DNA/RNA
Note
Cloning of the FAK cDNA and initial characterization of the kinase was accomplished independently by three groups in 1992 (Schaller et al., 1992; Hanks et al., 1992; Guan and Shalloway 1992). The cDNA of the human FAK homologue was first cloned by André and Becker-André (1993). The position of the human PTK2 gene encoding FAK on chromosome 8 was first predicted by Fiedorek and Kay (1995).
Transcription
Initial expression studies using reverse transcriptase PCR detected FAK mRNA in a series of lymphoid cell lines as well as HeLa and SK-N-SH neuroblastoma cells indicating ubiquitous expression. Only a lymphocyte adhesion deficient cell line tested negative for the FAK transcript (André and Becker-André 1993). Transcripts of different sizes were detected in different human tissues in the same study with differential expression patterns for these transcripts noted in brain, lung, heart, liver and placenta.
Several transcript variants encoding different FAK isoforms have been found for the PTK2 gene. The full-length nature of the following three has been determined.
(Sources: http://useast.ensembl.org/index.html; http://www.ncbi.nlm.nih.gov/pubmed/)
Several transcript variants encoding different FAK isoforms have been found for the PTK2 gene. The full-length nature of the following three has been determined.
(Sources: http://useast.ensembl.org/index.html; http://www.ncbi.nlm.nih.gov/pubmed/)
- Variant 1 differs in the 5 UTR and coding sequence compared to variant 2. The resulting isoform (a) is shorter at the N-terminus compared to isoform (b).
4414 bp - 33 exons - 1065 aa.
Ave. residue weight: 113.521.
Charge: 3.5.
Isoelectric point: 6.7311.
Molecular weight: 120899.54.
Number of residues: 1065.
- Variant 2 encodes the longest isoform (b).
4286 bp - 31 exons - 1073 aa.
Ave. residue weight: 113.366.
Charge: 2.0.
Isoelectric point: 6.6317.
Molecular weight: 121641.45.
Number of residues: 1073.
- Variant 3 differs in the 5 UTR and coding sequence, and contains two additional in-frame segments near the 3 end of the coding sequence, compared to variant 2. The resulting isoform (c) is shorter at the N-terminus and contains two additional segments in the C-terminus compared to isoform b.
Proteins
Note
Focal adhesion kinase (FAK) is a cytoplasmic non-receptor protein tyrosine kinase which was isolated for the first time by co-immunoprecipitation of tyrosine-phosphorylated proteins from cells transformed with Rous sarcoma virus v-Src (Kanner et al., 1990).
Description
Figure 1: Schematic of focal adhesion kinase domain structure with phosphorylation sites.
Expression
Ubiquitous.
Localisation
Cytoplasmic and nuclear.
Figure 2: Immunohistochemical staining of FAK in invasive cancer of the uterine cervix. (Note the accentuation of the FAK staining at the margin of the tumor nests. Size bar, 1 mm). Method and antibody: Schwock et al., 2009.
Function
FAK is characterized by a functional duality, serving as a kinase as well as a molecular scaffold. These two functions may be required independently or in concert depending on the context in which FAK-mediated signaling occurs (Sieg et al., 1999; Sieg et al., 2000). FAK regulates the dynamic of focal adhesion complexes which are sites of attachment between cells and extracellular matrix. Cyclic assembly and disassembly of these complexes at the leading and trailing edge of the cell is required for the migration of mesenchymal cells and those that adopt mesenchymal-like characteristics as a consequence of developmental processes or during disease states. The latter mainly encompasses forms of tissue repair (i.e. wound healing and fibrosis) as well as neoplasia (i.e. tumor invasion and metastasis). As an example, Figure 2 shows immunohistochemical staining for FAK in metastatic cancer of the uterine cervix. FAK has been implicated with the establishment of a front-back polarity (Tilghman et al., 2005), lamellipodial persistence at the leading edge (Owen et al., 2007) and release of adhesions at the trailing edge (Iwanicki et al., 2008).
Integrin engagement with the extracellular matrix results in integrin clustering and a sequence of inter- and intramolecular events that permit the autophosphorylation of FAK at Tyr397 (Dunty et al., 2004). Subsequent recruitment of Src-family kinases through SH2-domain binding is followed by a mutual activation of both kinases. In the case of FAK this further activation is accomplished by phosphorylation of other tyrosine residues, specifically Tyr407, 576, 577, 861 and 925. Phosphorylation of Tyr576 and 577 increases FAK kinase activity whereas the remaining tyrosine residues serve as docking sites for SH2-containing factors such as Grb2 which links FAK into the MAPK pathway. Tyr397 also constitutes a docking site for the p85 subunit of PI3K (Chen and Guan, 1994) and phospholipase C gamma (Zhang et al., 1999). The PRRs are sites of interaction with SH3-containing factors which transmit signals downstream of the kinase and regulate the activity of Rho-family GTPases in charge of cell motility through the formation of stress fibres (RhoA), lamellipodia (Rac) and filopodia (Cdc42). Crk-associated substrate (p130Cas), initially identified in a two-hybrid screen, is one of the main downstream factors that bind to the PRRs of FAK (Polte and Hanks, 1995). Signaling via p130Cas towards Crk, DOCK180 and Rac has been linked to membrane ruffling, lamellipodia formation and cell motility (Harte et al., 1996; Cho and Klemke, 2002). A second essential downstream target of FAK is paxillin (Bellis et al., 1995), an adaptor protein lacking intrinsic kinase activity which can be phosphorylated at two sites, Tyr31 and Tyr118, and binds FAK within the C-terminal focal adhesion targeting (FAT) region (Hayashi et al., 2002). Mutations in FAK that disrupt binding to paxillin affect the localization of the kinase to focal contacts. Paxillin may also be involved in regulation of MAPK downstream signaling due to an overlapping binding site with Grb2 which binds to Tyr925 within the FAT region (Liu et al., 2002).
