5747

PTK2

protein tyrosine kinase 2;PTK2;protein tyrosine kinase 2

FADK 1|FAK-related non-kinase polypeptide|PTK2 protein tyrosine kinase 2|focal adhesion kinase 1|focal adhesion kinase isoform FAK-Del33|focal adhesion kinase-related nonkinase|protein phosphatase 1 regulatory subunit 71|protein phosphatase 1, regulatory

8q24.3

protein-coding

Neuroblastomas express increased levels of gastrin-releasing peptide receptor (GRP-R). However, the exact molecular mechanisms involved in GRP-R-mediated cell signaling in neuroblastoma growth and metastasis are unknown. Here, we report that focal adhesion kinase (FAK), as a critical downstream target of GRP-R, is an important regulator of neuroblastoma tumorigenicity. We found that FAK expression correlates with GRP-R expression in human neuroblastoma sections and cell lines. GRP-R overexpression in SK-N-SH cells increased FAK, integrin alpha3 and beta1 expressions and cell migration. These cells demonstrated flatter cell morphology with broad lamellae, in which intense FAK expression was localized to the leading edges of lamellipodia. Interestingly, FAK activation was, in part, dependent on integrin alpha3 and beta1 expression. Conversely, GRP-R silencing decreased FAK as well as Mycn levels in BE(2)-C cells, which displayed a denser cellular morphology. Importantly, rescue experiments in GRP-R silenced BE(2)-C cells showed FAK overexpression significantly enhanced cell viability and soft agar colony formation; similarly, FAK overexpression in SK-N-SH cells also resulted in increased cell growth. These effects were reversed in FAK silenced BE(2)-C cells in vitro as well as in vivo. Moreover, we evaluated the effect of FAK inhibition in vivo. FAK inhibitor (Y15) suppressed GRP-induced neuroblastoma growth and metastasis. Our results indicate that FAK is a critical downstream regulator of GRP-R, which mediates tumorigenesis and metastasis in neuroblastoma.

cancer cells require sustained oncogenic signaling in order to maintain their malignant properties. It is, however, unclear whether they possess other dependencies that can be exploited therapeutically. We report here that in a large fraction of human breast cancers, the gene encoding focal adhesion kinase (FAK), a core component of integrin signaling, was amplified and FAK mRNA was overexpressed. A mammary gland-specific deletion of Fak in mice did not seem to affect normal mammary epithelial cells, and these mice were protected from tumors initiated by the polyoma middle T oncoprotein (PyMT), which activates Ras and PI3K. FAK-deficient PyMT-transformed cells displayed both growth arrest and apoptosis, as well as diminished invasive and metastatic capacity. Upon silencing of Fak, mouse mammary tumor cells transformed by activated Ras became senescent and lost their invasive ability. Further, Neu-transformed cells also underwent growth arrest and apoptosis if integrin beta4-dependent signaling was simultaneously inactivated. Human breast cancer cells carrying oncogenic mutations that activate Ras or PI3K signaling displayed similar responses upon silencing of FAK. Mechanistic studies indicated that FAK sustains tumorigenesis by promoting Src-mediated phosphorylation of p130Cas. These results suggest that FAK supports Ras- and PI3K-dependent mammary tumor initiation, maintenance, and progression to metastasis by orchestrating multiple core cellular functions, including proliferation, survival, and avoidance of senescence.

