INSULIN SIGNAL-TRANSDUCTION THROUGH PROTEIN-KINASE CASCADES

This review summarizes the evolution of ideas concerning insulin signa l transduction, the current information on protein ser/thr kinase casc ades as signalling intermediates, and their status as participants in insulin regulation of energy metabolism. Best characterized is the Ras -MAPK pathway, whose input is crucial to cell fate decisions, but rela tively dispensable in metabolic regulation. By contrast the effecters downstream of PI-3 kinase, although less well elucidated, include elem ents indispensable for the insulin regulation of glucose transport, gl ycogen and cAMP metabolism. Considerable information has accrued on PK B/cAkt, a protein kinase that interacts directly with Ptd Ins 3'OH pho sphorylated lipids, as well as some of the elements further downstream , such as glycogen synthase kinase-3 and the p70 S6 kinase. Finally, s ome information implicates other erk pathways (e.g. such as the SAPK/J NK pathway) and Nck/cdc42-regulated PAKs (homologs of the yeast Ste 20 ) as participants in the cellular response to insulin. Thus insulin re cruits a broad array of protein (ser/thr) kinases in its target cells to effectuate its characteristic anabolic and anticatabolic programs.