000168527 001__ 168527
000168527 005__ 20260209162330.0
000168527 0247_ $$2doi$$a10.1073/pnas.1317022111
000168527 0248_ $$2sideral$$a147935
000168527 037__ $$aART-2014-147935
000168527 041__ $$aeng
000168527 100__ $$0(orcid)0000-0003-4010-849X$$aGoñi, Guillermina M.
000168527 245__ $$aPhosphatidylinositol 4,5-bisphosphate triggers activation of focal adhesion kinase by inducing clustering and conformational changes
000168527 260__ $$c2014
000168527 5060_ $$aAccess copy available to the general public$$fUnrestricted
000168527 5203_ $$aSignificance
Nonreceptor tyrosine kinases are major players in cell signaling. Among them, focal adhesion kinase (FAK) is the key integrator of signals from growth factors and cell adhesion. In cancer, FAK is frequently overexpressed, and by promoting adhesion to the tumor stroma and ECM, FAK provides important signals for tumor invasion and metastasis. Although autoinhibitory mechanisms have previously been described and the players involved in FAK regulation are largely known, on a mechanistic level, FAK activation is currently not understood. Here, we present a multidisciplinary approach demonstrating a multistep mechanism resulting in FAK activation. This mechanistic insight enables the design of alternative strategies for the discovery of potential anticancer drugs that inhibit both catalytic and scaffolding functions of FAK with high specificity.
Abstract
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)P2]. 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)P2 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)P2 induces a partially open FAK conformation where the autophosphorylation site is exposed, facilitating efficient autophosphorylation and subsequent Src recruitment. However, PI(4,5)P2 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)P2 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.
000168527 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc-nd$$uhttps://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
000168527 590__ $$a9.674$$b2014
000168527 591__ $$aMULTIDISCIPLINARY SCIENCES$$b4 / 57 = 0.07$$c2014$$dQ1$$eT1
000168527 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/acceptedVersion
000168527 700__ $$aEpifano, Carolina
000168527 700__ $$aBoskovic, Jasminka
000168527 700__ $$aCamacho-Artacho, Marta
000168527 700__ $$aZhou, Jing
000168527 700__ $$aBronowska, Agnieszka
000168527 700__ $$aMartín, M. Teresa
000168527 700__ $$aEck, Michael J.
000168527 700__ $$aKremer, Leonor
000168527 700__ $$aGräter, Frauke
000168527 700__ $$aGervasio, Francesco Luigi
000168527 700__ $$aPerez-Moreno, Mirna
000168527 700__ $$aLietha, Daniel
000168527 773__ $$g111, 31 (2014), 3177-3186$$pProc. Natl. Acad. Sci.$$tProceedings of the National Academy of Sciences of the United States of America$$x0027-8424
000168527 8564_ $$s2738125$$uhttps://zaguan.unizar.es/record/168527/files/texto_completo.pdf$$yPostprint
000168527 8564_ $$s3784545$$uhttps://zaguan.unizar.es/record/168527/files/texto_completo.jpg?subformat=icon$$xicon$$yPostprint
000168527 909CO $$ooai:zaguan.unizar.es:168527$$particulos$$pdriver
000168527 951__ $$a2026-02-09-14:42:46
000168527 980__ $$aARTICLE