Focal adhesion kinase (FAK) is a 125-kDa non-receptor type tyrosine kinase that localizes to focal adhesions. FAK overexpression is frequently found in invasive and metastatic cancers of the breast, colon, thyroid, and prostate, but its role in osteolytic metastasis is not well understood. In this study, we have analyzed anti-tumor effects of the novel FAK Tyr(397) inhibitor TAE226 against bone metastasis in breast cancer by using TAE226. Oral administration of TAE226 in mice significantly decreased bone metastasis and osteoclasts involved which were induced by MDA-MB-231 breast cancer cells and increased the survival rate of the mouse models of bone metastasis. TAE226 also suppressed the growth of subcutaneous tumors in vivo and the proliferation and migration of MDA-MB-231 cells in vitro. Significantly, TAE226 inhibited the osteoclast formation in murine pre-osteoclastic RAW264.7 cells, and actin ring and pit formation in mature osteoclasts. Moreover, TAE226 inhibited the receptor activator for nuclear factor kappa B Ligand (RANKL) gene expression induced by parathyroid hormone-related protein (PTHrP) in bone stromal ST2 cells and blood free calcium concentration induced by PTHrP administration in vivo. These findings suggest that FAK was critically involved in osteolytic metastasis and activated in tumors, pre-osteoclasts, mature osteoclasts, and bone stromal cells and TAE226 can be effectively used for the treatment of cancer induced bone metastasis and other bone diseases.

OBJECTIVE: To analyze the expression of deleted in liver cancer 1 (DLC1) and phosphorelated focal adhesion kinase (p-FAK) in breast cancer tissue to further understand the molecular mechanisms of the carcinogenesis and metastasis of breast cancer. METHODS: Immunohistochemistry was employed to determine the protein level of DLC1 and p-FAK in 61 breast cancer, 30 benign breast disease and the adjacent normal breast tissues. RESULTS: The positivity rates of DLC1 differed significantly between breast cancer, benign and normal tissues (34.43%, 80.00% and 76.67%, respectively, P<0.001). The positivity rates of p-FAK in the 3 tissues were 77.05%, 33.33% and 26.67%, also showing significant differences (P<0.001). The aberrant expression of DLC1 showed an inverse correlation to p-FAK (kappa=-0.4591). Both DLC1 and p-FAK were closely correlated to the carcinogenesis, clinical stage, PR and lymphatic metastasis of breast cancer (P<0.05), but not to the patients age, pathological subtype, familial history, ER or CerbB-2 (P>0.05). CONCLUSION: The abnormal expression of DLC1 and p-FAK might participate in the carcinogenesis, progression, and metastasis of breast cancer. The role of DLC1 and p-FAK might be related to the regulation of progestone. DLC1 and p-FAK may serve as candidate markers for early diagnosis, prognostic evaluation and target treatment of breast cancer.

Kruppel-like factor 8 (KLF8) regulates critical gene transcription associated with cancer. The underlying mechanisms, however, remain largely unidentified. We have recently demonstrated that KLF8 expression enhances the activity but not expression of matrix metalloproteinase-2 (MMP2), the target substrate of MMP14. Here, we report a novel KLF8 to MMP14 signaling that promotes human breast cancer invasion and metastasis. Using cell lines for inducible expression and knockdown of KLF8, we demonstrate that KLF8 promotes MMP14 expression at the transcriptional level. Knocking down KLF8 expression inhibited the breast cancer cell invasion both in vitro and in vivo as well as the lung metastasis in mice, which could be rescued by ectopic expression of MMP14. Promoter reporter assays and oligonucleotide and chromatin immunoprecipitations determined that KLF8 activates the human MMP14 gene promoter by both directly acting on the promoter and indirectly via promoting the nuclear translocation of beta-catenin, the expression of T-cell factor-1 (TCF1) and subsequent activation of the promoter by the beta-catenin/TCF1 complex. Inhibition of focal adhesion kinase (FAK) using pharmacological inhibitor, RNA interference or knockout showed that the cell surface presentation of active MMP14 downstream of KLF8 depends on FAK expression and activity. Taken together, this work identified novel signaling mechanisms by which KLF8 and FAK work together to promote the extracellular activity of MMP14 critical for breast cancer metastasis.

