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      Emerging Roles of Focal Adhesion Kinase in Cancer

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          Abstract

          Focal adhesion kinase (FAK) is a cytoplasmic nonreceptor tyrosine kinase that enables activation by growth factor receptors or integrins in various types of human cancers. The kinase-dependent and kinase-independent scaffolding functions of FAK modulate the authentic signaling and fundamental functions not only in cancer cells but also in tumor microenvironment to facilitate cancer progression and metastasis. The overexpression and activation of FAK are usually investigated in primary or metastatic cancers and correlated with the poor clinical outcome, highlighting FAK as a potential prognostic marker and anticancer target. Small molecule inhibitors targeting FAK kinase activity or FAK-scaffolding functions impair cancer development in preclinical or clinical trials. In this review, we give an overview for FAK signaling in cancer cells as well as tumor microenvironment that provides new strategies for the invention of cancer development and malignancy.

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          FAK-Src signalling through paxillin, ERK and MLCK regulates adhesion disassembly.

          Donna J Webb, Karen Donais, Leanna Whitmore … (2004)
          Cell migration is a complex, highly regulated process that involves the continuous formation and disassembly of adhesions (adhesion turnover). Adhesion formation takes place at the leading edge of protrusions, whereas disassembly occurs both at the cell rear and at the base of protrusions. Despite the importance of these processes in migration, the mechanisms that regulate adhesion formation and disassembly remain largely unknown. Here we develop quantitative assays to measure the rate of incorporation of molecules into adhesions and the departure of these proteins from adhesions. Using these assays, we show that kinases and adaptor molecules, including focal adhesion kinase (FAK), Src, p130CAS, paxillin, extracellular signal-regulated kinase (ERK) and myosin light-chain kinase (MLCK) are critical for adhesion turnover at the cell front, a process central to migration.
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            Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src.

            M D Schaller, J D Hildebrand, J. D. Shannon … (1994)
            The phosphorylation of protein tyrosine kinases (PTKs) on tyrosine residues is a critical regulatory event that modulates catalytic activity and triggers the physical association of PTKs with Src homology 2 (SH2)-containing proteins. The integrin-linked focal adhesion kinase, pp125FAK, exhibits extracellular matrix-dependent phosphorylation on tyrosine and physically associates with two nonreceptor PTKs, pp60src and pp59fyn, via their SH2 domains. Herein, we identify Tyr-397 as the major site of tyrosine phosphorylation on pp125FAK both in vivo and in vitro. Tyrosine 397 is located at the juncture of the N-terminal and catalytic domains, a novel site for PTK autophosphorylation. Mutation of Tyr-397 to a nonphosphorylatable residue dramatically impairs the phosphorylation of pp125FAK on tyrosine in vivo and in vitro. The mutation of Tyr-397 to Phe also inhibits the formation of stable complexes with pp60src in cells expressing Src and FAK397F, suggesting that autophosphorylation of pp125FAK may regulate the association of pp125FAK with Src family kinases in vivo. The identification of Tyr-397 as a major site for FAK autophosphorylation provides one of the first examples of a cellular protein containing a high-affinity binding site for a Src family kinase SH2 domain. This finding has implications for models describing the mechanisms of action of pp125FAK, the regulation of the Src family of PTKs, and signal transduction through the integrins.
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              Signal transduction by focal adhesion kinase in cancer.

              Jihe Zhao, Jun-Lin Guan (2009)
              Cellular interactions with extracellular matrix play essential roles in tumor initiation, progression and metastasis. Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase identified as a key mediator of signaling by integrins, a major family of cell surface receptors for extracellular matrix, as well as other receptors in both normal and cancer cells. FAK is activated by integrins through disruption of an auto-inhibitory intra-molecular interaction between its kinase domain and the amino terminal FERM domain. The activated FAK forms a binary complex with Src family kinases which can phosphorylate other substrates and trigger multiple intracellular signaling pathways to regulate various cellular functions. Subcellular localization of FAK in focal adhesions is essential for FAK signaling, which is another distinguishing feature of the kinase. Integrin-FAK signaling has been shown to activate a number of signaling pathways through phosphorylation and protein-protein interactions to promote tumorigenesis. FAK also plays a prominent role in tumor progression and metastasis through its regulation of both cancer cells and their microenvironments including cancer cell migration, invasion, epithelial to mesenchymal transition, and angiogenesis. More recently, a role for FAK in tumor initiation and progression has been demonstrated directly using xenograft as well as conditional knockout mouse models. In agreement with these experimental data, overexpression and activation of FAK have been found in a variety of human cancers. A number of small molecule inhibitors for FAK have been developed and in various phases of testing for cancer treatments. Overall, the intensive research on FAK signaling in cancer have yielded a wealth of information on this pivotal kinase and these and future studies are leading to potentially novel therapies for cancer.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Biomed Res Int
                Journal ID (iso-abbrev): Biomed Res Int
                Journal ID (publisher-id): BMRI
                Title: BioMed Research International
                Publisher: Hindawi Publishing Corporation
                ISSN (Print): 2314-6133
                ISSN (Electronic): 2314-6141
                Publication date (Print): 2015
                Publication date (Electronic): 31 March 2015
                Volume: 2015
                Electronic Location Identifier: 690690
                Affiliations
                1Department of Plant Pathology and Microbiology, National Taiwan University, Taipei 10617, Taiwan
                2Department of Medicine, Mackay Medical College, New Taipei City 25245, Taiwan
                3Center for Biotechnology, National Taiwan University, Taipei 10617, Taiwan
                Author notes
                *Tang-Long Shen: shentl@ 123456ntu.edu.tw

                Academic Editor: Hiroshi Hasegawa

                Article
                DOI: 10.1155/2015/690690
                PMC ID: 4396139
                PubMed ID: 25918719
                SO-VID: bddbc61d-f29b-4dd6-9cb2-734ea1c07340
                Copyright © Copyright © 2015 Yu-Ling Tai et al.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 16 January 2015
                Date accepted : 20 February 2015
                Categories
                Subject: Review Article

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