Protein Kinase B/AKT and Focal Adhesion Kinase: Two Close Signaling Partners in Cancer

Abstract

AKT (or protein kinase B) and focal adhesion kinase (FAK) are two important kinases that regulate various cellular functions. Each is overexpressed and/or aberrantly activated in diverse cancers. Several small molecular inhibitors targeting either AKT or FAK are in development or in clinical trials. It is well established that FAK is an upstream regulator of AKT signaling pathway in various cancer cell lines and in xenograft tumor models. However, very recent reports from our laboratory and others demonstrate that AKT can also directly regulate FAK through direct association and serine phosphorylation. This indicates that AKT and FAK may be dual therapeutic targets for pharmacologic intervention in the treatment of primary and metastatic cancer. FAK-AKT interaction is particularly critical for metastatic adhesion. We review recent developments in AKT and FAK signaling in cancer with the particular emphasis on the novel signaling pathways in which FAK is downstream of AKT. We also provide an update on inhibitors targeting AKT or FAK currently in clinical trials.

A Novel Role for Keratin 17 in Coordinating Oncogenic Transformation and Cellular Adhesion in Ewing Sarcoma

“…Our data suggest that KRT17 is one of the critical cytoskeletal proteins downstream of EWS/FLI and GLI1 that is necessary to maintain basal levels of cellular adhesion in Ewing sarcoma by activating the AKT signaling pathway. Interestingly, the AKT signaling pathway was previously shown to activate focal adhesion kinase (FAK)-dependent adhesion in cancer (61), further supporting our finding that AKT signaling regulates cellular adhesion in Ewing sarcoma.…”

The Plasma Membrane Sialidase NEU3 Regulates the Malignancy of Renal Carcinoma Cells by Controlling β1 Integrin Internalization and Recycling

“…Second, the down-regulation of ␤1 integrin affected the phosphorylation/activation of FAK. FAK colocalizes with integrins and acts as an early sensor of signaling to directly stimulate tumor progression (35) or activate PI3K/AKT (26). Consistent with this view, the down-regulation of FAK was associated with a markedly reduced AKT activation in the NEU3-silenced cells.…”

“…6A). It is well known that FAK is an upstream regulator of the PI3K/AKT signaling pathway (26). Therefore, to assess whether this interaction between the FAK and PI3K/AKT pathways occurs in the CA-TC cells, we evaluated the inhibition of AKT and found a decrease in the phosphorylated/active form (90%, p Ͻ 0.01) in iNeu3Cl2 cells (Fig.…”

Sphingosine 1-Phosphate (S1P) Receptors 1 and 2 Coordinately Induce Mesenchymal Cell Migration through S1P Activation of Complementary Kinase Pathways*

“…18), which is an upstream activator of the PI3K/AKT signaling pathway (for review, see Ref. 19). We therefore examined S1P influences on FAK/AKT activation and observed rapid activation of both FAK and AKT (Fig.…”