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

Th, Chen; Pc, Chan; Cl, Chen; Hc, Chen

doi:10.1038/onc.2010.398

Cited by 38 publications

(33 citation statements)

References 31 publications

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“…As observed in our results, we can conclude that the action of PIP 2 is mainly of an electrostatic nature, by changing the electrostatic interactions between basic patch with its nearby a-helix and inducing a rearrangement at F2/ N-lobe interface. We believe that the other basic patch interaction partners, such as C-Met (35) or the FAT domain, might allosterically effect FAK dynamics in a similar fashion-a hypothesis straightforwardly testable by experiments.…”

Section: Discussionmentioning

confidence: 86%

Allosteric Regulation of Focal Adhesion Kinase by PIP2 and ATP

Zhou

Bronowska

Coq

et al. 2015

Biophysical Journal

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Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that regulates cell signaling, proliferation, migration, and development. A major mechanism of regulation of FAK activity is an intramolecular autoinhibitory interaction between two of its domains--the catalytic and FERM domains. Upon cell adhesion to the extracellular matrix, FAK is being translocated toward focal adhesion sites and activated. Interactions of FAK with phosphoinositide phosphatidylinsositol-4,5-bis-phosphate (PIP₂) are required to activate FAK. However, the molecular mechanism of the activation remains poorly understood. Recent fluorescence resonance energy transfer experiments revealed a closure of the FERM-kinase interface upon ATP binding, which is reversed upon additional binding of PIP₂. Here, we addressed the allosteric regulation of FAK by performing all-atom molecular-dynamics simulations of a FAK fragment containing the catalytic and FERM domains, and comparing the dynamics in the absence or presence of ATP and PIP₂. As a major conformational change, we observe a closing and opening motion upon ATP and additional PIP₂ binding, respectively, in good agreement with the fluorescence resonance energy transfer experiments. To reveal how the binding of the regulatory PIP₂ to the FERM F2 lobe is transduced to the very distant F1/N-lobe interface, we employed force distribution analysis. We identified a network of mainly charged residue-residue interactions spanning from the PIP₂ binding site to the distant interface between the kinase and FERM domains, comprising candidate residues for mutagenesis to validate the predicted mechanism of FAK activation.

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Section: Discussionmentioning

confidence: 86%

Allosteric Regulation of Focal Adhesion Kinase by PIP2 and ATP

Zhou

Bronowska

Coq

et al. 2015

Biophysical Journal

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“…Cytoplasmic portions of several growth factor receptors have been reported to activate FAK (28)(29)(30), and direct mechanisms have been proposed for some of them that involve the KAKTLRK region of FAK (28,29). Phosphorylated tails of the c-Met receptor are reported to interact with the KAKTLRK region, resulting in phosphorylation of Y194 in FAK (47). Intriguingly, Y194 is completely buried within the FERM F2 lobe, indicating that perhaps phospho-Met tail interactions could induce similar destabilization of the FERM F2 lobe as we describe for PI(4,5)P 2 ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol 4,5-bisphosphate triggers activation of focal adhesion kinase by inducing clustering and conformational changes

Goñi

Epifano

Boskovic

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

118

186

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Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase (NRTK) with key roles in integrating growth and cell matrix adhesion signals, and FAK is a major driver of invasion and metastasis in cancer. Cell adhesion via integrin receptors is well known to trigger FAK signaling, and many of the players involved are known; however, mechanistically, FAK activation is not understood. Here, using a multidisciplinary approach, including biochemical, biophysical, structural, computational, and cell biology approaches, we provide a detailed view of a multistep activation mechanism of FAK initiated by phosphatidylinositol-4,5-bisphosphate [PI(4,5)P 2 ]. Interestingly, the mechanism differs from canonical NRTK activation and is tailored to the dual catalytic and scaffolding function of FAK. We find PI(4,5)P 2 induces clustering of FAK on the lipid bilayer by binding a basic region in the regulatory 4.1, ezrin, radixin, moesin homology (FERM) domain. In these clusters, PI(4,5)P 2 induces a partially open FAK conformation where the autophosphorylation site is exposed, facilitating efficient autophosphorylation and subsequent Src recruitment. However, PI(4,5)P 2 does not release autoinhibitory interactions; rather, Src phosphorylation of the activation loop in FAK results in release of the FERM/kinase tether and full catalytic activation. We propose that PI(4,5)P 2 and its generation in focal adhesions by the enzyme phosphatidylinositol 4-phosphate 5-kinase type Iγ are important in linking integrin signaling to FAK activation.cell signaling | phosphoinositides C ell attachment to the ECM is mediated via integrin transmembrane receptors on the cell surface. Integrin engagement to ECM components results in activation and clustering of integrins. In response to integrin activation, a large number of proteins are recruited to their cytoplasmic tails, resulting in the formation of focal adhesions (FAs) (1). On the one side, FAs are anchoring points for actomyosin stress fibers, which allow tension forces to build up when contracting fibers exert their pulling force via FAs against the ECM. On the other hand, integrin activation and the generation of tension trigger intricate signaling cascades. A central signaling component in FAs is the nonreceptor tyrosine kinase (NRTK) focal adhesion kinase (FAK).

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“…Moreover, the FERM domain also binds the c-Met receptor, which mediates FAK phosphorylation, leading to hepatocyte growth factorenhanced invasion (Chen and Chen, 2006). FAK Tyr194 phosphorylation by c-Met appears to interfere with the inhibitory intramolecular interaction leading to its activation (Chen et al, 2011). The FAK FERM domain also binds EGF receptor, promoting migration via mediation of the intermediary protein SRC3D4 after EGF treatment (Long et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Tetraspan TM4SF5-dependent direct activation of FAK and metastatic potential of hepatocarcinoma cells

Jung¹,

Choi²,

Jang

et al. 2012

Journal of Cell Science

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SummaryTransmembrane 4 L six family member 5 (TM4SF5) plays an important role in cell migration, and focal adhesion kinase (FAK) activity is essential for homeostatic and pathological migration of adherent cells. However, it is unclear how TM4SF5 signaling mediates the activation of cellular migration machinery, and how FAK is activated during cell adhesion. Here, we showed that direct and adhesiondependent binding of TM4SF5 to FAK causes a structural alteration that may release the inhibitory intramolecular interaction in FAK. In turn, this may activate FAK at the cell's leading edge, to promote migration/invasion and in vivo metastasis. TM4SF5-mediated FAK activation occurred during integrin-mediated cell adhesion. TM4SF5 was localized at the leading edge of the cells, together with FAK and actin-organizing molecules, indicating a signaling link between TM4SF5/FAK and actin reorganization machinery. Impaired interactions between TM4SF5 and FAK resulted in an attenuated FAK phosphorylation (the signaling link to actin organization machinery) and the metastatic potential. Our findings demonstrate that TM4SF5 directly binds to and activates FAK in an adhesiondependent manner, to regulate cell migration and invasion, suggesting that TM4SF5 is a promising target in the treatment of metastatic cancer.

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

Cited by 38 publications

References 31 publications

Allosteric Regulation of Focal Adhesion Kinase by PIP2 and ATP

Allosteric Regulation of Focal Adhesion Kinase by PIP2 and ATP

Phosphatidylinositol 4,5-bisphosphate triggers activation of focal adhesion kinase by inducing clustering and conformational changes

Tetraspan TM4SF5-dependent direct activation of FAK and metastatic potential of hepatocarcinoma cells

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