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18 (20): 5567-5576

Copyright © 1999 by the European Molecular Biology Organization.

The EMBO Journal Vol. 18,pp. 5567-5576, 1999, Copyright © European Molecular Biology Organization

Cell-type specific phosphorylation of threonines T654 and T669 by PKD defines the signal capacity of the EGF receptor

Christoph P. Bagowski, Matthias Stein-Gerlach, Axel Choidas and Axel Ullrich

Department of Molecular Biology, Max-Planck-Institute for Biochemistry, Am Klopferspitz 18A, 82152 Martinsried, Germany
1   Present address: Stanford University, Department of Molecular Pharmacology, 300 Pasteur Drive, CA, USA
2   Present address: Virgene Pharmaceuticals, Am Klopferspitz 19, 82152 Martinsried, Germany
3   Corresponding author
   e-mail: ullrich{at}biochem.mpg.de

In Rat-1 fibroblasts epidermal growth factor (EGF), but not platelet-derived growth factor (PDGF) stimulates the activity of the c-Jun N-terminal kinase (JNK). Moreover, PDGF induced suppression of EGF-mediated JNK activation, apparently through protein kinase C (PKC) activation. Further analysis revealed that PKD was specifically activated by PDGF but not EGF in Rat-1 cells. In SF126 glioblastoma cells, however, EGF and PDGF synergistically activated JNK, while neither PDGF nor EGF stimulated PKD activity. In this cell line, overexpression of PKD blocked EGF- and PDGF-induced JNK activation. Mutational analysis further revealed that the EGFR mutant (T654/669E) was incapable of activating JNK and provided evidence that PKD-mediated dual phosphorylation of these critical threonine residues leads to suppression of EGF-induced JNK activation. Our results establish a novel crosstalk mechanism which allows signal integration and definition in cells with many different RTKs.

Keywords: c-Jun N-terminal kinase/epidermal growth factor receptor/platelet-derived growth factor receptor/protein kinase D/threonine phosphorylation

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