More recent studies link FAK to the regulation of cell-cell contacts, microtubule stability and control of gene transcription. Conflicting results have been reported from different experimental systems implicating FAK either with the dissolution (Avizienyte et al., 2002; Cicchini et al., 2008) or the promotion (Yano et al., 2004; Playford et al., 2008) of cell-cell contacts which suggests a dependency of this feature on the specific cellular context. Ezratty et al. (2005) reported on the role of FAK, Grb2 and dynamin in microtubule-induced focal adhesion disassembly. Earlier studies demonstrated an integrin-mediated activation of FAK at the leading edge of migrating cells as requirement for microtubule stabilization mediated by Rho and mDia (Palazzo et al., 2004). This mechanism also involves localization of a lipid raft marker, ganglioside GM1, to the leading edge. Xie et al. (2003) showed that Cdk5-mediated serine-phosphorylation of FAK was linked to the localization of the kinase at microtubule fork structures which contribute to nuclear repositioning in migrating neuronal cells. Recently, serine-phosphorylated FAK was shown to co-localize with centrosomes in mitotic endothelial cells. In this study by Park et al. (2009), FAK was also found associated with cytoplasmic dynein, and deletion of FAK resulted in mitotic defects. In 2005, Golubovskaya et al. reported results indicating a physical interaction between the N-terminal fragment of FAK and the N-terminal transactivation domain of p53. This interaction led to suppression of p53-mediated apoptosis and inhibition of the transcriptional activity of p53. Lim et al. (2008) subsequently provided data demonstrating a scaffolding role of nuclear FAK for MDM2-mediated p53 degradation mediated by the different lobes of the FERM domain. Also, basic sequences in the F2 lobe of the FERM domain were implicated in the nuclear localization of FAK (Lim et al., 2008), but alternative mechanisms independent from this putative nuclear localization signal are thought to exist (Schaller, 2010). Another nuclear function was recently uncovered by Luo et al. (2009) who described a role of FAK in chromatin remodelling via its interaction with MBD2 leading to increased myogenin expression and muscle-terminal differentiation. Liu et al. (2004), Li et al. (2004) and Ren et al. (2004) reported an involvement of FAK in netrin-1 signaling downstream of the netrin receptor DCC with consequences for axonal outgrowth and guidance in the developing brain.
- Mouse Models
Several mouse models have been generated to elucidate the functions of FAK both during normal development and neoplasia. A role of FAK in embryonal development was first observed in fak-/- mice which displayed defects in mesoderm development and anterior-posterior axis formation with embryonic lethality around day E8.5 (Ilic et al., 1995).
A conditional knockout model using a Cre-loxP system with Cre recombinase under the control of the nkx2-5 promoter was generated by Hakim et al. (2007). The major abnormality reported from this study was a profound disturbance of the development of the cardiac outflow tract. Knockout mice from this study died shortly after birth and displayed a range of cardiac defects which resemble the human congenital heart defects Tetralogy of Fallot and persistent truncus arteriosus. Peng et al. (2006) and DiMichele et al. (2006) reported results obtained with conditional knockout mice which carried Cre-recombinase under the control of the myosin light chain 2v promoter. Peng et al. (2006) found that knockout mice developed eccentric cardiac hypertrophy upon stimulation with angiotensin II or pressure overload. In contrast, the results by DiMichele et al. (2006) suggest that FAK functions to promote cardiac hypertrophy. In a later study by Peng at al. (2008) with myosin light chain-2a Cre mice they observed cardiac developmental abnormalities with thin ventricular walls and ventricular septal defects in the knockout mice, the majority of which died in the embryonic stage. Endothelial cell-specific knockout of FAK, again using a Cre-loxP approach, has been reported by Shen et al. (2005) and Braren et al. (2006). The observed phenotypes in knockout mice from both studies strongly suggest a role of FAK in vascular morphogenesis, particularly vascular remodelling and sprouting angiogenesis. The roles of FAK in the cardiovascular system were reviewed by Vadali et al. (2007).
A series of mouse models suggest an essential role of FAK during the development of the central nervous system. Beggs et al. (2003) created dorsal forebrain-specific conditional knockout mice using the Cre/loxP approach and observed an essential function of FAK for the formation of a normal basal lamina at the interface between radial glial end-feet and meningeal fibroblasts. They noted that the cortical changes seen in their study resembled lissencephaly phenotypes seen in some forms of human congenital muscular dystrophy.
Van Miltenburg et al. (2009) investigated the role of FAK in normal mammary gland using a conditional FAK-knockout mammary epithelial cell transplantation model based on FAK(lox/lox)/Rosa26Cre-ERT2 donor mice with loss of FAK in all mammary cells. They observed an abnormal mammary duct development with a disruption of myoepithelial and luminal epithelial cell layer and aberrant ductal morphogenesis during pregnancy.
Comprehensive reviews focused on the cellular functions of FAK have been published by Mitra et al. (2005) and Schaller (2010). Figure 3 schematically summarizes some of the diverse cellular functions of FAK.
- Regulation
The level of FAK expression is negatively and positively regulated by several transcription factors including p53, NF-kB and N-Myc (Golubovskaya et al., 2004; Beierle et al., 2007). Aside from the tyrosine residues implicated with FAK activation, at least four different serine phosphorylation sites (Ser722, 840, 843 and 910) have been recognized within FAK. Although the function of these serine sites has been examined less comprehensively, their phosphorylation has generally been associated with FAK inactivation, such as during mitosis (Ma et al., 2001), in suspension and under conditions that disturb the integrity of the actin cytoskeleton (Jacamo et al., 2007). FAK signaling is subject to additional levels of regulation which involve proteolytic cleavage (Dourdin et al., 2001), sumoylation (Kadaré et al., 2003), inhibition by FAK family interacting protein of 200 kDa (FIP200) (Abbi et al., 2002), dephosphorylation by protein-tyrosine phosphatases (Zeng et al., 2003), and generation of alternatively spliced isoforms such as FAK-related non-kinase (FRNK) (Schaller et al., 1993).
- Other protein family members: Pyk2.
