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Mol Cell Biol, April 1998, p. 2014-2022, Vol. 18, No. 4
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Activation of Src Family Members Is Not Required for the Platelet-Derived Growth Factor beta  Receptor To Initiate Mitogenesis

Kris A. DeMali and Andrius Kazlauskas*

Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts 02114, and University of Colorado Health Sciences Center, Department of Pharmacology, Denver, Colorado 80206

Received 18 September 1997/Returned for modification 21 October 1997/Accepted 20 January 1998

The basal activity of Src family kinases is readily detectable throughout the cell cycle and increases by two- to fivefold upon acute stimulation of cells with growth factors such as platelet-derived growth factor. Previous reports have demonstrated a requirement for Src activity for the G1/S and G2/M transitions. With a chimeric alpha -beta PDGF receptor (PDGFR) expressed in fibroblasts, we have investigated the importance of the PDGF-mediated increase in Src activity at the G0/G1 transition for subsequent cell cycle events. A mutant PDGFR chimera that was not able to detectably associate with or activate Src was compromised in its ability to mediate tyrosine phosphorylation of receptor-associated signaling molecules and initiated a submaximal activation of Erk. In contrast to these early cell cycle events, later responses such as entry of cells into S phase and cell proliferation proceeded normally when Src activity did not increase following acute stimulation with PDGF. We conclude that the initial burst of Src activity is required for efficient tyrosine phosphorylation of receptor-associated proteins such as PLCgamma , RasGAP, Shc, and SHP-2 and for maximal activation of Erk. Surprisingly, these events are not required for PDGF-dependent cell proliferation. Finally, later cell cycle events do not require that Src be activated at the G0/G1 transition and leave open the possibility that events such as the G1/S transition require the basal Src activity and/or activation of Src at later times in G1.

* Corresponding author. Mailing address: Schepens Eye Research Institute, Harvard Medical School, 20 Staniford St., Boston, MA 02114. Phone: (617) 912-2517. Fax: (617) 912-0111. E-mail: kazlauskas{at}vision.eri.harvard.edu.




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