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J. Biol. Chem., Vol. 281, Issue 14, 9450-9459, April 7, 2006

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Urokinase-type Plasminogen Activator Receptor Regulates a Novel Pathway of Fibronectin Matrix Assembly Requiring Src-dependent Transactivation of Epidermal Growth Factor Receptor^*

From the Center for Cell Biology and Cancer Research, Albany Medical College, Albany, New York 12208

Previous studies have indicated that the urokinase-type plasminogen activator receptor (uPAR) can functionally interact with integrins thereby modulating integrin activity. We have previously demonstrated that treatment of fibroblasts with the uPAR ligand, P25, results in an increase in the activation of the 1 integrin and a 35-fold increase in fibronectin matrix assembly (Monaghan, E., Gueorguiev, V., Wilkins-Port, C., and McKeown-Longo, P. J. (2004) J. Biol. Chem. 279, 1400-1407). Experiments were conducted to address the mechanism of uPAR regulation of matrix assembly. Treatment of fibroblasts with P25 led to an increase in the activation of the epidermal growth factor receptor (EGFR) and a colocalization of activated EGFR with 1 integrins in cell matrix contacts. The effects of P25 on matrix assembly and 1 integrin activation were inhibited by pretreatment with EGFR or Src kinase inhibitors, suggesting a role for both Src and EGFR in integrin activation by uPAR. Phosphorylation of EGFR in response to P25 occurred on Tyr-845, an Src-dependent phosphorylation site and was inhibited by PP2, the Src kinase inhibitor, consistent with Src kinase lying upstream of EGFR and integrin activation. Cells null for Src kinases also showed a loss of P25-induced matrix assembly, integrin activation, and EGFR phosphorylation. These P25-induced effects were restored following Src re-expression. The effects of P25 were specific for uPAR as enhanced matrix assembly by P25 was not seen in uPAR-/- cells, but was restored upon uPAR re-expression. These data provide evidence for a novel pathway of fibronectin matrix assembly through the uPAR-dependent sequential activation of Src kinase, EGFR, and 1 integrin.

Received for publication, February 18, 2005 , and in revised form, December 9, 2005.

^* These studies were supported in part by Grant CA-58626 from the National Institutes of Health (NIH) (to P. M.-L.). 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 Supported by NHLBI, NIH Training Grant T32-HL-07194.

² To whom correspondence should be addressed: Center for Cell Biology & Cancer Research, MC-165, Albany Medical College, 47 New Scotland Ave., Albany, NY 12208. Tel.: 518-262-5651; Fax: 518-262-5669; E-mail: mckeowp{at}mail.amc.edu.

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