Cell-type specific phosphorylation of threonines T654 and T669 by PKD defines the signal capacity of the EGF receptor.
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.
Bagowski
C P
CP
Department of Molecular Biology, Max-Planck-Institute for Biochemistry, Am Klopferspitz 18A, 82152 Martinsried, Germany.
Stein-Gerlach
M
M
Choidas
A
A
Ullrich
A
A
D016475:3T3 Cells; D000818:Animals; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016762:Genes, fos; D016758:Genes, jun; D006801:Humans; D051379:Mice; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020239:Receptor Cross-Talk; D015398:Signal Transduction; D013912:Threonine / Q000378:metabolism*
D010982:Platelet-Derived Growth Factor; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D013912:Threonine; D004815:Epidermal Growth Factor; D004247:DNA; C089212:protein kinase D; D066246:ErbB Receptors; D011493:Protein Kinase C