TY - JOUR
T1 - Differential effects of tumor necrosis factor-α on protein kinase C isoforms α and δ mediate inhibition of insulin receptor signaling
AU - Rosenzweig, Tovit
AU - Braiman, Liora
AU - Bak, Asia
AU - Alt, Addy
AU - Kuroki, Toshio
AU - Sampson, Sanford R.
PY - 2002
Y1 - 2002
N2 - Tumor necrosis factor-α (TNF-α) is a multifunctional cytokine that interferes with insulin signaling, but the molecular mechanisms of this effect are unclear. Because certain protein kinase C (PKC) isoforms are activated by insulin, we examined the role of PKC in TNF-α inhibition of insulin signaling in primary cultures of mouse skeletal muscle. TNF-α, given 5 min before insulin, inhibited insulin-induced tyrosine phosphorylation of insulin receptor (IR), IR substrate (IRS)-1, insulin-induced association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase (P13-K), and insulin-induced glucose uptake. Insulin and TNF-α each caused tyrosine phosphorylation and activation of PKCs δ and α, but when TNF-α preceded insulin, the effects were less than that produced by each substance alone. Insulin induced PKCδ specifically to coprecipitate with IR, an effect blocked by TNF-α. Both PKCα and -δ are constitutively associated with IRS-1. Whereas insulin decreased coprecipitation of IRS-1 with PKCδ, it increased coprecipitation of IRS-1 with PKCδ. TNF-α blocked the effects of insulin on association of both PKCs with IRS-1. To further investigate the involvement of PKCs in inhibitory actions of TNF-α on insulin signaling, we overexpressed specific PKC isoforms in mature myotubes. PKCα overexpression inhibited basal and insulin-induced IR autophosphorylation, whereas PKCδ overexpression increased IR autophosphorylation and abrogated the inhibitory effect of TNF-α on IR autophosphorylation and signaling to P13-K. Blockade of PKCα antagonized the inhibitory effects of TNF-α on both insulin-induced IR tyrosine phosphorylation and IR signaling to P13-K. We suggest that the effects of TNF-α on IR tyrosine phosphorylation are mediated via alteration of insulin-induced activation and association of PKCδ and -α with upstream signaling molecules.
AB - Tumor necrosis factor-α (TNF-α) is a multifunctional cytokine that interferes with insulin signaling, but the molecular mechanisms of this effect are unclear. Because certain protein kinase C (PKC) isoforms are activated by insulin, we examined the role of PKC in TNF-α inhibition of insulin signaling in primary cultures of mouse skeletal muscle. TNF-α, given 5 min before insulin, inhibited insulin-induced tyrosine phosphorylation of insulin receptor (IR), IR substrate (IRS)-1, insulin-induced association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase (P13-K), and insulin-induced glucose uptake. Insulin and TNF-α each caused tyrosine phosphorylation and activation of PKCs δ and α, but when TNF-α preceded insulin, the effects were less than that produced by each substance alone. Insulin induced PKCδ specifically to coprecipitate with IR, an effect blocked by TNF-α. Both PKCα and -δ are constitutively associated with IRS-1. Whereas insulin decreased coprecipitation of IRS-1 with PKCδ, it increased coprecipitation of IRS-1 with PKCδ. TNF-α blocked the effects of insulin on association of both PKCs with IRS-1. To further investigate the involvement of PKCs in inhibitory actions of TNF-α on insulin signaling, we overexpressed specific PKC isoforms in mature myotubes. PKCα overexpression inhibited basal and insulin-induced IR autophosphorylation, whereas PKCδ overexpression increased IR autophosphorylation and abrogated the inhibitory effect of TNF-α on IR autophosphorylation and signaling to P13-K. Blockade of PKCα antagonized the inhibitory effects of TNF-α on both insulin-induced IR tyrosine phosphorylation and IR signaling to P13-K. We suggest that the effects of TNF-α on IR tyrosine phosphorylation are mediated via alteration of insulin-induced activation and association of PKCδ and -α with upstream signaling molecules.
UR - http://www.scopus.com/inward/record.url?scp=0036263641&partnerID=8YFLogxK
U2 - 10.2337/diabetes.51.6.1921
DO - 10.2337/diabetes.51.6.1921
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C2 - 12031982
AN - SCOPUS:0036263641
SN - 0012-1797
VL - 51
SP - 1921
EP - 1930
JO - Diabetes
JF - Diabetes
IS - 6
ER -