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J. Biol. Chem., Vol. 281, Issue 13, 8497-8510, March 31, 2006

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Integrin 2-mediated ERK and Calpain Activation Play a Critical Role in Cell Adhesion and Motility via Focal Adhesion Kinase Signaling

IDENTIFICATION OF A NOVEL SIGNALING PATHWAY^*

From the Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263

Higher levels of focal adhesion kinase (FAK) are expressed in colon metastatic carcinomas. However, the signaling pathways and their mechanisms that control cell adhesion and motility, important components of cancer metastasis, are not well understood. We sought to identify the integrin-mediated mechanism of FAK cleavage and downstream signaling as well as its role in motility in human colon cancer GEO cells. Our results demonstrate that phosphorylated FAK (tyrosine 397) is cleaved at distinct sites by integrin signaling when cells attach to collagen IV. Specific blocking antibodies (clone P1E6) to integrin 2 inhibited FAK activation and cell motility (micromotion). Ectopic expression of the FAK C-terminal domain FRNK attenuated FAK and ERK phosphorylation and micromotion. Calpain inhibitor N-acetyl-leucyl-leucyl-norleucinal blocked FAK cleavage, cell adhesion, and micromotion. Antisense approaches established an important role for µ-calpain in cell motility. Expression of wild type µ-calpain increased cell micromotion, whereas its point mutant reversed the effect. Further, cytochalasin D inhibited FAK phosphorylation and cleavage, cell adhesion, locomotion, and ERK phosphorylation, thus showing FAK activation downstream of actin assembly. We also found a pivotal role for FAK Tyr⁸⁶¹ phosphorylation in cell motility and ERK activation. Our results reveal a novel functional connection between integrin 2 engagement, FAK, ERK, and µ-calpain activation in cell motility and a direct link between FAK cleavage and enhanced cell motility. The data suggest that blocking the integrin 2/FAK/ERK/µ-calpain pathway may be an important strategy to reduce cancer progression.

Received for publication, January 25, 2006

^* This work was supported by National Institutes of Health Grants CA 16056, 54807, 34432, and 50457, by the Oncologic Foundation of Buffalo/Alliance Foundation, and by the Shelby Rae Tengg Foundation. 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 may be addressed: Dept. of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton St., Buffalo, NY 14263. Tel.: 716-845-5874; Fax: 716-845-8857; E-mail: rajinder.sawhney{at}roswellpark.org. ² To whom correspondence may be addressed: Dept. of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton St., Buffalo, NY 14263. Tel.: 716-845-3044; Fax: 716-845-8857; E-mail: michael.brattain{at}roswellpark.org.

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