Focal Adhesion Kinase Functions as an Akt Downstream Target in Migration of Colorectal Cancer Cells

Abstract

Migration is a complex process that, besides its various physiological functions in embryogenesis and adult tissues, plays a crucial role in cancer cell invasion and metastasis. The focus of this study is the involvement and collaboration of Akt, focal adhesion kinase (FAK), and Src kinases in migration and invasiveness of colorectal cancer cells. We show that all three kinases can be found in one protein complex; nevertheless, the interaction between Akt and Src is indirect and mediated by FAK. Interestingly, induced Akt signaling causes an increase in tyrosine phosphorylation of FAK, but this increase is attenuated by the Src inhibitor SU6656. We also show that active Akt strongly stimulates cell migration, but this phenomenon is fully blocked by FAK knockdown or partly by inhibition of Src kinase. In addition, we found that all three kinases were indispensable for the successful invasion of colorectal cancer cells. Altogether, the presented data bring new insights into the mechanism how the phosphatidylinositol-3-kinase (PI3-K)/Akt pathway can influence migration of colorectal adenocarcinoma cells. Because FAK is indispensable for cell movements and functions downstream of Akt, our results imply FAK kinase as a potential key molecule during progression of tumors with active PI3-K/Akt signaling.

Neutral endopeptidase (NEP) is differentially involved in biological activities and cell signaling of colon cancer cell lines derived from various stages of tumor development

“…In tumor cells, including colon cancer cells, they are also responsible for the migration and invasive activity, similarly to FAK [7, 8, 12, 22–28]. In this study, it was examined whether these signaling pathways are mediated by NEP.…”

“…In the case of the latter, the action of the peptidase was coordinated with the PI3-K/Akt, PTEN, Src, and FAK signaling pathways [2, 6]. There are also studies showing that these signaling pathways mediate the function of colon cancer cells [22–28]. Surprisingly, there are no reports which would implicate NEP in the biology of colon cancer cells in connection with the mentioned signaling pathways.…”

“…This was accompanied by an increased phosphorylation of FAK at Tyr397 and Akt. The involvement of FAK as a downstream target of Akt in colon cancer cell migration has been investigated by Turečkova et al [28]. It seems likely that NEP silencing in LS 180 and SW 620 led to an enhanced activity of PI3-K and subsequently Akt.…”

Akt directly regulates focal adhesion kinase through association and serine phosphorylation: implication for pressure-induced colon cancer metastasis

“…However, recent results from our laboratory (41) and from others (44,48) suggest that FAK may also be regulated by Akt directly or indirectly in some contexts. In the present study, we used bioinformatic, biochemical, molecular biological, and pharmacological approaches in colon cancer cells exposed to extracellular pressure to demonstrate that Akt-1 binds directly to and phosphorylates FAK at S517/601/695.…”

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.…”