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.
Highlights
Cancer signaling emanated from the interaction between cancer cells and tumor microenvironment is critical for cancer development
In response to cell adhesion, activation of focal adhesion kinase (FAK) is prominent followed by initially recruited to focal contacts and subsequently autophosphorylated on its Tyr397 to participate in integrin-mediated signaling and functions [2,3,4]
In line of integrin activation, the FAT domain of FAK enables targets FAK onto focal adhesion sites via interactions with other focal adhesion complex proteins, such as paxillin, vinculin, and talin. Consistent with this scenario, we have deciphered an inhibitory mechanism of FAK activation in which the intramolecular interaction between the FERM and kinase domains confers FAK toward an inactive conformation, and the release of this autoinhibition rendered by upstream integrin signaling and/or growth factor signaling in a proximal fashion allows the kinase domain of FAK accessible to numerous catalytic substrates essential for its activation and downstream signaling events [6,7,8]
Summary
Cancer signaling emanated from the interaction between cancer cells and tumor microenvironment is critical for cancer development. In line of integrin activation, the FAT domain of FAK enables targets FAK onto focal adhesion sites via interactions with other focal adhesion complex proteins, such as paxillin, vinculin, and talin. Consistent with this scenario, we have deciphered an inhibitory mechanism of FAK activation in which the intramolecular interaction between the FERM and kinase domains confers FAK toward an inactive conformation, and the release of this autoinhibition rendered by upstream integrin signaling (i.e., cell adhesion) and/or growth factor signaling in a proximal fashion allows the kinase domain of FAK accessible to numerous catalytic substrates essential for its activation and downstream signaling events [6,7,8]. We summarize the potent anticancer drugs in relation to FAK-mediated signaling
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