Secondary dimerization between members of the epidermal growth factor receptor family.
Growth factor receptors of the epidermal growth factor (EGF) receptor family play pivotal roles in the regulation of cell proliferation and differentiation and are involved in the development of human cancers. It has been well documented that these receptors undergo growth factor-stimulated homo- and heterodimerization as a first step in the initiation of signaling cascades. Here we provide evidence for a new mechanism for growth factor-stimulated receptor dimer formation, designated secondary dimerization. The growth factor-induced dimerization and ensuing receptor trans-autophosphorylation results in the dissociation of the original (primary) receptor dimer. Each phosphorylated receptor monomer then interacts with a new (nonphosphorylated) receptor to form a secondary dimer. Treatment of cells with EGF yields Neu-ErbB3 secondary dimers, and heregulin treatment induces the formation of Neu-EGF receptor (secondary) dimers. The ability of EGF and heregulin to stimulate a cascade of dimerization events points to a novel mechanism by which multiple signaling activities and diverse biological responses are initiated by members of the EGF receptor family.
Gamett
D C
DC
Department of Pharmacology, Veterinary Medical Center, Cornell University, Ithaca, New York 14853, USA.
Pearson
G
G
Cerione
R A
RA
Friedberg
I
I
D000818:Animals; D002352:Carrier Proteins / Q000494:pharmacology; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000737:chemistry* / Q000378:metabolism*; D006023:Glycoproteins / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008961:Models, Structural; D020890:Neuregulin-1; D016716:PC12 Cells; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism; D020893:Receptor, ErbB-3; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D006023:Glycoproteins; D020890:Neuregulin-1; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D011994:Recombinant Proteins; C087230:heregulin beta1