Focal adhesion kinase (FAK) regulates cell adhesion, migration, proliferation, and survival. We identified a novel splicing mutant, FAK-Del33 (exon 33 deletion, KF437463), in both breast and thyroid cancers through colony sequencing. Considering the low proportion of mutant transcripts in samples, this mutation was detected by TaqMan-MGB probes based qPCR. In total, three in 21 paired breast tissues were identified with the FAK-Del33 mutation, and no mutations were found in the corresponding normal tissues. When introduced into a breast cell line through lentivirus infection, FAK-Del33 regulated cell motility and migration based on a wound healing assay. We demonstrated that the expression of Tyr397 (main auto-phosphorylation of FAK) was strongly increased in FAK-Del33 overexpressed breast tumor cells compared to wild-type following FAK/Src RTK signaling activation. These results suggest a novel and unique role of the FAK-Del33 mutation in FAK/Src signaling in breast cancer with significant implications for metastatic potential.

Vascular endothelial growth factor C (VEGF-C) is correlated positively with clinical cervical cancer metastasis and survival. Previously we showed that VEGF-C directly activated actin-binding protein moesin, leading to the formation of membrane protrusions. However, whether VEGF-C alters cervical cancer cell adhesion to the extra-cellular matrix is currently unknown. In this study, we investigated the effects of VEGF-C on the formation of focal adhesion complexes, which provide anchoring sites for cell attachment to the extracellular matrix. On cultured cervical carcinoma cell line SiHa cells, VEGF-C enhanced focal adhesion kinase (FAK) phosphorylation. As a result, VEGF-C led to increased formation of focal adhesion complexes and enhanced migration and invasion, which was reversed by siRNA abrogating FAK. VEGF-C resulted in increased interaction of its receptor Flt-4 with non-receptor tyrosine kinase c-Src, leading to c-Src phosphorylation. The specific inhibitor of c-Src kinase, PP2, or the transfection with specific c-Src siRNA largely impaired VEGF-C-enhanced FAK phosphorylation, suggesting that Flt-4/c-Src cascade plays a central role in these processes. These results implied that VEGF-C promotes cervical cancer metastasis by activation of FAK protein through Flt-4/c-Src pathway.

Micro-environmental clues, including the biophysical interpretation of the extracellular matrix, are critical to proliferation, apoptosis and migration. Here, we show that metastatic human colon cancer cell lines display altered matrix interaction. Interaction of colon cancer cells with collagen I depends on integrins (mainly alpha(1)/beta(1)) but metastatic cells display delayed spreading and reduced extension of lamellipodia. In addition, cells show defective strengthening of integrin-cytoskeleton linkages upon mechanical stimulation, as determined by laser trapping experiments and binding of large beads to the cell surface. However, adhesion to pliable surfaces is ameliorated in metastatic variants. These changes are caused by constitutive activation of focal adhesion kinase (FAK) and can be modulated by changing expression and/or activity of FAK via RNA-interference or expression of inhibitory constructs, respectively. In addition, consistent with defective strengthening of integrin-cytoskeleton linkages, metastatic cell lines show reduced random motility. Taken together these data suggest that constitutive activation of FAK causes defects in spreading, reinforcement of integrin-cytoskeleton linkages and migration and at the same time could ameliorate the adhesion of metastatic cells to suboptimal surfaces.

Pak1 has been reported to be overexpressed in colorectal cancer, but the role of Pak1 in colorectal cancer remains unclear. In this study, Pak1 expression and activity were associated with aggressive behavior of colorectal cancer. Overexpression of Pak1 increased colorectal cancer cell motility and invasion, whereas down-regulation of Pak1 expression or activity reduced colorectal cancer cell migration and invasion. In addition, activated Pak1 inhibited stress fiber and focal adhesion complex formation in colorectal cancer cells and led to formation of motile phenotypes. Importantly, activated Pak1 elicited phosphorylation of FAK at Ser-910 via an ERK-dependent pathway in colorectal cancer cell lines and clinical samples. In conclusion, our results suggest that activated Pak1 regulates colorectal cancer metastasis requiring an ERK-dependent phosphorylation of FAK at Ser-910.

