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Molecular and Cellular Biology, October 2001, p. 6387-6394, Vol. 21, No. 19
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.19.6387-6394.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Receptor Heterodimerization: Essential Mechanism for Platelet-Derived Growth Factor-Induced Epidermal Growth Factor Receptor Transactivation

Yuji Saito, Judith Haendeler, Yukihiro Hojo, Kei Yamamoto, and Bradford C. Berk*

Center for Cardiovascular Research, University of Rochester, Rochester, New York

Received 18 April 2001/Returned for modification 29 May 2001/Accepted 18 June 2001

Previous studies showed that the epidermal growth factor receptor (EGFR) can be transactivated by platelet-derived growth factor (PDGF) stimulation and that EGFR transactivation is required for PDGF-stimulated cell migration. To investigate the mechanism for cross talk between the PDGF beta  receptor (PDGFbeta R) and the EGFR, we stimulated rat aortic vascular smooth muscle cells (VSMC) with 20 ng of PDGF/ml. Transactivation of the EGFR, defined by receptor tyrosine phosphorylation, occurred with the same time course as PDGFbeta R activation. Basal formation of PDGFbeta R-EGFR heterodimers was shown by coimmunoprecipitation studies, and interestingly, disruption of this receptor heterodimer abolished EGFR transactivation. Breakdown of the heterodimer was observed when VSMC were pretreated with antioxidants or with a Src family kinase inhibitor. Disruption of heterodimers decreased ERK1 and ERK2 activation by PDGF. Although PDGF-induced PDGFbeta R activation was abolished after pretreatment with 1 µM AG1295 (a specific PDGF receptor kinase inhibitor), EGFR transactivation was still observed, indicating that PDGFbeta R kinase activity is not required. In conclusion, our data demonstrate that the PDGFbeta R and the EGFR form PDGFbeta R-EGFR heterodimers basally, and we suggest that heterodimers represent a novel signaling complex which plays an important role in PDGF signal transduction.

* Corresponding author. Mailing address: Center for Cardiovascular Research, University of Rochester, 601 Elmwood Ave., Box 679, Rochester, NY 14642. Phone: (716) 273-1946. Fax: (716) 273-1497. E-mail: bradford_berk{at}urmc.rochester.edu.

Molecular and Cellular Biology, October 2001, p. 6387-6394, Vol. 21, No. 19
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.19.6387-6394.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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