Signal transduction by epidermal growth factor and heregulin via the kinase-deficient ErbB3 protein.
The role of protein tyrosine kinase activity in ErbB3-mediated signal transduction was investigated. ErbB3 was phosphorylated in vivo in response to either heregulin (HRG) in cells expressing both ErbB3 and ErbB2, or epidermal growth factor (EGF) in cells expressing both ErbB3 and EGF receptor. A recombinant receptor protein (ErbB3-K/M, in which K/M stands for Lys-->Met amino acid substitution) containing an inactivating mutation in the putative ATP-binding site was also phosphorylated in response to HRG and EGF. Both the wild-type ErbB3 and mutant ErbB3-K/M proteins transduced signals to phosphatidylinositol 3-kinase, Shc and mitogen-activated protein kinases. Separate kinase-inactivating mutations in the EGF receptor and ErbB2 proteins abolished ErbB3 phosphorylation and signal transduction activated by EGF and HRG respectively. Hence the protein tyrosine kinase activity necessary for growth factor signalling via the ErbB3 protein seems to be provided by coexpressed EGF and ErbB2 receptor proteins.
Department of Pharmacology, The University of Iowa, College of Medicine, Iowa City, IA 52242-1109, USA.
H H
HH
Kim
U
U
Vijapurkar
N J
NJ
Hellyer
D
D
Bravo
J G
JG
Koland
D016475:3T3 Cells; D019943:Amino Acid Substitution; D000818:Animals; D019556:COS Cells; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006023:Glycoproteins / Q000494:pharmacology*; D051379:Mice; D016297:Mutagenesis, Site-Directed; D020880:Neuregulins; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D020893:Receptor, ErbB-3; D011994:Recombinant Proteins / Q000096:biosynthesis; D017384:Sequence Deletion; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D006023:Glycoproteins; D020880:Neuregulins; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D011994:Recombinant Proteins