Although focal adhesion kinase (FAK) is typically considered upstream of Akt, extracellular pressure stimulates cancer cell adhesion via Akt-dependent FAK activation. How Akt regulates FAK is unknown. We studied Akt-FAK interaction in colon cancer cells under 15 mmHg increased extracellular pressure. Pressure enhanced Akt-FAK association, blocked by inhibiting FAK or silencing Akt1 but not Akt2, and stimulated FAK serine phosphorylation in Caco-2 and human colon cancer cells from surgical specimens Akt1-dependently. FAK includes three serine (S517/601/695) and one threonine (T600)-containing consensus sequences for Akt phosphorylation. Studying S->A nonphosphorylatable point mutants suggests that these sites coordinately upregulate FAK Y397 tyrosine phosphorylation, which conventionally initiates FAK activation, and mediate pressure-induced cancer cell adhesion. FAK(T600A) mutation did not prevent pressure-induced FAK(Y397) phosphorylation or adhesion. Akt1 appeared to directly bind FAK, and this binding did not depend on the FAK autophosphorylation site (Y397). In addition, our results demonstrated that Akt phosphorylated FAK at three novel serine phosphorylation sites, which were also not required for FAK-Akt binding. This novel interaction suggests that FAK and Akt may be dual kinase targets to prevent cancer cell adhesion and metastasis.

The objective of the present study was to investigate the expression of paxillin and focal adhesion kinase (FAK) mRNA in esophageal carcinoma tissues, and their relationship with clinicopathological parameters, as well as to analyze the correlation of paxillin and FAK mRNA levels in esophageal carcinoma. By using reverse transcription polymerase chain reaction (RT-PCR), the mRNA expression levels of paxillin and FAK were detected in 121 samples of esophageal carcinoma, 43 samples of atypical hyperplasia and 56 samples of normal esophageal mucosa. The results showed that the positive rates of paxillin and FAK mRNA expression in esophageal carcinoma were 87.6 and 80.17%, respectively, which were significantly higher (P<0.05) than those in atypical hyperplasia (44.19 and 39.53%) and normal esophageal mucosa (5.36 and 12.5%). Notably, paxillin and FAK mRNA expression levels were significantly correlated with the differentiation degree and depth of invasion of esophageal carcinoma and with lymph node metastasis (P<0.05). In addition, paxillin and FAK mRNA expression levels in esophageal carcinoma were positively correlated (r=0.4804, P=0.000). In conclusion, the combined detection of paxillin and FAK mRNA expression is expected to provide a theoretical basis for the molecular diagnosis of esophageal carcinoma.

We have recently reported that activation of the Raf-1/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase 1/2 (MEK1/2)/ERK1/2 signaling cascade in gastrointestinal carcinoid cell line (BON) alters cellular morphology and neuroendocrine phenotype. The mechanisms by which Raf-1 mediates these changes in carcinoid cells are unclear. Here, we report that activation of the Raf-1 signaling cascade in BON cells induced the expression of focal adhesion kinase (FAK) protein, suppressed the production of neuroendocrine markers, and resulted in significant decreases in cellular adhesion and migration. Importantly, inactivation of MEK1/2 by 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene or abolition of FAK induction in Raf-1-activated BON cells by targeted siRNA led to reversal of the Raf-1-mediated reduction in neuroendocrine markers and cellular adhesion and migration. Phosphorylation site-specific antibodies detected the phosphorylated FAK(Tyr407), but not FAK(Tyr397), in these Raf-1-activated cells, indicating that FAK(Tyr407) may be associated with changes in the neuroendocrine phenotype. Overexpression of constitutively active FAK plasmids (wild-type FAK or FAK(Tyr397) mutant) into BON cells reduced neuroendocrine markers, whereas the FAK(Tyr407) mutant plasmid did not show any decrease in the levels of neuroendocrine markers, indicating that phosphorylation of FAK at the Tyr(407) residue may be important for these effects. Our results showed for the first time that FAK is an essential downstream effector of the Raf-1/MEK1/2/ERK1/2 signaling cascade and negatively regulated the neuroendocrine and metastatic phenotype in BON cells.

