title: Tyrosine kinase-independent activation of extracellular-regulated kinase (ERK) 1/2 by the insulin-like growth factor-1 receptor.
abstract: The extracellular-regulated kinase (ERK1/2) is a key conduit for transduction of signals from growth factor receptors to the nucleus. Previous work has shown that ERK1/2 activation in response to IGF-1 may require the participation of G proteins, but the role of the receptor tyrosine kinase in this process has not been clearly resolved. This investigation of IGF-1 receptor function was therefore designed to examine the contribution of the receptor tyrosine kinase to ERK1/2 activation. Phosphorylation of ERK1/2 in smooth muscle cells following treatment with IGF-1 was not blocked by pretreatment with AG1024 or picropodophylin, inhibitors of the IGF-1 receptor tyrosine kinase. Likewise, IGF-1 activated ERK1/2 in cells expressing a kinase-dead mutant of the IGF-1 receptor. ERK1/2 activation was unaffected by the phosphatidylinositol 3-kinase inhibitor LY-294002, but was sensitive to inhibitors of Src kinase, phospholipase C and Gβγ subunit signalling. Treatment with αIR-3, a neutralizing monoclonal antibody, also stimulated ERK1/2 phosphorylation without concomitant activation of the receptor tyrosine kinase. Phosphoprotein mapping of IGF-1 and αIR-3 treated cells confirmed that antibody-induced ERK1/2 phosphorylation occurred in the absence of tyrosine kinase phosphorylation, and enabled extension of these findings to p38 MAPK. These results suggest that stimulation of ERK1/2 phosphorylation by IGF-1 does not require activation of the receptor tyrosine kinase.
authors.affiliation: Department of Physiology, University of Manitoba, and Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, 351 Tache Avenue, Winnipeg, Manitoba, Canada.
authors.forename: Raissa
authors.initials: R
authors.lastname: Perrault
authors.forename: Brenda
authors.initials: B
authors.lastname: Wright
authors.forename: Benjamin
authors.initials: B
authors.lastname: Storie
authors.forename: Avril
authors.initials: A
authors.lastname: Hatherell
authors.forename: Peter
authors.initials: P
authors.lastname: Zahradka
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D018929:Cell Culture Techniques; D003331:Coronary Vessels / Q000166:cytology / Q000378:metabolism; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D044387:GTP-Binding Protein beta Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism; D044388:GTP-Binding Protein gamma Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D013552:Swine; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D007334:Insulin-Like Growth Factor I; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D017479:Receptors, Platelet-Derived Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases