FERM control of FAK function: implications for cancer therapy.
Integrins are transmembrane receptors that bind to extracellular matrix proteins and convey anchorage-dependent signals regulating normal cell proliferation. Integrin signals within the tumor micro-environment also impact cancer cell survival and invasion during tumor progression. These integrin-associated signaling events are transduced in part through the activation of non-receptor protein-tyrosine kinases. Focal adhesion kinase (FAK) is activated by beta-subunit integrins in both normal and transformed cells. As genetic inactivation of beta1 integrin or FAK yield early embryonic lethal phenotypes associated with decreased cell proliferation, and dominant-negative inhibition of FAK can cause increased cell apoptosis, there is a concern that FAK inhibition may have cytotoxic effects on cell growth or survival. However, FAK-specific small molecule inhibitors do not directly impact cell growth in culture, but yet show potent anti-tumor growth effects in vivo. Additionally, recent studies have shed new insight into the FAK kinase-independent regulation of cell proliferation and survival mediated by the FAK N-terminal FERM (band 4.1, ezrin, radixin, moesin homology) domain. Herein, we review the role of the FAK FERM domain in both the intrinsic regulation of FAK kinase activity and how FERM-mediated nuclear localization of FAK promotes enhanced cell survival through the inhibition of tumor suppressor p53 activation during development and under conditions of cellular stress. As we find that FAK FERM-mediated regulation of p53 occurs in human carcinoma cells, elevated FAK expression in tumors may promote both kinase-dependent and -independent survival mechanisms. We discuss how the pharmacological inhibition of FAK kinase activity may impact tumor progression through combined effects of blocking both tumor- and stromal-associated signaling regulating neo-vascularization.
Lim
Ssang-Taek
ST
Department of Reproductive Medicine, UCSD Moores Cancer Center, La Jolla, California 92093-0803, USA.
Mikolon
David
D
Stupack
Dwayne G
DG
Schlaepfer
David D
DD
D000970:Antineoplastic Agents / Q000627:therapeutic use; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D003598:Cytoskeletal Proteins / Q000737:chemistry; D004789:Enzyme Activation; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D016158:Genes, p53 / Q000502:physiology; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors / Q000502:physiology; D008565:Membrane Proteins / Q000737:chemistry; D008954:Models, Biological; D009369:Neoplasms / Q000628:therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport; D015398:Signal Transduction / Q000502:physiology
D000970:Antineoplastic Agents; D003598:Cytoskeletal Proteins; D016023:Integrins; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; C028841:erythrocyte membrane band 4.1 protein; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human