OBJECTIVE: To investigate the effect of the wild type phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumor-suppressor gene on the proliferation and apoptosis of human chronic myeloid leukemia (CML) cells line (K562) in vitro and explore the influence of PTEN-FAK signaling pathway on invasion and metastasis of leukemia cells. METHODS: The recombinant Ad-PTEN gene containing green fluorescent protein gene (Ad-PTEN-GFP) or the empty vector (Ad-GFP) was transfected into K562 cells and fresh leukemia cells from CML patients in blast crisis. The growth of K562 cells was assayed by MTT assay; the apoptosis rate was assessed by flow cytometry (FCM). PTEN and FAK mRNA levels were detected by real-time fluorescent relative- quantification reverse transcriptional PCR (FQ-PCR) and its protein levels by Western blot. The metastasis and invasive ability was examined by transwell chamber assay. RESULTS: The growth of K562 cells was suppressed markedly when Ad-PTEN-GFP was transfected into K562 cells at the 200 multiplicity of infection (MOI). The maximum growth inhibition rate was 35.2%. Transwell results showed the number of cells entered the lower chamber in Ad-GFP group was 9.1 fold more than that in Ad-PTEN-GFP group;The ability of metastasis and invasion of fresh leukemia cells was also suppressed after transfection with Ad-PTEN-GFP. FAK and p-FAK proteins were down-regulated by 0.72 and 0.16 fold lower after transfected with Ad-PTEN-GFP compared with Ad-GFP group. CONCLUSIONS: PTEN gene might inhibit the proliferation, metastasis and invasive ability of leukemia cells via down-regulating FAK expression.

Mechanism of HAb18G/CD147 underlying the metastasis process of human hepatoma cells has not been determined. In the present study, we found that integrin alpha3beta1 colocalizes with HAb18G/CD147 in human 7721 hepatoma cells. The enhancing effect of HAb18G/CD147 on adhesion, invasion capacities and matrix metalloproteinases (MMPs) secretion was decreased by integrin alpha3beta1 antibodies (p<0.01). The expressions of integrin downstream molecules including focal adhesion kinase (FAK), phospho-FAK (p-FAK), paxillin, and phospho-paxillin (p-paxillin) were increased in human hepatoma cells overexpressing HAb18G/CD147. Deletion of HAb18G/CD147 reduces the quantity of focal adhesions and rearranges cytoskeleton. Wortmannin and LY294002, specific phosphatidylinositol kinase (PI3K) inhibitors, reversed the effect of HAb18G/CD147 on the regulation of intracellular Ca(2+) mobilization, significantly reducing cell adhesion, invasion and MMPs secretion potential (p<0.01). Together, these results suggest that HAb18G/CD147 enhances the invasion and metastatic potentials of human hepatoma cells via integrin alpha3beta1-mediated FAK-paxillin and FAKPI3K-Ca(2+) signal pathways.

Focal adhesion kinase plays a critical role in cancer progression, invasion, and metastasis. Although focal adhesion kinase overexpression indicates poor prognoses for hepatocellular carcinoma, its role in hepatocellular carcinoma metastasis has not been well investigated. In this study, 55 hepatocellular carcinoma patients were enrolled, and their primary liver tumors as well as 18 matched metastases were subjected to semiquantitative immunohistochemistry analysis of focal adhesion kinase expression. Overexpression of focal adhesion kinase was observed in 34 (61.8%) of 55 primary tumors and significantly predicted subsequent extrahepatic metastases (P = .04). metastatic tumors expressed higher focal adhesion kinase than their matched primaries (P = .010). Focal adhesion kinase overexpression indicated both worse overall 5-year survival rate (51.5% +/- 8.7% versus 90.2% +/- 6.6%; P = .004) and 5-year progression-free survival rate (51.5% +/- 8.7% versus 90.2% +/- 6.6%; P = .041). Taken together, we demonstrated here that focal adhesion kinase expression is significantly related to subsequent hepatocellular carcinoma metastasis. Focal adhesion kinase is thus considered as a reasonable target for novel therapies against hepatocellular carcinoma progression and metastasis.

