title: Insulin induces SOCS-6 expression and its binding to the p85 monomer of phosphoinositide 3-kinase, resulting in improvement in glucose metabolism.
abstract: The suppressors of cytokine signaling (SOCS) family is thought to act largely as a negative regulator of signaling by cytokines and some growth factors. Surprisingly, the SOCS-6 transgenics had no significant defects in the cytokine signaling and hematopoietic system but displayed significant improvements in glucose metabolism. Insulin stimulation of Akt/protein kinase B was also potentiated. Biochemical analysis showed that, after insulin stimulation, SOCS-6 interacted with the monomeric p85 subunit of class-Ia phosphoinositide (PI) 3-kinase but not with p85/p110 dimers. Furthermore, SOCS-6 expression is transiently increased by serum and insulin in normal fibroblasts. However, both the mRNA and protein of SOCS-6 were rapidly degraded after induction by insulin. The degradation of the SOCS-6 protein was partially inhibited by a proteasome inhibitor, suggesting a proteasome-mediated degradation mechanism. In contrast, SOCS-6-associated p85 was not degraded and could be recruited to the newly synthesized SOCS-6 molecules in the presence of insulin, suggesting that SOCS-6 expression and its interaction with p85, but not the degradation, is regulated by insulin. The phenotype of SOCS-6 transgenic mice bears a striking resemblance to p85 knock-out mouse models in which glucose metabolism stimulated by insulin is significantly improved despite reduced activation of PI 3-kinase. This suggests that monomeric p85 might play a physiologically important role in attenuating signaling through PI 3-kinase-dependent pathways in unstimulated cells. Therefore, our results indicate that SOCS-6 may provide a dynamically regulated mechanism by which insulin can transiently overcome the negative effects that p85 monomers have on signaling via PI 3-kinase-dependent signaling pathways.
authors.affiliation: Immunology Group, Institute of Cell and Molecular Sciences, St. Barts and The Royal London School of Medicine, 59 Bartholomew's Close, London EC1A 7ED, United Kingdom.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Line M
authors.initials: LM
authors.lastname: Grønning
authors.forename: Per O
authors.initials: PO
authors.lastname: Anderson
authors.forename: Suling
authors.initials: S
authors.lastname: Li
authors.forename: Klaus
authors.initials: K
authors.lastname: Edvardsen
authors.forename: Jim
authors.initials: J
authors.lastname: Johnston
authors.forename: Dimitris
authors.initials: D
authors.lastname: Kioussis
authors.forename: Peter R
authors.initials: PR
authors.lastname: Shepherd
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015152:Blotting, Northern; D016466:CHO Cells; D002455:Cell Division; D002478:Cells, Cultured; D006224:Cricetinae; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005347:Fibroblasts / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins; D013997:Time Factors; D014162:Transfection; D019076:Transgenes
chemical_list: D001786:Blood Glucose; D003546:Cysteine Endopeptidases; D005947:Glucose; D007328:Insulin; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D050826:Suppressor of Cytokine Signaling Proteins; C473085:SOCS6 protein, human; C108775:SOCS7 protein, human