Abstract
Focal adhesion kinase (FAK) is a tyrosine kinase that associates with focal adhesion complexes upon agonist stimulation. FAK plays a role in diverse cellular responses including cell adhesion, migration, proliferation, and cytoskeletal reorganization. FAK can phosphorylate paxillin and other substrates and recruit effectors such as calpain to focal adhesion complexes. Calpain, a Ca2+-dependent protease, sequentially cleaves 125 kDa FAK into 90 and 45 kDa fragments. Lysophosphatidic acid (LPA) serves as a lipid mediator for various cellular responses including proliferation and survival. We tested the hypothesis that LPA can exert a protective effect on FAK-related signaling events. Ionomycin, a calcium ionophore, was incubated with serum-starved PC3 (human prostate cancer) or OVCAR3 (human ovarian cancer) cells. Western blots were performed to identify intact and degraded FAK in whole-cell extracts. FAK exhibited significant proteolysis when incubated with ionomycin, as compared to untreated control cells. When cells were briefly pre-incubated with LPA and then subsequently exposed to ionomycin, FAK degradation was significantly reduced. The ability of LPA to protect against ionomycin-induced FAK degradation was blocked by Ki16425, an LPA receptor antagonist, and by pertussis toxin. In conclusion, LPA provides transitory protection against calpain-mediated FAK degradation. This effect, which is mediated by LPA receptors, may contribute to the ability of LPA to enhance survival of cancer cells. (Supported by DAMD17-01-1-0730).
Published Version
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