Defect of insulin signal in peripheral tissues: Important role of ceramide

Figure 3 Ceramide inhibits insulin-induced activation of protein kinase B via two distinct mechanisms. Ceramide inhibits insulin-activation of protein kinase B (PKB/Akt) either by activating atypical PKC (PKCζ) or by stimulating the phosphatase PP2A. Activation of either mechanism depends on plasma membrane enrichment with caveolae: (1) Ceramide-activated PKCζ phosphorylates the PH domain of PKB/Akt on Thr/Ser34, changing the recognition site of PKB/Akt, and disabling its activation by PIP3; (2) PP2A dephosphorylates PKB/Akt, inhibiting its kinase activity. IR: Insulin receptor; IRS: IR substrates; PI3K: Phosphoinositide-3-kinase; PP2A: Protein phosphatase 2A.