title: Identification of novel signalling roles and targets for G(α) and G(βγ) downstream of the insulin-like growth factor 1 receptor in vascular smooth muscle cells.
abstract: Vascular dysfunction is the underlying cause of nearly 80% of heart disease cases, and its initiation and progression can be exacerbated by circulating factors, such as IGF-1 (insulin-like growth factor 1). IGF-1, which is highly homologous with insulin, elicits a response via a classical tyrosine kinase receptor, the IGF-1R (IGF-1 receptor). However, it has been suggested that the IGF-1R may also be coupled to a heterotrimeric G-protein and can thus modulate cellular processes via this alternate pathway. The objective of the present study was to investigate the structural aspects of IGF-1R coupling to a heterotrimeric G-protein in VSMCs [vascular SMCs (smooth muscle cells)], as well as examine the contribution of this pathway to cellular responses that are related to vascular disease. We found that the intracellular subunit of the IGF-1R precipitates with two G-protein subunits. The G(βγ)-mediated pathway contributes to both proliferation and migration. We also show that IGF-1 specifically activates G(αi) and can directly interact with both G(αi1) and G(αi2). A phospho-screen using a novel specific G(αi)-peptide inhibitor reveals a number of potential downstream effectors of this pathway, although our results show that it is not essential for SMC proliferation or migration.
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada, R3E 0J9.
authors.forename: Raissa
authors.initials: R
authors.lastname: Perrault
authors.forename: Peter
authors.initials: P
authors.lastname: Zahradka
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism*; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction; D013552:Swine
chemical_list: D044385:GTP-Binding Protein alpha Subunits; D044387:GTP-Binding Protein beta Subunits; D017526:Receptor, IGF Type 1