OBJECTIVES: PTPN13 is a new candidate tumor-suppressing gene. To investigate the PTPN13 expression and its potential function in the invasion and metastasis of lung squamous cell carcinoma (LSCC), we performed this study in 91 primary LSCC tissues and the adjacent non-cancerous tissues. METHODS: The mRNA expression of PTPN13 and FAK was quantitated by reverse transcription polymerase chain reaction. The protein expression of PTPN13, focal adhesion kinase (FAK) and phosphorylated FAK (P-FAK) was evaluated using immunohistochemical staining and western blotting. The association among PTPN13 expression, FAK expression and the clinicopathological parameters were analyzed. RESULTS: PTPN13 expression was down-regulated in LSCC, and was negatively correlated with the cancer grade and stage. FAK mRNA, as well as FAK protein level was elevated in LSCC tissues. P-FAK level, also found increased, had no association with FAK mRNA and FAK protein expression, but had a negative correlation with the PTPN13 expression. P-FAK level had a significant positive correlation with the TNM classification. CONCLUSION: The over-expression of FAK and increased FAK phosphorylation plays an important role in the invasion and metastasis of LSCC.

In metastatic cancer, high expression levels of vitronectin (VN) receptors (integrins), FAK, and ERK5 are reported. We hypothesized that integrin-mediated ERK5 activation via FAK may play a pivotal role in cell adhesion, motility, and metastasis. ERK5 and FAK phosphorylation when metastatic MDA-MB-231 and PC-3 cells were plated on VN was enhanced. Further experiments showed co-immunoprecipitation of integrins beta1, alpha V beta 3, or alpha V beta 5 with ERK5 and FAK. To gain better insight into the mechanism of ERK5, FAK, and VN receptors in cell adhesion and motility, we performed loss-of-function experiments using integrin blocking antibodies, and specific mutants of FAK and ERK5. Ectopic expression of dominant negative ERK5/AEF decreased ERK5 and FAK (Y397) phosphorylation, cell adhesion, and haptotactic motility (micromotion) on VN. Additionally, DN FAK expression attenuated ERK5 phosphorylation, cell adhesion, and motility. This study documents the novel finding that in breast and prostate cancer cells, ERK5 is a critical target of FAK in cell adhesion signaling. Using different cancer cells, our experiments unveil a novel mechanism by which VN receptors and FAK could promote cancer metastasis via ERK5 activation.

We have recently reported that activation of the Raf-1/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase 1/2 (MEK1/2)/ERK1/2 signaling cascade in gastrointestinal carcinoid cell line (BON) alters cellular morphology and neuroendocrine phenotype. The mechanisms by which Raf-1 mediates these changes in carcinoid cells are unclear. Here, we report that activation of the Raf-1 signaling cascade in BON cells induced the expression of focal adhesion kinase (FAK) protein, suppressed the production of neuroendocrine markers, and resulted in significant decreases in cellular adhesion and migration. Importantly, inactivation of MEK1/2 by 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene or abolition of FAK induction in Raf-1-activated BON cells by targeted siRNA led to reversal of the Raf-1-mediated reduction in neuroendocrine markers and cellular adhesion and migration. Phosphorylation site-specific antibodies detected the phosphorylated FAK(Tyr407), but not FAK(Tyr397), in these Raf-1-activated cells, indicating that FAK(Tyr407) may be associated with changes in the neuroendocrine phenotype. Overexpression of constitutively active FAK plasmids (wild-type FAK or FAK(Tyr397) mutant) into BON cells reduced neuroendocrine markers, whereas the FAK(Tyr407) mutant plasmid did not show any decrease in the levels of neuroendocrine markers, indicating that phosphorylation of FAK at the Tyr(407) residue may be important for these effects. Our results showed for the first time that FAK is an essential downstream effector of the Raf-1/MEK1/2/ERK1/2 signaling cascade and negatively regulated the neuroendocrine and metastatic phenotype in BON cells.

