A primary role of the hormone insulin is regulation of concentrations of glucose in the bloodstream. Two main pathways have been identified that transmit signals from the insulin receptor and result in increased glucose transport into cells. These pathways appeared to represent independent branches, but Katsanakis and Pillay now present results suggesting interaction between them. One pathway leads to activation of phosphoinositide 3-kinase (PI3K) and consequent activation of the protein kinase known as protein kinase B (PKB) or Akt. Activation of this PI3K pathway is necessary but not sufficient for stimulating glucose transport. Furthermore, other signals that activate PKB do not activate glucose transport as insulin does. The other pathway that appears to be required for insulin signaling is mediated by the protein APS (adaptor protein with a pleckstrin homology domain and a Src-homology 2 domain), which binds to the phosphorylated insulin receptor and becomes phosphorylated itself on tyrosine residues, which in turn allows it to interact with other proteins that propagate the insulin signal. Katsanakis and Pillay describe several experiments that indicate that APS is also a direct substrate of PKB. APS in lysates from cultured cells treated with insulin interacted with antibodies that specifically recognize substrates phosphorylated by PKB. Pharmacological inhibition of PKB or treatment of cells with small inhibitory RNA to deplete PKB inhibited such interaction with the antibodies, as did mutation of a likely target serine residue in APS. In vitro, PKB directly phosphorylated APS on this same site (Ser588). The new findings indicate that APS is regulated by serine phosphorylation as well as tyrosine phosphorylation and show that PKB may couple the two pathways that are activated by the insulin receptor. The effect of the serine phosphorylation of APS is not yet clear, but the authors propose that it could alter cellular localization of the protein and its binding partners, thus contributing to signaling specificity.
K. D. Katsanakis, T. S. Pillay, Cross-talk between the two divergent insulin signaling pathways is revealed by the protein kinase B (Akt)-mediated phosphorylation of adapter protein APS on serine 588. J. Biol. Chem. 280, 37827-37832 (2005). [Abstract] [Full Text]