Integrin engagement with the extracellular matrix results in integrin clustering and a sequence of inter- and intramolecular events that permit the autophosphorylation of FAK at Tyr397 (Dunty et al., 2004). Subsequent recruitment of Src-family kinases through SH2-domain binding is followed by a mutual activation of both kinases. In the case of FAK this further activation is accomplished by phosphorylation of other tyrosine residues, specifically Tyr407, 576, 577, 861 and 925. Phosphorylation of Tyr576 and 577 increases FAK kinase activity whereas the remaining tyrosine residues serve as docking sites for SH2-containing factors such as Grb2 which links FAK into the MAPK pathway. Tyr397 also constitutes a docking site for the p85 subunit of PI3K (Chen and Guan, 1994) and phospholipase C gamma (Zhang et al., 1999). The PRRs are sites of interaction with SH3-containing factors which transmit signals downstream of the kinase and regulate the activity of Rho-family GTPases in charge of cell motility through the formation of stress fibres (RhoA), lamellipodia (Rac) and filopodia (Cdc42). Crk-associated substrate (p130Cas), initially identified in a two-hybrid screen, is one of the main downstream factors that bind to the PRRs of FAK (Polte and Hanks, 1995). Signaling via p130Cas towards Crk, DOCK180 and Rac has been linked to membrane ruffling, lamellipodia formation and cell motility (Harte et al., 1996; Cho and Klemke, 2002). A second essential downstream target of FAK is paxillin (Bellis et al., 1995), an adaptor protein lacking intrinsic kinase activity which can be phosphorylated at two sites, Tyr31 and Tyr118, and binds FAK within the C-terminal focal adhesion targeting (FAT) region (Hayashi et al., 2002). Mutations in FAK that disrupt binding to paxillin affect the localization of the kinase to focal contacts. Paxillin may also be involved in regulation of MAPK downstream signaling due to an overlapping binding site with Grb2 which binds to Tyr925 within the FAT region (Liu et al., 2002).
More recent studies link FAK to the regulation of cell-cell contacts, microtubule stability and control of gene transcription. Conflicting results have been reported from different experimental systems implicating FAK either with the dissolution (Avizienyte et al., 2002; Cicchini et al., 2008) or the promotion (Yano et al., 2004; Playford et al., 2008) of cell-cell contacts which suggests a dependency of this feature on the specific cellular context. Ezratty et al. (2005) reported on the role of FAK, Grb2 and dynamin in microtubule-induced focal adhesion disassembly. Earlier studies demonstrated an integrin-mediated activation of FAK at the leading edge of migrating cells as requirement for microtubule stabilization mediated by Rho and mDia (Palazzo et al., 2004). This mechanism also involves localization of a lipid raft marker, ganglioside GM1, to the leading edge. Xie et al. (2003) showed that Cdk5-mediated serine-phosphorylation of FAK was linked to the localization of the kinase at microtubule fork structures which contribute to nuclear repositioning in migrating neuronal cells. Recently, serine-phosphorylated FAK was shown to co-localize with centrosomes in mitotic endothelial cells. In this study by Park et al. (2009), FAK was also found associated with cytoplasmic dynein, and deletion of FAK resulted in mitotic defects. In 2005, Golubovskaya et al. reported results indicating a physical interaction between the N-terminal fragment of FAK and the N-terminal transactivation domain of p53. This interaction led to suppression of p53-mediated apoptosis and inhibition of the transcriptional activity of p53. Lim et al. (2008) subsequently provided data demonstrating a scaffolding role of nuclear FAK for MDM2-mediated p53 degradation mediated by the different lobes of the FERM domain. Also, basic sequences in the F2 lobe of the FERM domain were implicated in the nuclear localization of FAK (Lim et al., 2008), but alternative mechanisms independent from this putative nuclear localization signal are thought to exist (Schaller, 2010). Another nuclear function was recently uncovered by Luo et al. (2009) who described a role of FAK in chromatin remodelling via its interaction with MBD2 leading to increased myogenin expression and muscle-terminal differentiation. Liu et al. (2004), Li et al. (2004) and Ren et al. (2004) reported an involvement of FAK in netrin-1 signaling downstream of the netrin receptor DCC with consequences for axonal outgrowth and guidance in the developing brain.
- Mouse Models
Several mouse models have been generated to elucidate the functions of FAK both during normal development and neoplasia. A role of FAK in embryonal development was first observed in fak-/- mice which displayed defects in mesoderm development and anterior-posterior axis formation with embryonic lethality around day E8.5 (Ilic et al., 1995).
A conditional knockout model using a Cre-loxP system with Cre recombinase under the control of the nkx2-5 promoter was generated by Hakim et al. (2007). The major abnormality reported from this study was a profound disturbance of the development of the cardiac outflow tract. Knockout mice from this study died shortly after birth and displayed a range of cardiac defects which resemble the human congenital heart defects Tetralogy of Fallot and persistent truncus arteriosus. Peng et al. (2006) and DiMichele et al. (2006) reported results obtained with conditional knockout mice which carried Cre-recombinase under the control of the myosin light chain 2v promoter. Peng et al. (2006) found that knockout mice developed eccentric cardiac hypertrophy upon stimulation with angiotensin II or pressure overload. In contrast, the results by DiMichele et al. (2006) suggest that FAK functions to promote cardiac hypertrophy. In a later study by Peng at al. (2008) with myosin light chain-2a Cre mice they observed cardiac developmental abnormalities with thin ventricular walls and ventricular septal defects in the knockout mice, the majority of which died in the embryonic stage. Endothelial cell-specific knockout of FAK, again using a Cre-loxP approach, has been reported by Shen et al. (2005) and Braren et al. (2006). The observed phenotypes in knockout mice from both studies strongly suggest a role of FAK in vascular morphogenesis, particularly vascular remodelling and sprouting angiogenesis. The roles of FAK in the cardiovascular system were reviewed by Vadali et al. (2007).
A series of mouse models suggest an essential role of FAK during the development of the central nervous system. Beggs et al. (2003) created dorsal forebrain-specific conditional knockout mice using the Cre/loxP approach and observed an essential function of FAK for the formation of a normal basal lamina at the interface between radial glial end-feet and meningeal fibroblasts. They noted that the cortical changes seen in their study resembled lissencephaly phenotypes seen in some forms of human congenital muscular dystrophy.
Van Miltenburg et al. (2009) investigated the role of FAK in normal mammary gland using a conditional FAK-knockout mammary epithelial cell transplantation model based on FAK(lox/lox)/Rosa26Cre-ERT2 donor mice with loss of FAK in all mammary cells. They observed an abnormal mammary duct development with a disruption of myoepithelial and luminal epithelial cell layer and aberrant ductal morphogenesis during pregnancy.
Comprehensive reviews focused on the cellular functions of FAK have been published by Mitra et al. (2005) and Schaller (2010). Figure 3 schematically summarizes some of the diverse cellular functions of FAK.
