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J. Biol. Chem., Vol. 281, Issue 41, 30383-30392, October 13, 2006

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Perlecan Proteolysis Induces an 21 Integrin- and Src Family Kinase-dependent Anti-apoptotic Pathway in Fibroblasts in the Absence of Focal Adhesion Kinase Activation^*

Patrick Laplante, Marc-André Raymond, Andrée Labelle, Jun-Ichi Abe, Renato V. Iozzo^¶, and Marie-Josée Hébert¹

From the Centre de Recherche du Centre Hospitalier de l'Université de Montreal, University of Montreal, 1560 Sherbrooke East, Montreal, Quebec H2L 4M1, Canada, Center for Cardiovascular Research, University of Rochester, Rochester, New York 14642, and ^¶Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Dysregulation of apoptosis in endothelial cells (EC) and fibroblasts contributes to fibrosis. We have shown previously that apoptosis of EC triggers the proteolysis of extracellular matrix components and the release of a C-terminal fragment of perlecan, which in turn inhibits apoptosis of fibroblasts. Here we have defined the receptors and pathways implicated in this anti-apoptotic response in fibroblasts. Neutralizing 21 integrin activity in fibroblasts exposed to either medium conditioned by apoptotic EC (SSC) or a recombinant perlecan C-terminal fragment (LG3) prevented resistance to apoptosis and is associated with decreased levels of Akt phosphorylation. Co-incubation of fibroblasts for 24 h with SSC or LG3 in the presence of PP2 (AG1879), a biochemical inhibitor of Src family kinases (SFKs) and focal adhesion kinase, showed a significantly decreased anti-apoptotic response. However, focal adhesion kinase gene silencing with RNA interference did not inhibit the anti-apoptotic response in fibroblasts. Src phosphorylation was increased in fibroblasts exposed to SSC, and transfection of fibroblasts with constitutively active Src mutants induced an anti-apoptotic response that was not further increased by SSC. Also, Src^–/–Fyn^–/– fibroblasts failed to mount an anti-apoptotic response in presence of SSC for 24 h but developed a complete anti-apoptotic response when exposed to SSC for 7 days. These results suggest that extracellular matrix fragments produced by apoptotic EC initiate a state of resistance to apoptosis in fibroblasts via an 21 integrin/SFK (Src and Fyn)/phosphatidylinositol 3-kinase (PI3K)-dependent pathway. In the long term, additional SFK members are recruited for sustaining the anti-apoptotic response, which could play crucial roles in abnormal fibrogenic healing.

Received for publication, July 5, 2006

^* This work was supported by an operating grant (MT-15447) from the Canadian Institutes of Health Research and the Kidney Foundation of Canada (to M.-J. H.). 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 Scholar of the Fonds de la Recherche en Santé du Québec. To whom correspondence and reprint requests should be addressed: CRCHUM, 1560 Sherbrooke E., Montreal, Quebec H2L 4M1, Canada. Tel.: 514-890-8000 (ext. 25393); Fax: 514-412–7661; E-mail: marie-josee.hebert.chum{at}ssss.gouv.qc.ca.

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