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.
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
receptor (PDGF
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 PDGF
R
activation. Basal formation of PDGF
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
PDGF
R activation was abolished after pretreatment with 1 µM AG1295
(a specific PDGF receptor kinase inhibitor), EGFR transactivation was
still observed, indicating that PDGF
R kinase activity is not
required. In conclusion, our data demonstrate that the PDGF
R and the
EGFR form PDGF
R-EGFR heterodimers basally, and we suggest that
heterodimers represent a novel signaling complex which plays an
important role in PDGF signal transduction.
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