Focal adhesion kinase and p53 signal transduction pathways in cancer

Abstract

Human cancer is characterized by a process of tumor cell motility, invasion, and metastasis. One of the critical tyrosine kinases that is linked to these processes of tumor invasion and survival is the Focal Adhesion Kinase (FAK). Our laboratory was the first to isolate FAK from human tumors, and we had demonstrated that FAK mRNA was up-regulated in invasive and metastatic human breast and colon cancer samples. We have cloned FAK promoter and have found that FAK promoter contains p53 binding sites, and that p53 inhibits FAK transcription and regulates its expression in tumor samples. In addition, we have found a high correlation between FAK overexpression and p53 mutations in 600 population-based series of breast cancer patients. found that N-myc binds FAK promoter and induces FAK transcription in neuroblastoma cells. Thus, this review will be focused on FAK and p53 signal transduction pathways in cancer.

Figure 1

Focal Adhesion Kinase is overexpressed in tumor samples. Immunohistochemical staining is shown for colon cancer sample. Left panel: normal tissue, right panel: matched tumor tissue from the same patient.

Figure 2

Focal Adhesion Kinase (FAK) structure. FAK has the N-terminal, Kinase domain and the C-terminal domains. The N-terminal domain has Y-397-Y-autophosphorylation site. The Kinase domain has Y576/577 tyrosines important for catalytic activity of FAK. The C-terminal domain of FAK has Y861 and Y925 tyrosines. Different proteins bind to these domains and involved in motility and survival signaling, The N-terminal domain (205–422 a.a.) of FAK is involved in interaction with Src, RIP, p53, PI3Kinase, PIAS-1, PI3Kinase, Grb-7, EGFR/PDGFR, Ezrin, Bmx, Trio and others. Kinase domain is involved in binding with FIP200 protein. ASAP, p130Cas, Grb-2, Paxillin, Talin, RhoGEFp190 and other proteins bind C-terminal domain of FAK. Interactions of FAK and other proteins demonstrated by group are shown in Italics.

Figure 3

Immunohistochemical staining of FAK and p53 in colon tumor. FAK is stained with FITC, p53 is stained with Rhodamin and nuclei with Hoechst. Arrow indicate co-localization of FAK and p53 (yellow color).

Figure 4

Sequestration and Integration Model of FAK functions in cells and signal transduction pathways from extracellular matrix to the cytoplasm and nucleus. The central part of the scheme is modified from (12). Focal Adhesion Kinase integrates signals from growth factor receptors (EGFR, IGFR), vascular endothelial growth factor receptors (VEGFR-3), Src and integrins to control motility, survival, proliferation, metastasis, lymphangiogenesis and angiogenesis. Numerous binding partners of FAK mediate this signaling. FAK sequesters pro-apoptotic proteins, such as p53 from apoptotic signaling. P53 binds FAK promoter and inhibits its transcription. There is a feedback loop in FAK-p53 regulation. Thus, FAK mediate signaling from extracellular matrix to the cytoplasm and nucleus.