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Insulin induces SOCS-6 expression and its binding to the p85 monomer of phosphoinositide 3-kinase, resulting in improvement in glucose metabolism

Li, Li LU ; Gronning, LM; Anderson, Per LU ; Li, Su-Ling LU ; Edvardsen, Klaus LU ; Johnston, J; Kioussis, D; Shepherd, PR and Wang, P (2004) In Journal of Biological Chemistry 279(33). p.34107-34114
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
279
issue
33
pages
34107 - 34114
publisher
ASBMB
external identifiers
  • wos:000223134800007
  • scopus:4544287063
ISSN
1083-351X
DOI
10.1074/jbc.M312672200
language
English
LU publication?
yes
id
0b2da48a-1b0b-4ade-b8f6-0fb6b193edaa (old id 270783)
date added to LUP
2007-10-24 18:26:18
date last changed
2017-01-01 05:13:57
@article{0b2da48a-1b0b-4ade-b8f6-0fb6b193edaa,
  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.},
  author       = {Li, Li and Gronning, LM and Anderson, Per and Li, Su-Ling and Edvardsen, Klaus and Johnston, J and Kioussis, D and Shepherd, PR and Wang, P},
  issn         = {1083-351X},
  language     = {eng},
  number       = {33},
  pages        = {34107--34114},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Insulin induces SOCS-6 expression and its binding to the p85 monomer of phosphoinositide 3-kinase, resulting in improvement in glucose metabolism},
  url          = {http://dx.doi.org/10.1074/jbc.M312672200},
  volume       = {279},
  year         = {2004},
}