Cellular functions of FAK kinases: insight into molecular mechanisms and novel functions

Abstract

SummaryFocal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) are related tyrosine kinases that have important cellular functions, primarily through regulation of the cytoskeleton. Recent studies have identified multiple molecular mechanisms that regulate cytoskeletal responses, and have provided important and exciting insights into how FAK and Pyk2 control cellular processes such as cell migration. Equally exciting are reports of novel and originally unanticipated functions of these kinases, providing the groundwork for future avenues of investigation. This Commentary summarizes some of these recent discoveries that are relevant to the control of biological responses of the cell. Key words: FAK, Pyk2, Rho, Cell migration, MicrotubulesJournal of Cell Science 1008 relocalization of the Golgi to the side of the nucleus closest to the wound. There is some evidence suggesting that this event is important for directional motility into the wound; perturbation of proteins whose primary function is regulation of Golgi structure alters relocalization of the Golgi and impairs cell migration in a wound-healing assay (Yadav et al., 2009). Whether this is a universal event associated with directional motility is clearly questionable, as there is no correlation between Golgi location and direction of movement in randomly migrating fibroblasts (Uetrecht and Bear, 2009). Regardless, there is a defect in relocalization of the Golgi in wounded monolayers of cells lacking FAK (Tilghman et al., 2005;). In the absence of FAK, cells at the edge of the wound fail to form prominent lamellipodia that protrude into the wound. Interestingly, Pyk2 also functions in controlling cell polarization; macrophages that lack Pyk2 are defective in establishing a polarized morphology in response to a chemotactic stimulus (Okigaki et al., 2003). These findings show a role for FAK and Pyk2 in the establishment of cell polarity in response to a stimulus to migrate (Fig. 2).Time-lapse video microscopy of individual cells migrating in two dimensions reveals a defect in directional persistence in cells with impaired FAK function (Owen et al., 2007;Wang et al., 2001). Analysis of lamellipodial behavior in macrophages lacking FAK reveals increased protrusion and retraction of lamellipodia, but defective persistence compared with wild-type macrophages (Owen et al., 2007). Pyk2 also functions in the control of macrophage motility; Pyk2-null cells also exhibit migration defects (Okigaki et al., 2003). Inhibition of FAK or Pyk2 expression in macrophages impairs colony-stimulating factor-1 (CSF-1)-induced invasion by about 60%, but simultaneous inhibition of the expression of both does not inhibit invasion further (Owen et al., 2007). Thus, both FAK and Pyk2 are required for invasion and, in this scenario, appear to function non-redundantly. These studies demonstrate a role for FAK and Pyk2 in controlling macrophage migration, and a role for FAK in regulating events at the leading edge of migrating cells (Fig. 2).There is also evidence that FAK ...

CCN1 (CYR61) and CCN3 (NOV) signaling drives human trophoblast cells into senescence and stimulates migration properties

“…FAK is involved in integrinmediated signal transduction pathways of the extracellular matrix and plays an important role in the regulation of cell proliferation, migration, and invasion. 53 It is known that the activation of Akt and ERK1/2 is related to cell migration and the activation of FAK [54][55][56][57] and that these kinases are involved in trophoblast migration and invasion (reviewed by Chakraborty et al 8 ). In SGHPL-5 cells, phosphorylation and thereby activation of FAK occurs only after treatment with glycosylated CCN3.…”

Germinal center kinases in immune regulation

“…The activity, localization and downstream signaling of FAK are regulated by its interactions with other partners through the FERM, proline-rich and FAT domains. 89,90 FAK is involved in integrin signaling, cytoskeletal remodeling, cell polarity and migration. 89 FAK is involved with TLR-induced MyD88 signaling, which plays a role in initiating innate immune responses.…”

“…89,90 FAK is involved in integrin signaling, cytoskeletal remodeling, cell polarity and migration. 89 FAK is involved with TLR-induced MyD88 signaling, which plays a role in initiating innate immune responses. 87 FAK and CD4 have been implicated in a signaling complex in T cells stimulated by the HIV protein gp120.…”

Nuclear FAK: a New Mode of Gene Regulation from Cellular Adhesions

“…Extracellular signals through integrin and growth factor receptor modulate focal adhesion kinase (FAK) function in development, cell migration, cell proliferation, tumor metastasis and angiogenesis (McLean et al, 2005;Mitra et al, 2005;Schaller, 2010). Increasing attention to the importance of FAK activity in triggering cancer progression has elicited, and small molecule FAK inhibitors have been extensively tested to develop anti-cancer therapeutics (Roberts et al, 2008;Stokes et al, 2011;Walsh et al, 2010).…”