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J. Biol. Chem., Vol. 283, Issue 29, 19948-19956, July 18, 2008

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Proliferation Versus Migration in Platelet-derived Growth Factor Signaling

THE KEY ROLE OF ENDOCYTOSIS^*

Alina De Donatis, Giusy Comito, Francesca Buricchi, Maria C. Vinci, Astrid Parenti, Anna Caselli, Guido Camici, Giampaolo Manao, Giampietro Ramponi, and Paolo Cirri¹

From the Dipartimento di Scienze Biochimiche and the Dipartimento di Farmacologia Preclinica e Clinica, Università degli Studi di Firenze, Viale Morgagni 50, 50134 Firenze, Italy

It is common knowledge that platelet-derived growth factor (PDGF) is a critical regulator of mesenchymal cell migration and proliferation. Nevertheless, these two cellular responses are mutually exclusive. To solve this apparent contradiction, we studied the behavior of NIH3T3 fibroblasts in response to increasing concentrations of PDGF. We found that there is strong cell proliferation induction only with PDGF concentrations >5 ng/ml, whereas the cell migration response arises starting from 1 ng/ml and is negligible at higher PDGF concentrations. According to these phenotypic evidences, our data indicate that cells display a differential activation of the main signaling pathways in response to PDGF as a function of the stimulation dose. At low PDGF concentrations, there is maximal activation of signaling pathways linked to cytoskeleton rearrangement needed for cell motility, whereas high PDGF concentrations activate pathways linked to mitogenesis induction. Our results suggest a mechanism by which cells switch from a migrating to a proliferating phenotype sensing the increasing gradient of PDGF. In addition, we propose that the cell decision to proliferate or migrate relies on different endocytotic routes of the PDGF receptor in response to different PDGF concentrations.

Received for publication, November 16, 2007 , and in revised form, April 11, 2008.

^* This work was supported in part by FIRB 2001 Grant RBNE01KJHT_003 (to G. C.) and the Ente Cassa di Risparmio di Firenze. 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. Tel.: 39-55-459-8302; Fax: 39-55-459-8905; E-mail: paolo.cirri{at}unifi.it.

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