Desensitization of Ras activation by a feedback disassociation of the SOS-Grb2 complex.
Activation of Ras by the exchange of bound GDP for GTP is predominantly catalyzed by the guanylnucleotide exchange factor SOS. Receptor tyrosine kinases increase Ras-GTP loading by targeting SOS to the plasma membrane location of Ras through the small adaptor protein Grb2. However, despite the continuous stimulation of receptor tyrosine kinase activity, Ras activation is transient and, in the case of insulin, begins returning to the GDP-bound state within 5 min. We report here that the cascade of serine kinases activated directly by Ras results in a mitogen-activated protein kinase kinase (MEK)-dependent phosphorylation of SOS and subsequent disassociation of the Grb2-SOS complex, thereby interrupting the ability of SOS to catalyze nucleotide exchange on Ras. These data demonstrate a molecular feedback mechanism accounting for the desensitization of Ras-GTP loading following insulin stimulation.
Waters
S B
SB
Department of Physiology, University of Iowa, Iowa City 52242, USA.
Holt
K H
KH
Ross
S E
SE
Syu
L J
LJ
Guan
K L
KL
Saltiel
A R
AR
Koretzky
G A
GA
Pessin
J E
JE
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004789:Enzyme Activation; D005246:Feedback; D005419:Flavonoids / Q000494:pharmacology; D051380:GRB2 Adaptor Protein; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D020664:Son of Sevenless Proteins; D018631:ras Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D005419:Flavonoids; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D007328:Insulin; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D011506:Proteins; D020664:Son of Sevenless Proteins; D006160:Guanosine Triphosphate; D011494:Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one