- Regulation
The level of FAK expression is negatively and positively regulated by several transcription factors including p53, NF-kB and N-Myc (Golubovskaya et al., 2004; Beierle et al., 2007). Aside from the tyrosine residues implicated with FAK activation, at least four different serine phosphorylation sites (Ser722, 840, 843 and 910) have been recognized within FAK. Although the function of these serine sites has been examined less comprehensively, their phosphorylation has generally been associated with FAK inactivation, such as during mitosis (Ma et al., 2001), in suspension and under conditions that disturb the integrity of the actin cytoskeleton (Jacamo et al., 2007). FAK signaling is subject to additional levels of regulation which involve proteolytic cleavage (Dourdin et al., 2001), sumoylation (Kadaré et al., 2003), inhibition by FAK family interacting protein of 200 kDa (FIP200) (Abbi et al., 2002), dephosphorylation by protein-tyrosine phosphatases (Zeng et al., 2003), and generation of alternatively spliced isoforms such as FAK-related non-kinase (FRNK) (Schaller et al., 1993).
- Other protein family members: Pyk2.
Figure 3: Schematic of the Cellular Functions of FAK.
Homology
| Homo sapiens PTK2 | % Identity for | Protein | DNA |
| vs. Pan troglodytes PTK2 | 99.8 | 99.7 | |
| vs. Canis lupus familiaris PTK2 | 97.0 | 91.7 | |
| vs. Mus musculus Ptk2 | 97.2 | 90.7 | |
| vs. Rattus norvegicus Ptk2 | 97.0 | 90.8 | |
| vs. Gallus gallus PTK2 | 94.9 | 83.9 | |
| vs. Danio rerio ptk2.1 | 83.2 | 74.2 | |
| vs. Drosophila melanogaster Fak56D | 42.9 | 48.9 | |
| vs. Caenorhabditis elegans kin-32 | 36.5 | 47.8 |
Implicated in
Entity name
Neoplasia
Note
Increased expression of FAK was first noticed in high-grade and metastatic sarcomas (Weiner et al., 1994) and later in pre-invasive as well as invasive epithelial neoplasms (Owens et al., 1995). In general, lower levels of FAK expression are found in normal tissues whereas the higher levels are present in metastatic cancer suggesting an involvement of the kinase in oncogenesis. In neoplastic conditions the kinase has been credited with a range of functions including tumor cell motility (Sieg et al., 1999), matrix degradation leading to distant spread (Hauck et al., 2002), suppression of apoptosis (Sonoda et al., 2000), anoikis (Frisch et al., 1996) and senescence (Pylayeva et al., 2009) as well as positive effects on angiogenesis (Mitra et al., 2006), vasculogenic mimicry (Hess et al., 2005) and hypoxia response (Skuli et al., 2009). Results from a Cre/loxP-mediated FAK-knockout model specific to mouse mammary epithelial cells revealed a reduced pool of cancer stem/progenitor cells after FAK deletion which suggests that the kinase may not only support tumor cell dissemination to distant sites, but also the colonization of the target organ and establishment of a new tumor mass (Luo et al., 2009). Other transgenic mouse models focused on the role of FAK in neoplasia have been reported by McLean et al. (2004) for skin and by Lahlou et al. (2007), Provenzano et al. (2008) and Pylayeva et al. (2009) for mammary tumor formation and progression.
Entity name
Nervous system
Note
The role of FAK in glioma tumor progression and in the regulation of the permeability of tumor-associated vasculature has been described, as well as the therapeutic efficacy of FAK inhibition by both pharmacologic compounds and liposomal-mediated RNA interference (Shi et al., 2007; Lipinski et al., 2008; Lee et al., 2010; Wang et al., 2011). Immunohistochemical analysis of 96 patient biopsies demonstrated higher levels of total and phosphorylated FAK in high grade tumors which correlated with inferior patient survival (Ding et al., 2010).
Beierle et al. (2007) reported on the relevance of FAK as cellular survival factor in N-myc-amplified neuroblastoma and identified N-myc binding sites in the FAK promoter. Recently, the same group also provided data indicating greater in vivo-therapeutic efficacy of pharmacologic FAK inhibition in N-myc-positive model systems (Beierle et al., 2010a; Beierle et al., 2010b). Efficacy of a novel small molecule dual IGF1R/FAK tyrosine kinase inhibitor (TAE226) leading to decreased FAK phosphorylation and cellular viability, cell cycle arrest and apoptosis has been described in human neuroblastoma cell lines (Beierle et al., 2008b). FAK expression was demonstrated in 51 of 70 clinical neuroblastoma samples by immunohistochemistry. FAK protein levels correlated with mRNA transcript levels and with advanced disease stage in this study (Beierle et al., 2008a).
Beierle et al. (2007) reported on the relevance of FAK as cellular survival factor in N-myc-amplified neuroblastoma and identified N-myc binding sites in the FAK promoter. Recently, the same group also provided data indicating greater in vivo-therapeutic efficacy of pharmacologic FAK inhibition in N-myc-positive model systems (Beierle et al., 2010a; Beierle et al., 2010b). Efficacy of a novel small molecule dual IGF1R/FAK tyrosine kinase inhibitor (TAE226) leading to decreased FAK phosphorylation and cellular viability, cell cycle arrest and apoptosis has been described in human neuroblastoma cell lines (Beierle et al., 2008b). FAK expression was demonstrated in 51 of 70 clinical neuroblastoma samples by immunohistochemistry. FAK protein levels correlated with mRNA transcript levels and with advanced disease stage in this study (Beierle et al., 2008a).
Entity name
Head and neck squamous cell carcinoma
Note
FAK has been linked to invasion in squamous cell carcinoma of the head and neck through promotion of cell motility and MMP-2 production (Canel et al., 2008). FAK gene and protein expression were previously evaluated in 211 clinical samples which included tissue from cases of dysplasia and benign hyperplasia (Canel et al., 2006). In this study, 62% of the primary cancers had high FAK protein expression, and the levels were consistent with those seen in corresponding lymph node metastases. A recent preclinial study has implicated FAK phosphorylation levels with radioresistance (Hehlgans et al., 2009).
Entity name
Thyroid carcinoma
Note
Immunohistochemical staining of 108 patient samples for FAK protein discriminated malignant from benign thyroid lesions. FAK levels correlated with tumor size and capsular/lymphatic invasion (Michailidi et al., 2010). Previously, Kim et al. (2004) reported FAK expression in follicular, papillary, medullary and anaplastic thyroid carcinomas. FAK was not expressed in normal thyroid tissue and nodular hyperplasia, but in some of the follicular adenomas included in their study.
