tavora et al. (2014) concluded that their data identified endothelial cell FAK as a regulator of tumor chemosensitivity.
Ransom et al. (2018) developed a genetically dissectible mouse model of mandibular distraction osteogenesis, a process that is used in humans to correct an undersized lower jaw that involves surgically separating the jaw bone, which elicits new bone growth in the gap. Ransom et al. (2018) used this model to show that regions of newly formed bone are clonally derived from stem cells that reside in the skeleton. Using chromatin and transcriptional profiling, Ransom et al. (2018) showed that these stem cell populations gain activity within the FAK signaling pathway, and that inhibiting FAK abolishes new bone formation. Mechanotransduction via FAK in skeletal stem cells during distraction activates a gene regulatory program and retrotransposons that are normally active in primitive neural crest cells, from which skeletal stem cells arise during development. This reversion to a developmental state underlies the robust tissue growth that facilitates stem cell-based regeneration of adult skeletal tissue.
Using heterologous expression systems and mouse brain extracts, Rama et al. (2022) showed that the actin-binding protein Simiate (ABITRAM; 620392) interacted specifically with both cytosolic and nuclear Fak1. Simiate associated with full-length Fak1 and the Fak80 fragment. In nucleus, Simiate showed a significant preference for Fak80. In mature neurons, Fak1 was most abundant in somata and dendrites, whereas Simiate was significantly enriched in nuclear speckles. However, during neuronal development, Fak1 and Simiate displayed significant variation in their levels of expression and colocalization in both nuclei and dendrites, indicating an involvement in dendritogenesis. Despite their colocalization and interaction, Fak1 and Simiate regulated distinct aspects of dendritogenesis, as the effects of Fak1 and Simiate depended on dendrite order and distance to the soma. Moreover, the proteins' effects on primary dendrites implied that they interacted to counterbalance each other to control dendrite formation. Mechanistically, Fak1 and Simiate colocalized in nuclear speckles and regulated transcriptional processes during dendritogenesis. In addition, stimulation by external signaling agents caused functional cooperation of Fak1 and Simiate in dendrites.
By PCR analysis of somatic cell hybrids, Fiedorek and Kay (1995) mapped the PTK2 gene to chromosome 8. By interspecific backcross analysis, they mapped the mouse Fadk (Ptk2) gene to chromosome 15, linked to the Myc gene. Since the human MYC gene (190080) maps to 8q24, this is likely the site of the human PTK2 gene.
Ilic et al. (1995) found pronounced mesodermal defects in Fak-null embryos at embryonic day 8.5. Development of the anterioposterior axis was retarded and that of mesoderm was poor: head mesenchyme was involuted, and no notochord or somite was formed. Cultured mesodermal cells from mutant embryos showed reduced mobility, and the number of focal adhesions was increased. Ilic et al. (1995) concluded that FAK may be involved in the turnover of focal adhesion contacts during cell migration.
McLean et al. (2004) examined the role of FAK in skin tumor formation using mice with a regulated deletion of Fak targeted to the epidermis. Deletion of Fak prior to chemical induction of skin tumors inhibited papilloma formation, and deletion of Fak after benign tumors had formed inhibited malignant progression. Fak deletion was associated with reduced keratinocyte migration in vitro and increased keratinocyte cell death in vitro and in vivo, but it had no effect on wound reepithelialization in vivo. McLean et al. (2004) concluded that FAK enhances apoptosis and modulates the efficiency of benign tumor formation and malignant conversion.
Peng et al. (2006) stated that the lethal embryonic phenotype of Fak gene inactivation in mice included an abnormal heart and lack of fully developed blood vessels. Peng et al. (2006) generated ventricular cardiomyocyte-specific Fak-null mice and found Fak inactivation promoted eccentric cardiac hypertrophy and fibrosis in response to angiotensin II (see 106150) stimulation. By 9 months of age, these mice also developed spontaneous left ventricular chamber dilation. Peng et al. (2006) concluded that FAK is a regulator of heart hypertrophy.
Peng et al. (2008) showed that targeted inactivation of Fak in embryonic mouse heart resulted in thin ventricular walls and ventricular septal defects leading to high embryonic mortality. Decreased cell proliferation, but not increased apoptosis or differentiation, caused the thin ventricular walls. Surviving knockout mice displayed spontaneous right ventricular hypertrophy, which was related to downregulation of Mef2a (600660)-mediated signal transduction.