The Pax-5 gene encodes a B-cell-specific activator protein (BSAP) that plays a key role in B lymphocyte differentiation and embryogenesis. The deregulation of this transcription factor is also linked to B cell malignancies and recently to other cancers. More specifically, the downstream effects of Pax-5 promote cell-cell interactions and mediate the activation of adhesion genes which result in an epithelial phenotypic behavior of human carcinoma cells. To gain a better understanding of Pax-5-mediated gene regulation, we studied available gene expression data in depth and identified several Pax-5 downstream targets. Among these, we found that Pax-5 activity is consistently inversely correlated with the expression of Focal Adhesion Kinase 1 (FAK1). FAK1 is known to enhance migration of cancer cells and promote metastatic dissemination to distant sites. Further analysis looking at genome wide profiling of Pax-5 DNAbinding points to both direct and indirect regulation of FAK1 expression by Pax-5 and its downstream targets. These findings suggest a key role for Pax-5 in phenotypic transitioning during metastasis through the regulation of FAK1 activity.

Protein tyrosine phosphatase (PTP)-PEST is a critical regulator of cell adhesion and migration. However, the mechanism by which PTP-PEST is regulated in response to oncogenic signaling to dephosphorylate its substrates remains unclear. Here, we demonstrate that activated Ras induces extracellular signal-regulated kinase 1 and 2-dependent phosphorylation of PTP-PEST at S571, which recruits PIN1 to bind to PTP-PEST. Isomerization of the phosphorylated PTP-PEST by PIN1 increases the interaction between PTP-PEST and FAK, which leads to the dephosphorylation of FAK Y397 and the promotion of migration, invasion, and metastasis of v-H-Ras-transformed cells. These findings uncover an important mechanism for the regulation of PTP-PEST in activated Ras-induced tumor progression.

Clinical evidence links neuroendocrine differentiation (NED) to prostate cancer progression. In the prostate carcinoma PC-3 cell model, the action of the gastrin releasing peptide (GRP) analog, bombesin (BN), on the activation of focal adhesion kinase (FAK) and invasiveness suggests that this kinase might favor metastasis. Given that components of the FAK signalling pathway are also up regulated in prostate cancer, the aim of the present investigation was to test if FAK function is required for BN-induced motility in PC-3 cells. In wound assays designed to investigate the fate of FAK in cells undergoing BN-induced motility, it was observed that BN treatment resulted in relocalization of FAK in focal contacts concomitantly with its tyrosine phosphorylation on residue 397 (FAK [pY(397)]) and with the formation of actin lamellipodia. Moreover, BN-induced cell motility was significantly reduced in the presence of FAK inhibitors (either anti-FAK [pY(397)] antibody or FRNK, the FAK-related non-kinase). Altogether, these observations point towards a critical role for FAK in the action of BN on PC-3 cell motility.

PURPOSE: The aims of the present study were to examine whether focal adhesion kinase (FAK) expression is correlated with cervical lymph node metastasis of tongue cancer and to investigate the roles of FAK in the process of cancer cell migration, invasion and anoikis resistance using the human tongue cancer cell line, Tca8113. METHODS: FAK expression was evaluated in 5 normal oral mucosa, 10 premalignant lesions, 80 primary tongue cancers and 41 lymph node metastases using anti-FAK immunohistochemistry. The migration, invasion and anoikis resistance of tongue cancer cells were evaluated using wound healing assays, invasion assays and anoikis induction. The effect of FAK inhibition was evaluated using RNA interference (RNAi). RESULTS: In total, 55 of 80 primary tongue cancers (69%) showed high expression of FAK, and 25 of 80 tumors (31%) and all normal oral mucosa or premalignant lesions showed low expression of FAK. There was a significant correlation between FAK expression and the cervical lymph node metastasis of tongue cancer. Moreover, RNAi-mediated FAK reduction decreased tongue cancer cell migration, invasion and anoikis resistance. CONCLUSIONS: These results suggest that FAK may serve as a marker of cervical lymph node metastasis of tongue cancer and that RNAi targeting FAK could serve as a potential therapeutic for the treatment of tongue cancer.