Title

Divergent mechanisms for homologous desensitization of p21ras by insulin and growth factors

UMMS Affiliation

Program in Molecular Medicine

Date

10-6-1995

Document Type

Article

Subjects

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

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

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.

Rights and Permissions

Citation: J Biol Chem. 1995 Oct 6;270(40):23421-8.

Related Resources

Link to Article in PubMed

Journal Title

The Journal of biological chemistry

PubMed ID

7559502