title: Distinct mechanisms determine the patterns of differential activation of H-Ras, N-Ras, K-Ras 4B, and M-Ras by receptors for growth factors or antigen.
abstract: Although GTPases of the Ras family have been implicated in many aspects of the regulation of cells, little is known about the roles of individual family members. Here, we analyzed the mechanisms of activation of H-Ras, N-Ras, K-Ras 4B, and M-Ras by two types of external stimuli, growth factors and ligation of the antigen receptors of B or T lymphocytes (BCRs and TCRs). The growth factors interleukin-3, colony-stimulating factor 1, and epidermal growth factor all preferentially activated M-Ras and K-Ras 4B over H-Ras or N-Ras. Preferential activation of M-Ras and K-Ras 4B depended on the presence of their polybasic carboxy termini, which directed them into high-buoyant-density membrane domains where the activated receptors, adapters, and mSos were also present. In contrast, ligation of the BCR or TCR resulted in activation of H-Ras, N-Ras, and K-Ras 4B, but not M-Ras. This pattern of activation was not influenced by localization of the Ras proteins to membrane domains. Activation of H-Ras, N-Ras, and K-Ras 4B instead depended on the presence of phospholipase C-gamma and RasGRP. Thus, the molecular mechanisms leading to activation of Ras proteins vary with the stimulus and can be influenced by either colocalization with activated receptors or differential sensitivity to the exchange factors activated by a stimulus.
authors.affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, Canada.
authors.forename: Annette
authors.initials: A
authors.lastname: Ehrhardt
authors.forename: Muriel D
authors.initials: MD
authors.lastname: David
authors.forename: Götz R A
authors.initials: GR
authors.lastname: Ehrhardt
authors.forename: John W
authors.initials: JW
authors.lastname: Schrader
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism; D051380:GRB2 Adaptor Protein; D011905:Genes, ras; D006133:Growth Substances / Q000378:metabolism*; D006801:Humans; D007377:Interleukin-3 / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D010703:Phorbol Esters / Q000378:metabolism; D051966:Phospholipase C gamma; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D020837:SOS1 Protein / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D010738:Type C Phospholipases / Q000378:metabolism; D018631:ras Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D006133:Growth Substances; D007377:Interleukin-3; C117307:KRAS protein, human; D010703:Phorbol Esters; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; C528024:SHC1 protein, human; D020837:SOS1 Protein; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D004815:Epidermal Growth Factor; D016173:Macrophage Colony-Stimulating Factor; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; C109418:Mras protein, mouse; C501009:HRAS protein, human; D020559:Monomeric GTP-Binding Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins