Involvement of sphingomyelinase in insulin‐induced phosphatidylinositol 3‐kinase activation

Abstract

Insulin plays a key role in regulating a wide range of cellular functions. Most functions of insulin are believed to occur through activation of phosphatidylinositol‐3 kinase (PI‐3 kinase) signaling pathways. The present study demonstrates that insulin, C2‐ceramide, or phosphocholine (PCho) induced a strong activation of PI‐3 kinase activity. This activation was dramatically inhibited by either pretreatment of cells with wortmannin, a widely used PI‐3 kinase inhibitor, or constitutive overexpression of a dominant negative p85 subunit of PI‐3 kinase (ΔΡ85). Insulin‐induced activation of PI‐3 kinase was observed only in the normal human lymphoblast cell line, JY, but not in the sphingomyelinase (SMase)‐deficient cell line, MS1418. The PI‐3 kinase activation in MS1418 cells could be restored by exposure of the cells to either SMase, C2‐ceramide, or PCho. These data provide direct evidence that SMase and its products act as mediators in insulin‐induced activation of PI‐3 kinase.