Entity name
Breast cancer
Note
Lahlou et al. (2007) reported a block in tumor progression in a transgenic mouse model of breast cancer with disrupted FAK function based on Cre/loxP recombination. An earlier immunohistochemical study on clinical breast tissue showed increased FAK expression in ductal carcinoma in situ compared to atypical ductal hyperplasia and invasive ductal carcinoma (Lightfoot et al., 2004). The authors of this study concluded that FAK overexpression precedes tumor cell invasion and metastasis. Subsequently, a study by Lark et al. (2005) in 629 breast cancer samples correlated high FAK protein expression with poor prognostic indicators such as high mitotic index and nuclear grade, negative hormone receptor status, and Her2/neu over-expression. Schmitz et al. (2005) provided further evidence to support Her2/neu downstream signaling through FAK/Src-mediated pathways. Recently, a positive correlation between FAK over-expression and p53 mutation status has been reported (Golubovskaya et al., 2008; Golubovskaya et al., 2009). Yom et al. (2010) evaluated 435 cases of invasive ductal cancer for FAK gene copy number by fluorescence in situ hybridization (FISH) and FAK protein expression by immunohistochemistry, both of which correlated with features of aggressive tumor biology. Concordance between FISH and immunohistochemistry results was observed in 74.9%. An increased gene copy number by FISH correlated significantly with inferior patient outcome in this study.
Entity name
Lung cancer
Note
Array comparative genomic hybridization studies on clinical samples of small cell lung cancer demonstrated regions of copy number alternations (gains and losses) enriched for genes involved in focal adhesion signaling. This included gains of FAK copy number which was confirmed in a smaller subset of the original 46 cases by FISH and quantitative RT-PCR. FAK was also highly expressed in tumor tissue (90% of 52 samples) in comparison with normal lung samples (Ocak et al., 2010). Wang et al. (2009) reported results of their study focused on FAK expression in bronchio-alveolar carcinoma (BAC) and lung adenocarcinomas. They found that in lung adenocarcinoma overall survival was better for patients with FAK-negative compared with FAK-positive tumors. A study by Hiratsuka et al. (2011) implicated endothelial FAK and E-selectin with the formation of lung metastasis from distant primary tumors due to the formation of discrete foci of vascular hyper-permeability important for the initial homing of metastatic cancer cells to the lungs.
Entity name
Gastro-intestinal tract cancer
Note
Giaginis et al. (2009) reported results of an immunohistochemical study performed on the two major subtypes of gastric adenocarcinoma, including 30 cases of intestinal- and 36 cases of diffuse-type. Although FAK staining in diffuse-type gastric cancer correlated with larger tumor size and advanced disease stage, it also correlated with longer overall survival. For intestinal type cancer, however, an association with increased proliferative capacity and a non-significant trend to inferior survival was reported. A retrospective study including 444 surgical samples demonstrated a positive correlation between FAK gene amplification and protein expression levels with tumor size, lymphovascular invasion and nodal/distant metastases (Park et al., 2010). Focal adhesion kinase protein expression and gene amplification were positively correlated with each other in this study, and each of them was found to be an independent poor prognostic factor.
FAK has been implicated in invasion and metastasis as well as chemoresistance in pancreatic cancer (Duxbury et al., 2003; Duxbury et al., 2004). FAK overexpression by immunohistochemistry, demonstrated in 24 of 50 (48%) patient samples, correlated with tumor size, but no other features including grade, lymph node involvement or metastasis in a study by Furuyama et al. (2006). Another study included an examination of both FAK and Src protein levels. FAK expression correlated significantly with tumor stage while Src expression correlated with both tumor stage and patient survival, and was identified as an independent prognostic factor by multivariate analysis (Chatzizacharias et al., 2010).
Hayashi et al. (2010) demonstrated high levels of cytoplasmic FAK expression in normal biliary epithelium and observed a gradual loss of staining from dysplasia to extra-hepatic bile duct carcinoma. In this study, positive FAK staining was associated with a significantly better survival. Increased levels of FAK mRNA and protein have also been observed in a study of 60 patients with hepatocellular cancers. Increased mRNA levels correlated with tumor size, serum AFP and inferior disease-free and overall survival (Fujii et al., 2004).
RNA interference studies in colorectal cancer cell line xenografts demonstrated that FAK inhibition resulted in inhibition of cell proliferation and angiogenesis, induction of apoptosis and tumor growth suppression (Lei et al., 2010). Elevated levels of FAK mRNA and protein were noted in a small cohort of 34 matched primary colon cancers and liver metastases (Lark et al., 2003). More recently a larger series of colorectal cancers with matched liver metastases was used to evaluate the correlation of FAK staining with clinical outcome. In this study, FAK staining was equivalent in primary and metastatic lesions, and elevated levels of FAK and Src were associated with a reduced time to recurrence (de Heer et al., 2008).
FAK has been implicated in invasion and metastasis as well as chemoresistance in pancreatic cancer (Duxbury et al., 2003; Duxbury et al., 2004). FAK overexpression by immunohistochemistry, demonstrated in 24 of 50 (48%) patient samples, correlated with tumor size, but no other features including grade, lymph node involvement or metastasis in a study by Furuyama et al. (2006). Another study included an examination of both FAK and Src protein levels. FAK expression correlated significantly with tumor stage while Src expression correlated with both tumor stage and patient survival, and was identified as an independent prognostic factor by multivariate analysis (Chatzizacharias et al., 2010).
Hayashi et al. (2010) demonstrated high levels of cytoplasmic FAK expression in normal biliary epithelium and observed a gradual loss of staining from dysplasia to extra-hepatic bile duct carcinoma. In this study, positive FAK staining was associated with a significantly better survival. Increased levels of FAK mRNA and protein have also been observed in a study of 60 patients with hepatocellular cancers. Increased mRNA levels correlated with tumor size, serum AFP and inferior disease-free and overall survival (Fujii et al., 2004).
