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J. Biol. Chem., Vol. 281, Issue 46, 35567-35575, November 17, 2006

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Suppression of Cancer Cell Migration and Invasion by Protein Phosphatase 2A through Dephosphorylation of µ- and m-Calpains^*

From the Shands Cancer Center, Department of Medicine and Department of Anatomy and Cell Biology, University of Florida Health Science Center, Gainesville, Florida 32610-3633

The µ- and m-calpains are major members of the calpain family that play an essential role in regulating cell motility. We have recently discovered that nicotine-activated protein kinase C enhances calpain phosphorylation in association with enhanced calpain activity and accelerated migration and invasion of human lung cancer cells. Here we found that specific disruption of protein phosphatase 2A (PP2A) activity by expression of SV40 small tumor antigen up-regulates phosphorylation of µ- and m-calpains whereas C2-ceramide, a potent PP2A activator, reduces nicotine-induced calpain phosphorylation, suggesting that PP2A may function as a physiological calpain phosphatase. PP2A co-localizes and interacts with µ- and m-calpains. Purified, active PP2A directly dephosphorylates µ- and m-calpains in vitro. Overexpression of the PP2A catalytic subunit (PP2A/C) suppresses nicotine-stimulated phosphorylation of µ- and m-calpains, which is associated with inhibition of calpain activity, wound healing, cell migration, and invasion. By contrast, depletion of PP2A/C by RNA interference enhances calpain phosphorylation, calpain activity, cell migration, and invasion. Importantly, C2-ceramide-induced suppression of calpain phosphorylation results in decreased secretion of µ- and m-calpains from lung cancer cells into culture medium, which may have potential clinic relevance in controlling metastasis of lung cancer. These findings reveal a novel role for PP2A as a physiological calpain phosphatase that not only directly dephosphorylates but also inactivates µ- and m-calpains, leading to suppression of migration and invasion of human lung cancer cells.

Received for publication, August 11, 2006 , and in revised form, September 12, 2006.

^* This work was supported by a Flight Attendant Medical Research Institute Clinical Innovator Award and by NCI, National Institutes of Health Grant R01 CA112183 (to X. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: University of Florida Shands Cancer Center, 1376 Mowry Rd., Cancer/Genetics Research Complex, Rm. 262, P. O. Box 103633, Gainesville, FL 32610-3633. Tel.: 352-273-8170; Fax: 352-273-8285; E-mail: xdeng{at}ufscc.ufl.edu.

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