Fig. 4.

Compartmentalized PDK1 and PTEN activity in membrane microdomains is essential for proper PI3K/Akt signaling. (A) Preferential activation of Akt in membrane rafts is mediated by activated PDK1 in rafts and lack of PTEN-mediated down-regulation in these microdomains. (B) Dysregulation of the raft-localized PI3K/Akt signaling as the underlying mechanism for insulin resistance. Ceramide may inhibit Akt signaling through promoting PKCζ phosphorylation of Akt or activating the Akt phosphatase PP2A. The ceramide-induced mislocalization of PTEN to membrane rafts critically contributes to the inhibitory effect of ceramide on PI3K/Akt signaling.