Synergistic Effect of Focal Adhesion Kinase Overexpression and Hepatocyte Growth Factor Stimulation on Cell Transformation

Chan, Po Chao; Liang, Chun Chi; Yu, Kuo Ching; Chang, Ming Chen; Ho, William L.; Chen, Bor Huah; Chen, Hong Chen

doi:10.1074/jbc.m204691200

Cited by 26 publications

(29 citation statements)

References 54 publications

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“…We have previously demonstrated that FAK overexpression promotes the effect of HGF on cell migration (Lai et al, 2000) and renders epithelial cells susceptible to cellular transformation by HGF (Chan et al, 2002). In this study, we found that unlike the wt FAK, overexpression of Y194F or Y397F mutant in MadinDarby canine kidney (MDCK) cells failed to promote their migration towards HGF ( Figure 5c).…”

Section: Role Of Y194 Phosphorylation In Fak Activation T-h Chen Et Almentioning

confidence: 61%

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Phosphorylation of focal adhesion kinase on tyrosine 194 by Met leads to its activation through relief of autoinhibition

et al. 2010

Oncogene

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Focal adhesion kinase (FAK) has a crucial role in integration of signals from integrins and growth factor receptors. In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor Met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate FAK on Tyr194 in the FERM domain (band 4.1 and ezrin/radixin/moesin homology domain). Upon binding to Met or phosphoinositides, FAK may undergo conformational changes, which renders Tyr194 accessible for phosphorylation. Substitution of Tyr194 with Phe significantly suppresses the activation of FAK by Met. In contrast, substitution of Tyr194 with Glu (Y194E substitution) leads to constitutive activation of FAK. The phosphorylation of FAK on Tyr194 may cause conformational changes in the FERM domain, which disrupts the intramolecular inhibitory interaction between the FERM and kinase domains of FAK. Moreover, substitution of the basic residues in the 216 KAKTLRK 222 patch in the FERM domain with Ala antagonizes the effect of the Y194E substitution on FAK activation, thus suggesting that the interactions between the phosphorylated Tyr194 and the basic resides in the 216 KAKTLRK 222 patch may allow FAK to be activated through relief of its autoinhibition. Collectively, this study provides the first example to explain how FAK is activated by receptor tyrosine kinases.

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Section: Role Of Y194 Phosphorylation In Fak Activation T-h Chen Et Almentioning

confidence: 61%

“…In addition, elevated expression of FAK renders epithelial cells susceptible to cellular transformation by HGF stimulation (Chan et al, 2002). Recently, we demonstrated that FAK directly interacts with the HGF receptor (that is, Met) upon HGF stimulation (Chen and Chen, 2006).…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of focal adhesion kinase on tyrosine 194 by Met leads to its activation through relief of autoinhibition

et al. 2010

Oncogene

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“…In particular, FAK is an important tyrosine kinase in the control of cytoskeletal function and cell motility. FAK overexpression has also been shown to have synergistic effect with HGF on cell transformation (Chan et al, 2002). Focal adhesion kinase activation can also promote aggressive uveal and cutaneous melanoma phenotype (Hess et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Downstream signalling and specific inhibition of c-MET/HGF pathway in small cell lung cancer: implications for tumour invasion