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Beggs, H. E., Schahin-Reed, D., Zang, K., Goebbels, S., Nave, K.-A., Gorski, J., Jones, K. R., Sretavan, D., Reichardt, L. F. FAK deficiency in cells contributing to the basal lamina results in cortical abnormalities resembling congenital muscular dystrophies. Neuron 40: 501-514, 2003. [PubMed: 14642275] [Full Text: https://doi.org/10.1016/s0896-6273(03)00666-4]
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Kanchanawong, P., Shtengel, G., Pasapera, A. M., Ramko, E. B., Davidson, M. W., Hess, H. F., Waterman, C. M. Nanoscale architecture of integrin-based cell adhesions. Nature 468: 580-584, 2010. [PubMed: 21107430] [Full Text: https://doi.org/10.1038/nature09621]
Li, W., Lee, J., Vikis, H. G., Lee, S.-H., Liu, G., Aurandt, J., Shen, T.-L., Fearon, E. R., Guan, J.-L., Han, M., Rao, Y., Hong, K., Guan, K.-L. Activation of FAK and Src are receptor-proximal events required for netrin signaling. Nature Neurosci. 7: 1213-1221, 2004. [PubMed: 15494734] [Full Text: https://doi.org/10.1038/nn1329]
Liu, G., Beggs, H., Jurgensen, C., Park, H.-T., Tang, H., Gorski, J., Jones, K. R., Reichardt, L. F., Wu, J., Rao, Y. Netrin requires focal adhesion kinase and Src family kinases for axon outgrowth and attraction. Nature Neurosci. 7: 1222-1232, 2004. [PubMed: 15494732] [Full Text: https://doi.org/10.1038/nn1331]
McLean, G. W., Komiyama, N. H., Serrels, B., Asano, H., Reynolds, L., Conti, F., Hodivala-Dilke, K., Metzger, D., Chambon, P., Grant, S. G. N., Frame, M. C. Specific deletion of focal adhesion kinase suppresses tumor formation and blocks malignant progression. Genes Dev. 18: 2998-3003, 2004. [PubMed: 15601818] [Full Text: https://doi.org/10.1101/gad.316304]
Peng, X., Kraus, M. S., Wei, H., Shen, T.-L., Pariaut, R., Alcaraz, A., Ji, G., Cheng, L., Yang, Q., Kotlikoff, M. I., Chen, J., Chien, K., Gu, H., Guan, J.-L. Inactivation of focal adhesion kinase in cardiomyocytes promotes eccentric cardiac hypertrophy and fibrosis in mice. J. Clin. Invest. 116: 217-227, 2006. [PubMed: 16374517] [Full Text: https://doi.org/10.1172/JCI24497]
Peng, X., Wu, X., Druso, J. E., Wei, H., Park, A. Y.-J., Kraus, M. S., Alcaraz, A., Chen, J., Chien, S., Cerione, R. A., Guan, J.-L. Cardiac developmental defects and eccentric right ventricular hypertrophy in cardiomyocytes focal adhesion kinase (FAK) conditional knockout mice. Proc. Nat. Acad. Sci. 105: 6638-6643, 2008. [PubMed: 18448675] [Full Text: https://doi.org/10.1073/pnas.0802319105]
Polte, T. R., Hanks, S. K. Interaction between focal adhesion kinase and Crk-associated tyrosine kinase substrate p130-Cas. Proc. Nat. Acad. Sci. 92: 10678-10682, 1995. [PubMed: 7479864] [Full Text: https://doi.org/10.1073/pnas.92.23.10678]
Rama, R., Derlig, K., Viessmann, N., Gossmann, R., Oriold, F., Giessl, A., Brandstatter, J. H., Enz, R., Dahlhaus, R. Simiate and the focal adhesion kinase FAK1 cooperate in the regulation of dendritogenesis. Sci. Rep. 12: 11274, 2022. [PubMed: 35787638] [Full Text: https://doi.org/10.1038/s41598-022-14460-y]
Ransom, R. C., Carter, A. C., Salhotra, A., Leavitt, T., Marecic, O., Murphy, M. P., Lopez, M. L., Wei, Y., Marshall, C. D., Shen, E. Z., Jones, R. E., Sharir, A., Klein, O. D., Chan, C. K. F., Wan, D. C., Chang, H. Y., Longaker, M. T. Mechanoresponsive stem cells acquire neural crest fate in jaw regeneration. Nature 563: 514-521, 2018. [PubMed: 30356216] [Full Text: https://doi.org/10.1038/s41586-018-0650-9]
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Schaller, M. D., Borgman, C., Cobb, B. S., Vines, R. R., Reynolds, A. B., Parsons, J. T. pp125(FAK), a structurally distinctive protein-tyrosine kinase associated with focal adhesions. Proc. Nat. Acad. Sci. 89: 5192-5196, 1992. [PubMed: 1594631] [Full Text: https://doi.org/10.1073/pnas.89.11.5192]
Tavora, B., Reynolds, L. E., Batista, S., Demircioglu, F., Fernandez, I., Lechertier, T., Lees, D. M., Wong, P.-P., Alexopoulou, A., Elia, G., Clear, A., Ledoux, A., Hunter, J., Perkins, N., Gribben, J. G., Hodivala-Dilke, K. M. Endothelial-cell FAK targeting sensitizes tumours to DNA-damaging therapy. Nature 514: 112-116, 2014. [PubMed: 25079333] [Full Text: https://doi.org/10.1038/nature13541]
Tegtmeyer, N., Wittelsberger, R., Hartig, R., Wessler, S., Martinez-Quiles, N., Backert, S. Serine phosphorylation of cortactin controls focal adhesion kinase activity and cell scattering induced by Helicobacter pylori. Cell Host Microbe 9: 520-531, 2011. [PubMed: 21669400] [Full Text: https://doi.org/10.1016/j.chom.2011.05.007]
Torsoni, A. S., Constancio, S. S., Nadruz, W., Jr., Hanks, S. K., Franchini, K. G. Focal adhesion kinase is activated and mediates the early hypertrophic response to stretch in cardiac myocytes. Circ. Res. 93: 140-147, 2003. [PubMed: 12805241] [Full Text: https://doi.org/10.1161/01.RES.0000081595.25297.1B]
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Xie, Z., Sanada, K., Samuels, B. A., Shih, H., Tsai, L.-H. Serine 732 phosphorylation of FAK by Cdk5 is important for microtubule organization, nuclear movement, and neuronal migration. Cell 114: 469-482, 2003. [PubMed: 12941275] [Full Text: https://doi.org/10.1016/s0092-8674(03)00605-6]