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J. Biol. Chem., Vol. 276, Issue 29, 26741-26744, July 20, 2001

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ACCELERATED PUBLICATION
Platelet-derived Growth Factor Requires Epidermal Growth Factor Receptor to Activate p21-activated Kinase Family Kinases^*

Hong He^§, Alexander Levitzki^¶, Hong-Jian Zhu, Francesca Walker, Antony Burgess, and Hiroshi Maruta

From the  Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Parkville, Melbourne, Australia 3050 and the ^¶ Department of Biological Chemistry, Alexander Silvermann Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel

The platelet-derived growth factor (PDGF) receptor (PDGFR) transactivates the epidermal growth factor (EGF) receptor (ErbB1) to stimulate the cell migration of fibroblasts through an unknown mechanism (Li, J., Kim, Y. N. & Bertics, P. (2000) J. Biol. Chem. 275, 2951-2958). In this paper we provide evidence that the transactivation of the EGF receptor (EGFR) by PDGFR is essential for PDGF to activate p21-activated kinase (PAK) family kinases. Fetal calf serum (10%) transiently stimulates the PAK activity in NIH 3T3 fibroblasts. The activation of PAK was completely inhibited by either PDGFR-specific inhibitor (AG1295) or EGFR-specific inhibitor (AG1478), suggesting that serum requires either the PDGF- or EGF-dependent pathway or the combination of both to activate PAK. PDGF-induced activation of PAK is completely inhibited by either AG1295 or AG1478, indicating that PDGF requires both PDGFR and EGFR for PAK activation. In support of this notion, a mouse embryo fibroblast cell line derived from the EGFR / mouse (from Dr. Erwin Wagner) doesn't activate PAK in response to PDGF. Expression of human EGFR in this cell line restores the ability of the PDGF to induce PAK activation. Our results indicate that PDGF activates PAK through transactivation of ErbB1.

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