et al. 2007

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The c-MET receptor can be overexpressed, amplified, or mutated in solid tumours including small cell lung cancer (SCLC). In c-MET-overexpressing SCLC cell line NCI-H69, hepatocyte growth factor (HGF) dramatically induced c-MET phosphorylation at phosphoepitopes pY1230/1234/1235 (catalytic tyrosine kinase), pY1003 (juxtamembrane), and also of paxillin at pY31 (CRKL-binding site). We utilised a global proteomics phosphoantibody array approach to identify further c-MET/HGF signal transduction intermediates in SCLC. Strong HGF induction of specific phosphorylation sites in phosphoproteins involved in c-MET/HGF signal transduction was detected, namely adducin- α [S724], adducin- γ [S662], CREB [S133], ERK1 [T185/Y187], ERK1/2 [T202/Y204], ERK2 [T185/Y187], MAPKK (MEK) 1/2 [S221/S225], MAPKK (MEK) 3/6 [S189/S207], RB [S612], RB1 [S780], JNK [T183/Y185], STAT3 [S727], focal adhesion kinase (FAK) [Y576/S722/S910], p38 α -MAPK [T180/Y182], and AKT1[S473] and [T308]. Conversely, inhibition of phosphorylation by HGF in protein kinase C (PKC), protein kinase R (PKR), and also CDK1 was identified. Phosphoantibody-based immunohistochemical analysis of SCLC tumour tissue and microarray established the role of c-MET in SCLC biology. This supports a role of c-MET activation in tumour invasive front in the tumour progression and invasion involving FAK and AKT downstream. The c-MET serves as an attractive therapeutic target in SCLC, as shown through small interfering RNA (siRNA) and selective prototype c-MET inhibitor SU11274, inhibiting the phosphorylation of c-MET itself and its downstream molecules such as AKT, S6 kinase, and ERK1/2. Investigation of mechanisms of invasion and, ultimately, metastasis in SCLC would be very useful with these signal transduction molecules.

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“…Signaling of HGF is transmitted via c-MET into cells through both RAS-MAPKand PI3K-AKT-mediated signaling pathways, each accounting for the mitogenic and anti-apoptotic effect of HGF, respectively (Chan et al, 2002;Liang and Chen, 2001). Importantly, HGF is distinct among other migration-inducing growth factors in its ability to induce epithelial cells undergoing 'invasive growth', a genetic program to initiate a variety of cellular features required for cell migration and invasion (Boccaccio and Comoglio, 2006).…”

Section: Introductionmentioning

confidence: 99%

Krüppel-like factor 4 is involved in cell scattering induced by hepatocyte growth factor

Lai

Shen

et al. 2012

Journal of Cell Science

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SummaryHepatocyte growth factor/scatter factor (HGF) is unique by inducing epithelial cell scattering, a cellular event pivotal to HGF-mediated invasive-growth response essential for embryonic development and metastasis. Krüppel-like factor 4 (KLF4) is a multifunctional zincfinger transcription factor involved in cell proliferation, differentiation and self-renewal. We herein present the first evidence for the functional connection between KLF4 and HGF-induced cell scattering. In particular, we found that KLF4 was upregulated by HGF in two independent epithelial cell types, HepG2 and MDCK, whereas KLF4 knockdown inhibited HGF-induced E-cadherin suppression and cell scattering. Moreover, enforced nuclear KLF4 expression alone was sufficient to upregulate KLF4, downregulate E-cadherin and trigger scattering. Chromatin immunoprecipitation (ChIP) analysis further revealed that KLF4 induced suppression of E-cadherin transcription by directly binding to the E-cadherin promoter. Additionally, we proved that HGF-induced upregulation of KLF4 transcription and cell scattering require activation of the MEK/ERK signaling pathway and the induction of early growth response 1 (EGR-1). At the mechanistic level, ChIP analysis validated a direct binding of EGR-1 to the KLF4 promoter to induce KLF4 transcription; in turn, EGR-1-induced KLF4 binds to its own promoter, thus creating a positive feedback mechanism to sustain KLF4 expression and the resultant cell scattering. We conclude that KLF4 upregulation by HGF represents a novel mechanism mediating HGF-induced cell scattering and perhaps other associated events such as cell migration and invasion.

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Synergistic Effect of Focal Adhesion Kinase Overexpression and Hepatocyte Growth Factor Stimulation on Cell Transformation

Cited by 26 publications

References 54 publications

Phosphorylation of focal adhesion kinase on tyrosine 194 by Met leads to its activation through relief of autoinhibition

Phosphorylation of focal adhesion kinase on tyrosine 194 by Met leads to its activation through relief of autoinhibition

Downstream signalling and specific inhibition of c-MET/HGF pathway in small cell lung cancer: implications for tumour invasion

Krüppel-like factor 4 is involved in cell scattering induced by hepatocyte growth factor

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