Inactivation of kinase cascades in mesangial cells grown on collagen type I.
Growth on collagen type I gels is known to suppress the mitogenic responsiveness of mesangial cells. Because these cells proliferate in some renal diseases and themselves synthesize collagen type I, we examined the influence of growth on collagen upon several kinase signaling cascades involved in mesangial cell proliferation. Quiescent mesangial cells grown on collagen type I and then stimulated with serum showed a markedly diminished induction of the protooncogene c-fos, compared with their counterparts on plastic or fibronectin. This effect was accompanied by decreased activation of mitogen-activated (Erk family) and Ca2+/calmodulin-dependent protein kinases. Cells on collagen showed lower basal protein kinase C (PKC) activity and diminished levels of PKC-alpha and -zeta isoforms. Global phosphorylation of tyrosine residues was diminished on collagen, and tyrosine phosphorylation of Erk and focal adhesion kinase in response to serum was not detected, in contrast to cells on plastic. We conclude that attachment of mesangial cells to collagen type I results in a broad suppression of protein phosphorylation that is reflected in diminished induction of the c-fos gene and probably underlies the conversion of cultured mesangial cells to a nonproliferative phenotype.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada M5G 1L5.
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D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D018929:Cell Culture Techniques / Q000379:methods; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000494:pharmacology*; D005353:Fibronectins / Q000494:pharmacology; D016762:Genes, fos; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008297:Male; D011107:Polylysine / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic
D005353:Fibronectins; D016760:Proto-Oncogene Proteins c-fos; D011107:Polylysine; D003094:Collagen; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D013755:Tetradecanoylphorbol Acetate