Divergent mechanisms for homologous desensitization of p21ras by insulin and growth factors
UMass Chan Affiliations
Program in Molecular MedicineDocument Type
Journal ArticlePublication Date
1995-10-06Keywords
3T3 Cells*Adaptor Proteins, Signal Transducing
Animals
Epidermal Growth Factor
GRB2 Adaptor Protein
Guanosine Triphosphate
Insulin
Membrane Proteins
Mice
Platelet-Derived Growth Factor
Proteins
Proto-Oncogene Proteins p21(ras)
Signal Transduction
Son of Sevenless Proteins
Life Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
Previous work suggested that desensitization of p21ras in response to growth factors such as epidermal growth factor (EGF) results from receptor down-regulation. Here we show that p21ras is desensitized by insulin in 3T3-L1 adipocytes in the continued presence of activated insulin receptors, while loss of epidermal growth factor and platelet-derived growth factor (PDGF) receptors in response to their ligands correlates with p21ras desensitization. Furthermore, elevated amounts of Grb2/Shc complexes persisted throughout p21ras desensitization by insulin. However, immunoblotting of anti-Son-of-sevenless (Sos) 1 and 2 immunoprecipitates with anti-Grb2 antisera revealed that p21ras desensitization in response to insulin and PDGF, but not EGF, is associated with a marked decrease in cellular complexes containing Sos and Grb2 proteins. Nonetheless, the desensitization of p21ras in response to these stimuli was homologous, in that each peptide could reactivate [32P]GTP loading of p21ras after desensitization by any of the others. Taken together, these data indicate that insulin, EGF, and PDGF all cause disassembly of Sos proteins from signaling complexes during p21ras desensitization, but at least two mechanisms are involved. Insulin elicits dissociation of Sos from Grb2 SH3 domains, whereas EGF signaling is reversed by receptor down-regulation and Shc dephosphorylation, releasing Grb2 SH2 domains. PDGF action triggers both mechanisms of Grb2 disassembly, which probably operate in concert with GAP to attenuate p21ras signaling.Source
J Biol Chem. 1995 Oct 6;270(40):23421-8.
DOI
10.1074/jbc.270.40.23421Permanent Link to this Item
http://hdl.handle.net/20.500.14038/42460PubMed ID
7559502Related Resources
ae974a485f413a2113503eed53cd6c53
10.1074/jbc.270.40.23421
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