Insulin-Sensitive Phospholipid Signaling Systems and Glucose Transport: An Update 1

Abstract

During the past few years, remarkable progress has been made in elucidating the signaling systems that are used by insulin to regulate glucose metabolism and other metabolic functions. Most notably, tyrosine kinase functions of the insulin receptor have been more clearly linked to the activation of a network of interacting proteins, which in turn activate a number of downstream signaling systems. This review will focus largely upon a group of downstream, insulin-sensitive, phospholipid signaling systems that seem to play important roles in regulating glucose homeostasis. We will first review how these phospholipid signaling systems interdigitate both with each other, and with other nonphospholipid signaling systems. We will then examine how these phospholipid signaling systems may impact glucose transport, presumably a rate-limiting step in glucose metabolism in muscle, fat, and a number of other insulin target tissues.

Overview of Insulin-Sensitive Signaling Pathways

Insulin uses multiple cross-talking and, in some cases, seemingly redundant signaling systems (Fig. 1) to regulate many metabolic processes. Initially, insulin binds to the a subunit of the insulin receptor (IR) and activates an intracellular tyrosine kinase contained within the cytoplasmic domain of the IR p subunit, leading to tyrosine phosphorylation of the IR itself and a number of extra-receptor proteins, including IRS-1, Shc, pp60, p120, etc. Interactions ensue between specific phosphotyrosine-containing peptide sequences of these proteins and SH2 or other (e.g., newly recognized PID and PTB) domains in a second set of proteins (e.g., phosphatidylinositol 3-kinase [PI3K], GRB2, Shc, Syp, Nck, etc.). These interactions, in turn, trigger the direct activation of some of these proteins as kinases (PI3K) or phosphatases (Syp), as well as additional protein/protein interactions, for example, between SH3 domains of proteins, such as GRB2, and proline-rich or other amino acid sequences in downstream proteins, such as SOS. SOS, for instance, in turn increases GTP loading of ras, which successively activates a series of protein kinases (viz., raf-I, MEK, MAPK, and MAPKAP; this pathway may also be activated through other mechanisms)