Insulin-induced desensitization of extracellular signal-regulated kinase activation results from an inhibition of Raf activity independent of Ras activation and dissociation of the Grb2-SOS complex
- PMID: 10373477
- DOI: 10.1074/jbc.274.26.18651
Insulin-induced desensitization of extracellular signal-regulated kinase activation results from an inhibition of Raf activity independent of Ras activation and dissociation of the Grb2-SOS complex
Abstract
Previous studies have suggested that the interaction between the small adaptor protein Grb2 with the Ras guanyl nucleotide exchange factor SOS is functionally important in the regulation of the Ras activation/inactivation cycle. To examine the relationship between the Grb2-SOS complex and Ras activation, we observed that insulin stimulation results in a rapid but transient activation of Ras and the extracellular-signal regulated kinase (ERK) followed by dissociation of the Grb2-SOS complex. Although treatment with the phorbol myristate acetate resulted in ERK activation and complete dissociation of the Grb2-SOS complex, there was no effect on subsequent insulin-stimulated Ras activation. Similarly, insulin stimulation followed by insulin removal resulted in a time-dependent restoration of the Grb2-SOS complex but which was significantly slower than the recovery of insulin-stimulated Ras activation. In addition, although insulin was able to activate Ras under these conditions, there was a complete desensitization of Raf and ERK activation. This apparent homologous desensitization of insulin action was specific for Raf and ERK as the insulin re-stimulation of insulin receptor autophosphorylation and protein kinase B activation were unaffected. Together, these data demonstrate the presence of a pathway independent of the Grb2-SOS complex that can lead to Ras activation but that the desensitization of Raf accounts for the homologous desensitization of ERK.
Similar articles
-
SOS phosphorylation and disassociation of the Grb2-SOS complex by the ERK and JNK signaling pathways.J Biol Chem. 1996 Mar 15;271(11):6328-32. doi: 10.1074/jbc.271.11.6328. J Biol Chem. 1996. PMID: 8626428
-
Association between GRB2/Sos and insulin receptor substrate 1 is not sufficient for activation of extracellular signal-regulated kinases by interleukin-4: implications for Ras activation by insulin.Mol Cell Biol. 1995 Mar;15(3):1778-85. doi: 10.1128/MCB.15.3.1778. Mol Cell Biol. 1995. PMID: 7862167 Free PMC article.
-
Negative feedback regulation and desensitization of insulin- and epidermal growth factor-stimulated p21ras activation.J Biol Chem. 1995 Oct 27;270(43):25320-3. doi: 10.1074/jbc.270.43.25320. J Biol Chem. 1995. PMID: 7592690
-
Insulin receptor-mediated dissociation of Grb2 from Sos involves phosphorylation of Sos by kinase(s) other than extracellular signal-regulated kinase.J Biol Chem. 1998 May 15;273(20):12061-7. doi: 10.1074/jbc.273.20.12061. J Biol Chem. 1998. PMID: 9575148
-
Tnk1/Kos1: a novel tumor suppressor.Trans Am Clin Climatol Assoc. 2010;121:281-92; discussion 292-3. Trans Am Clin Climatol Assoc. 2010. PMID: 20697568 Free PMC article. Review.
Cited by
-
Inhibition of Rab5 Activation During Insulin Receptor-Mediated Endocytosis.Curr Cell Biochem. 2011 Dec 28;1(1):20-32. Curr Cell Biochem. 2011. PMID: 24765621 Free PMC article.
-
Systems-level interactions between insulin-EGF networks amplify mitogenic signaling.Mol Syst Biol. 2009;5:256. doi: 10.1038/msb.2009.19. Epub 2009 Apr 7. Mol Syst Biol. 2009. PMID: 19357636 Free PMC article.
-
Adapter protein with a pleckstrin homology (PH) and an Src homology 2 (SH2) domain (APS) and SH2-B enhance insulin-receptor autophosphorylation, extracellular-signal-regulated kinase and phosphoinositide 3-kinase-dependent signalling.Biochem J. 2003 Apr 15;371(Pt 2):405-12. doi: 10.1042/BJ20021589. Biochem J. 2003. PMID: 12521378 Free PMC article.
-
Protein phosphatase 2A forms a molecular complex with Shc and regulates Shc tyrosine phosphorylation and downstream mitogenic signaling.Mol Cell Biol. 2002 Apr;22(7):2375-87. doi: 10.1128/MCB.22.7.2375-2387.2002. Mol Cell Biol. 2002. PMID: 11884620 Free PMC article.
-
A MAP kinase-signaling pathway mediates neurite outgrowth on L1 and requires Src-dependent endocytosis.J Neurosci. 2000 Jun 1;20(11):4177-88. doi: 10.1523/JNEUROSCI.20-11-04177.2000. J Neurosci. 2000. PMID: 10818153 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Medical
Research Materials
Miscellaneous