RNA interference studies in colorectal cancer cell line xenografts demonstrated that FAK inhibition resulted in inhibition of cell proliferation and angiogenesis, induction of apoptosis and tumor growth suppression (Lei et al., 2010). Elevated levels of FAK mRNA and protein were noted in a small cohort of 34 matched primary colon cancers and liver metastases (Lark et al., 2003). More recently a larger series of colorectal cancers with matched liver metastases was used to evaluate the correlation of FAK staining with clinical outcome. In this study, FAK staining was equivalent in primary and metastatic lesions, and elevated levels of FAK and Src were associated with a reduced time to recurrence (de Heer et al., 2008).
Entity name
Female genital tract cancer
Note
FAK has been implicated in the invasive and metastatic phenotype of ovarian cancer through multiple pathways (Hu et al., 2008; Yagi et al., 2008). In one report, MUC4-induced epithelial-mesenchymal transition was partially mediated by FAK, and pharmacologic FAK inhibition successfully abrogated MUC4-induced cell motility (Ponnusamy et al., 2010). In another study, cooperative signaling of c-met and alpha5beta1 integrin through FAK/Src was associated with promotion of invasion and metastases (Mitra et al., 2010). FAK activation also appears to be relevant to the development of resistance to standard cytotoxics (Halder et al., 2005; Villedieu et al., 2006) and preclinical studies have demonstrated therapeutic efficacy of various methods of FAK inhibition including pharmacologic inhibition and RNA interference (Halder et al., 2006; Halder et al., 2007; Yang et al., 2007). Sood et al. (2010) recently described protection from anoikis by catecholamine signaling mediated by FAK. They concluded that these results support a role for FAK signaling in the stress-mediated promotion of aggressive tumor biology. They also demonstrated increased levels of FAK and phosphorylated FAK in greater than 50% of the examined tumors, both of which correlated with inferior patient survival. Two earlier studies documented up-regulation of FAK protein and phosphorylated FAK in invasive ovarian cancers in comparison with normal epithelium (Sood et al., 2004; Grisaru-Granovsky et al., 2005). Sood et al. (2004) also noted associations between FAK immunohistochemical staining and more advanced tumor stage, tumor grade, metastasis and inferior overall survival.
Immunohistochemical analysis of 134 cases of endometrial cancer demonstrated moderate to strong staining in the majority (89%) of cases. Weak FAK staining was noted in the remaining 11% and associated with a trend to improved survival. Increased FAK staining, however, correlated with measures of poor outcome including tumor grade, lymphovascular invasion and lymph node metastases (Gabriel et al., 2009). A different study demonstrated high levels of FAK expression in endometrial cancers of different histologies (endometrioid, serous and clear cell) as well as in regions of endometrial hyperplasia. The authors concluded that their data implicate FAK in endometrial carcinogenesis (Livasy et al., 2004).
An analysis of 166 surgical samples demonstrated cytoplasmic and membranous FAK staining in regions of cervical dysplasia and frankly invasive cancer of the uterine cervix with absent staining in adjacent normal cervical epithelium (Gabriel et al., 2006). One third of the patients, with tumors exhibiting weak FAK staining, had an inferior survival compared to those with moderate/strong FAK staining, and weak FAK staining correlated with lymph node positivity in this study. Oktay et al. (2003) demonstrated positive FAK staining in premalignant lesions. Similarly, Schwock et al. (2009) demonstrated an increase in FAK expression and concurrent decrease of E-cadherin in metastatic cervical cancer and carcinoma in-situ compared to normal cervical epithelium. An association between E-cadherin loss and FAK was also noted in an earlier study that included 26 carcinomas and 5 carcinoma in situ cases (Moon et al., 2003). Although FAK protein expression remained constant in this study, elevated levels of phosphorylated FAK were found in carcinoma samples.
Immunohistochemical analysis of 134 cases of endometrial cancer demonstrated moderate to strong staining in the majority (89%) of cases. Weak FAK staining was noted in the remaining 11% and associated with a trend to improved survival. Increased FAK staining, however, correlated with measures of poor outcome including tumor grade, lymphovascular invasion and lymph node metastases (Gabriel et al., 2009). A different study demonstrated high levels of FAK expression in endometrial cancers of different histologies (endometrioid, serous and clear cell) as well as in regions of endometrial hyperplasia. The authors concluded that their data implicate FAK in endometrial carcinogenesis (Livasy et al., 2004).
An analysis of 166 surgical samples demonstrated cytoplasmic and membranous FAK staining in regions of cervical dysplasia and frankly invasive cancer of the uterine cervix with absent staining in adjacent normal cervical epithelium (Gabriel et al., 2006). One third of the patients, with tumors exhibiting weak FAK staining, had an inferior survival compared to those with moderate/strong FAK staining, and weak FAK staining correlated with lymph node positivity in this study. Oktay et al. (2003) demonstrated positive FAK staining in premalignant lesions. Similarly, Schwock et al. (2009) demonstrated an increase in FAK expression and concurrent decrease of E-cadherin in metastatic cervical cancer and carcinoma in-situ compared to normal cervical epithelium. An association between E-cadherin loss and FAK was also noted in an earlier study that included 26 carcinomas and 5 carcinoma in situ cases (Moon et al., 2003). Although FAK protein expression remained constant in this study, elevated levels of phosphorylated FAK were found in carcinoma samples.
Entity name
Male genital tract cancer
Note
FAK has been linked with aggressive tumor behavior in models of androgen-independent prostate cancer (Johnson et al., 2008). An early study comparing normal and hyperplastic prostatic tissue with localized and advanced prostate cancers demonstrated increased levels of total and activated FAK in more advanced disease (Tremblay et al., 1996). Association of FAK with paxillin and p50csk was noted in cases of metastatic cancer. Rovin et al. (2002) described increased FAK expression in pre-malignant lesions that was maintained at different stages of tumor progression. A study by Zheng et al. (1999) proposed that the migratory behavior of prostate cancer cells is related to the de novo expression of alphaVbeta3 integrin with signaling through FAK.
Entity name
Genito-urinary tract cancer
Note
Increased levels of FAK and paxillin mRNA transcript have been noted in metastasizing renal carcinoma cell lines in comparison with normal renal cortex epithelial cells (Jenq et al., 1996). FAK/Src signaling was also demonstrated to be relevant to the aggressive behavior of bladder carcinoma cells in vitro, and inhibition of the phosphatase HD-PTP resulted in an enhanced FAK phosphorylation and increased cell motility (Mariotti et al., 2009).
