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J. Biol. Chem., Vol. 278, Issue 41, 39882-39891, October 10, 2003

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The Pattern of Enhancement of Src Kinase Activity on Platelet-derived Growth Factor Stimulation of Glioblastoma Cells Is Affected by the Integrin Engaged^*

Qiang Ding , Jerry Stewart, Jr. , Mitchell A. Olman , Michelle R. Klobe  and Candece L. Gladson  ¶

From the Department of Pathology, Division of Neuropathology and the Department of Medicine, Division of Pulmonary and Critical Care Medicine, The University of Alabama at Birmingham, Birmingham, Alabama 35294

Enhanced expression of both integrin _v3 and platelet-derived growth factor receptor (PDGFr) has been described in glioblastoma tumors. We therefore explored the possibility that integrin _v3 cooperates with PDGFr to promote cell migration in glioblastoma cells, and extended the study to identify the Src family members that are activated on PDGF stimulation. Glioblastoma cells utilize integrins _v3 and _v5 to mediate vitronectin attachment. We found that physiologic PDGF stimulation (83 pM, 10 min) of vitronectin-adherent cells promoted the specific recruitment of integrin _v3-containing focal adhesions to the cell cortex and _v3-mediated cell motility. Analysis of PDGFr immunoprecipitates indicated an association of the PDGFr with integrin _v3, but not integrin _v5. Cells plated onto collagen or laminin, which engage different integrins, exhibited significantly less migration on PDGF stimulation, indicating a cooperation of _v3 and the PDGFr in glioblastoma cells that promotes migration. Further analysis of the cells plated onto vitronectin indicated that PDGF stimulation caused an increase in Src kinase activity, which was associated with integrin _v3. In the vitronectin-adherent cells, Lyn was associated preferentially with _v3 both in the presence and absence of PDGF stimulation. In contrast, Fyn was associated with both _v3 and _v5. Moreover, PDGF stimulation increased the activity of Lyn, but not Fyn, in vitronectin-adherent cells, and the activity of Fyn, but not Lyn, in laminin-adherent cells. Using cells attached to mAb anti-_v3 or mAb anti-integrin ₆, we confirmed the activation of specific members of the Src kinase family with PDGF stimulation. Down-regulation of Lyn expression by siRNA significantly inhibited the cell migration mediated by integrin _v3 in PDGF-stimulated cells, demonstrating the PDGFr cooperates with integrin _v3 in promoting the motility of vitronectin-adherent glioblastoma cells through a Lyn kinase-mediated pathway. Notably, the data indicate that engagement of different integrins alters the identity of the Src family members that are activated on stimulation with PDGF.

Received for publication, May 5, 2003 , and in revised form, July 18, 2003.

^* This work was supported by Grants CA59958 and CA97110 from the NCI, National Institutes of Health (to C. L. G.) and by Grant HL58655 from the HLB, National Institutes of Health and the Veterans Administration Merit Review Board (to M. A. O.). 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.

^¶ To whom correspondence should be addressed: University of Alabama at Birmingham, LHRB 567, 701 South 19th St., Birmingham, AL 35294. Tel.: 205-975-7847; Fax: 205-934-7346; E-mail: gladson{at}uab.edu.

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