Membrane targeting of the nucleotide exchange factor Sos is sufficient for activating the Ras signaling pathway.
Activation of growth factor receptors results in tyrosine autophosphorylation and recruitment of SH2 domain-containing effectors, including Grb2. Grb2 recruitment mediates activation of the Ras nucleotide exchanger Sos by an unknown mechanism. To examine the role of membrane recruitment, we prepared Sos derivatives containing either myristoylation or farnesylation signals. This resulted in plasma membrane targeting of Sos and stimulation of the Ras signaling pathway, including ERK and AP-1 activities leading to oncogenic transformation. Sos derivatives with nonfunctional myristoylation or farnesylation sequences were inactive. Farnesylation of Sos also activated Ras signaling in yeast. In both mammalian cells and yeast, membrane-targeted Sos derivatives lacking the C-terminal region were considerably more active. Therefore, targeting of Sos to the plasma membrane in the vicinity of Ras appears to be the primary mechanism leading to activation of the Ras pathway. A secondary mechanism could involve relief of the inhibitory effect of the Sos C-terminal region.
Aronheim
A
A
Department of Pharmacology, University of California, San Diego, La Jolla 92093-0636.
Engelberg
D
D
Li
N
N
al-Alawi
N
N
Schlessinger
J
J
Karin
M
M
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001692:Biological Transport; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002451:Cell Compartmentation; D002462:Cell Membrane / Q000378:metabolism*; D004789:Enzyme Activation; D005204:Farnesol / Q000378:metabolism; D051380:GRB2 Adaptor Protein; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D008954:Models, Biological; D008969:Molecular Sequence Data; D019814:Myristic Acid; D009227:Myristic Acids / Q000378:metabolism; D009857:Oncogenes; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism; D020663:ras Guanine Nucleotide Exchange Factors; D020666:ras-GRF1
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D009227:Myristic Acids; D011506:Proteins; D018808:Transcription Factor AP-1; D020663:ras Guanine Nucleotide Exchange Factors; D020666:ras-GRF1; D019814:Myristic Acid; D005204:Farnesol; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)