Entity name
Skin cancer
Note
Preclinical studies have implicated FAK with the promotion of an aggressive melanoma phenotype through its effects on invasion and migration (Hess et al., 2005; Hess and Hendrix 2006; Smit et al., 2007; Kaneda et al., 2008; Sun et al., 2009). FAK also has importance early in the metastatic dissemination of melanoma cells (Abdel-Ghany et al., 2002). A study by Smith et al. (2005) demonstrated that downregulation of FAK by antisense oligonucleotide sensitizes melanoma cells to 5-fluorouracil treatment. A preliminary clinical report suggests that FAK may function as a universal tumor-associated antigen that could be exploited for cancer immunotherapy including melanoma (Kobayashi et al., 2009). A recent study by Trimmer et al. (2010) reported reduced levels of caveolin-1 in clinical metastases of melanoma as well as in highly metastatic melanoma cell lines. They demonstrated that caveolin-1 expression in B16F10 melanoma cells promotes cell proliferation while suppressing invasion and migration via FAK/Src.
McLean et al. (2004) demonstrated a role for FAK in the malignant progression from papilloma to squamous cell carcinoma in a transgenic mouse model combined with chemical carcinogenesis. No effect of the FAK deletion was noted on wound re-epithelialization.
McLean et al. (2004) demonstrated a role for FAK in the malignant progression from papilloma to squamous cell carcinoma in a transgenic mouse model combined with chemical carcinogenesis. No effect of the FAK deletion was noted on wound re-epithelialization.
Entity name
Soft tissues, bone and hemato-lymphoid tissues
Note
Yui et al. (2010) developed a highly metastatic osteosarcoma cell line through in vivo selection which, in comparison with the parental line, demonstrated higher levels of activated FAK and cdc42. Hanada et al. (2005) showed localization of phosphorylated FAK at the infiltrative edge in a three dimensional culture model using invasive murine fibrosarcoma cells. In the same study, expression of FAK-related non-kinase (FRNK) inhibited experimental metastases in syngenic mice without significant effects on primary tumor growth. In a study on bone metastasis, the dual FAK/Pyk2 inhibitor PF-271 suppressed the growth of experimental intra-tibial tumors in rats and restored tumor-induced bone loss (Bagi et al., 2008).
Immunohistochemical analysis of normal and neoplastic hemato-lymphoid tissues demonstrated FAK staining in B cells of the germinal center, marginal and mantle zones (Ozkal et al., 2009). Corresponding staining was present in most B-cell lymphomas while T-cell lymphomas were predominantly negative. Neoplastic cells of classical Hodgkins lymphoma were negative for FAK while those of lymphocyte-predominant Hodgkins lymphoma were positive in the same study.
A study of 60 primary acute myeloid leukemia samples demonstrated FAK transcript and protein expression in 48% cases and Pyk2 expression in 81% cases (Recher et al., 2004). FAK-positive acute myeloid leukemia cells displayed a higher migratory efficiency and lower sensitivity to chemotherapy. FAK expression positively correlated with white blood count at diagnosis, death rate and median survival.
Immunohistochemical analysis of normal and neoplastic hemato-lymphoid tissues demonstrated FAK staining in B cells of the germinal center, marginal and mantle zones (Ozkal et al., 2009). Corresponding staining was present in most B-cell lymphomas while T-cell lymphomas were predominantly negative. Neoplastic cells of classical Hodgkins lymphoma were negative for FAK while those of lymphocyte-predominant Hodgkins lymphoma were positive in the same study.
A study of 60 primary acute myeloid leukemia samples demonstrated FAK transcript and protein expression in 48% cases and Pyk2 expression in 81% cases (Recher et al., 2004). FAK-positive acute myeloid leukemia cells displayed a higher migratory efficiency and lower sensitivity to chemotherapy. FAK expression positively correlated with white blood count at diagnosis, death rate and median survival.
Entity name
Non-neoplastic disorders
Note
Shahrara et al. (2007) reported on the elevated expression of phosphorylated FAK, Pyk2 and other signaling molecules, in synovial tissues of patients with rheumatoid or osteoarthritis. They postulated that FAK signaling may be important for the recruitment of inflammatory cells into susceptible joints and required to promote the disease process.
Chen et al. (2001) found that keratinocytes from patients with psoriasis have elevated levels of phosphorylated FAK and concluded that integrin/FAK signaling contributes to a pre-activation of uninvolved keratinocytes that predisposes to the development of psoriatic plaques in response to certain stimuli.
FAK has a role in the development of the cardiovascular system since FAK-null mice are embryonically lethal with phenotypic abnormalities approximating those seen in human congenital heart defects (Vadali et al., 2007). FAK also appears to be involved cardiac hypertrophy and heart failure through its involvement in the cardiac response to biochemical stress and hypertrophic agonists. The relevance of FAK to cardiac physiology likely differs with the cellular context. Although FAK activation has been suggested to accelerate function deterioration of an overloaded heart, selective FAK deletion in cardiomyoctes has also been associated with maladaptive cardiac remodeling (Franchini et al., 2009).
FAK appears to be essential for normal glucose transport and glycogen synthesis due to cross talk between integrin and insulin signaling pathways (Huang et al., 2002; Huang et al., 2006). FAK has also been implicated in hyperglycemia-related vascular complications in Diabetes mellitus (Mori et al., 2002). Two independent studies reported on increased levels of activated FAK in the glomeruli from diabetic rats that could be abrogated by insulin treatment (Clark et al., 1995; Shikano et al., 1996).
FAK signaling has been implicated with non-neoplastic renal disease. Holzapfel et al. (2007) documented a role for FAK during restoration of tubular integrity in renal ischemia and reperfusion, and an earlier study by Morino et al. (1999) indicated activated FAK-signaling during the development and progression of autoimmune-mediated nephritis in an animal model.
Chen et al. (2001) found that keratinocytes from patients with psoriasis have elevated levels of phosphorylated FAK and concluded that integrin/FAK signaling contributes to a pre-activation of uninvolved keratinocytes that predisposes to the development of psoriatic plaques in response to certain stimuli.
