Suppression of integrin activation: a novel function of a Ras/Raf-initiated MAP kinase pathway.
Rapid modulation of ligand binding affinity ("activation") is a central property of the integrin cell adhesion receptors. Using a screen for suppressors of integrin activation, we identified the small GTP-binding protein, H-Ras, and its effector kinase, Raf-1, as negative regulators of integrin activation. H-Ras inhibited the activation of integrins with three distinct alpha and beta subunit cytoplasmic domains. Suppression was not associated with integrin phosphorylation and was independent of both mRNA transcription and protein synthesis. Furthermore, suppression correlated with activation of the ERK MAP kinase pathway. Thus, regulation of integrin affinity state is a novel, transcription-independent function of a Ras-linked MAP kinase pathway that may mediate a negative feedback loop in integrin function.
Hughes
P E
PE
Department of Vascular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Renshaw
M W
MW
Pfaff
M
M
Forsyth
J
J
Keivens
V M
VM
Schwartz
M A
MA
Ginsberg
M H
MH
D000818:Animals; D016466:CHO Cells / Q000737:chemistry / Q000166:cytology / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D048429:Cell Size / Q000502:physiology; D006224:Cricetinae; D003593:Cytoplasm / Q000737:chemistry / Q000201:enzymology; D018076:DNA, Complementary / Q000502:physiology; D004722:Endoribonucleases / Q000378:metabolism; D004789:Enzyme Activation; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005434:Flow Cytometry; D005656:Fungal Proteins; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D016023:Integrins / Q000737:chemistry / Q000378:metabolism*; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D018631:ras Proteins / Q000378:metabolism*
D018076:DNA, Complementary; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D005656:Fungal Proteins; D016023:Integrins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D004722:Endoribonucleases; D018631:ras Proteins