FAK has a role in the development of the cardiovascular system since FAK-null mice are embryonically lethal with phenotypic abnormalities approximating those seen in human congenital heart defects (Vadali et al., 2007). FAK also appears to be involved cardiac hypertrophy and heart failure through its involvement in the cardiac response to biochemical stress and hypertrophic agonists. The relevance of FAK to cardiac physiology likely differs with the cellular context. Although FAK activation has been suggested to accelerate function deterioration of an overloaded heart, selective FAK deletion in cardiomyoctes has also been associated with maladaptive cardiac remodeling (Franchini et al., 2009).
FAK appears to be essential for normal glucose transport and glycogen synthesis due to cross talk between integrin and insulin signaling pathways (Huang et al., 2002; Huang et al., 2006). FAK has also been implicated in hyperglycemia-related vascular complications in Diabetes mellitus (Mori et al., 2002). Two independent studies reported on increased levels of activated FAK in the glomeruli from diabetic rats that could be abrogated by insulin treatment (Clark et al., 1995; Shikano et al., 1996).
FAK signaling has been implicated with non-neoplastic renal disease. Holzapfel et al. (2007) documented a role for FAK during restoration of tubular integrity in renal ischemia and reperfusion, and an earlier study by Morino et al. (1999) indicated activated FAK-signaling during the development and progression of autoimmune-mediated nephritis in an animal model.
Article Bibliography
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| 20185162 | 2010 | Decreased expression of focal adhesion kinase is associated with a poor prognosis in extrahepatic bile duct carcinoma. | Hayashi A et al |
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| 15494734 | 2004 | Activation of FAK and Src are receptor-proximal events required for netrin signaling. | Li W et al |
| 15564794 | 2004 | Upregulation of focal adhesion kinase (FAK) expression in ductal carcinoma in situ (DCIS) is an early event in breast tumorigenesis. | Lightfoot HM Jr et al |
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| 18648907 | 2008 | Extended survival of Pyk2 or FAK deficient orthotopic glioma xenografts. | Lipinski CA et al |
| 15494732 | 2004 | Netrin requires focal adhesion kinase and Src family kinases for axon outgrowth and attraction. | Liu G et al |
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| 15601818 | 2004 | Specific deletion of focal adhesion kinase suppresses tumor formation and blocks malignant progression. | McLean GW et al |
| 20405349 | 2010 | Evaluation of FAK and Src expression in human benign and malignant thyroid lesions. | Michailidi C et al |
| 21119598 | 2011 | Ligand-independent activation of c-Met by fibronectin and α(5)β(1)-integrin regulates ovarian cancer invasion and metastasis. | Mitra AK et al |
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| 16682956 | 2006 | Intrinsic FAK activity and Y925 phosphorylation facilitate an angiogenic switch in tumors. | Mitra SK et al |
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| 12515828 | 2003 | PTP alpha regulates integrin-stimulated FAK autophosphorylation and cytoskeletal rearrangement in cell spreading and migration. | Zeng L et al |
| 10430888 | 1999 | Focal adhesion kinase promotes phospholipase C-gamma1 activity. | Zhang X et al |
| 10197643 | 1999 | Prostatic carcinoma cell migration via alpha(v)beta3 integrin is modulated by a focal adhesion kinase pathway. | Zheng DQ et al |
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Other Information
Locus ID:
NCBI: 5747
MIM: 600758
HGNC: 9611
Ensembl: ENSG00000169398
Variants:
dbSNP: 5747
ClinVar: 5747
TCGA: ENSG00000169398
COSMIC: PTK2
RNA/Proteins
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 37878047 | 2024 | HuR-induced circ_0082319 contributes to hepatocellular carcinoma by elevating PTK2 through miR-505-3p. | 1 |
| 37950040 | 2024 | VPS35 promotes gastric cancer progression through integrin/FAK/SRC signalling-mediated IL-6/STAT3 pathway activation in a YAP-dependent manner. | 0 |
| 38184221 | 2024 | DPP-4 exacerbates LPS-induced endothelial cells inflammation via integrin-α5β1/FAK/AKT signaling. | 0 |
| 38233791 | 2024 | ZDHHC5-mediated S-palmitoylation of FAK promotes its membrane localization and epithelial-mesenchymal transition in glioma. | 2 |
| 38269431 | 2024 | Exploring the therapeutic potential of focal adhesion kinase inhibition in overcoming chemoresistance in pancreatic ductal adenocarcinoma. | 0 |
| 38281617 | 2024 | ING3 inhibits the malignant progression of lung adenocarcinoma by negatively regulating ITGB4 expression to inactivate Src/FAK signaling. | 0 |
| 38326036 | 2024 | ICAM-1 Deletion Using CRISPR/Cas9 Protects the Brain from Traumatic Brain Injury-Induced Inflammatory Leukocyte Adhesion and Transmigration Cascades by Attenuating the Paxillin/FAK-Dependent Rho GTPase Pathway. | 0 |
| 38396816 | 2024 | THSD1 Suppresses Autophagy-Mediated Focal Adhesion Turnover by Modulating the FAK-Beclin 1 Pathway. | 0 |
| 38488492 | 2024 | FAK mediates hypoxia-induced pulmonary artery smooth muscle cell proliferation by modulating mitochondrial transcription termination factor 1/cyclin D1. | 0 |
| 38532364 | 2024 | A decrease in integrin α5β1/FAK is associated with increased apoptosis of aortic smooth muscle cells in acute type a aortic dissection. | 0 |
| 38648767 | 2024 | Effect of Focal Adhesion Kinase and Vinculin Expression on Migration Parameters of Normal and Tumor Epitheliocytes. | 0 |
| 38725858 | 2024 | The dysadherin/FAK axis promotes individual cell migration in colon cancer. | 0 |
| 38824643 | 2024 | FAK regulates tension transmission to the nucleus and endothelial transcriptome independent of kinase activity. | 0 |
| 38835117 | 2024 | T-plastin contributes to epithelial-mesenchymal transition in human lung cancer cells through FAK/AKT/Slug axis signaling pathway. | 0 |
| 37878047 | 2024 | HuR-induced circ_0082319 contributes to hepatocellular carcinoma by elevating PTK2 through miR-505-3p. | 1 |
Citation
Joerg Schwock ; Neesha Dhani
PTK2 (PTK2 protein tyrosine kinase 2)
Atlas Genet Cytogenet Oncol Haematol. 2011-03-01
Online version: http://atlasgeneticsoncology.org/gene/41898/ptk2-(ptk2-protein-tyrosine-kinase-2)
