How insulin signals globally and acts locally

Insulin stimulation in adipocytes sends signals through two pathways, one dependent on phosphatidylinositol-3-kinase (PI3K) and the other acting through the small membrane-associated GTPase TC10. On page 279, Kanzaki et al. reveal an unexpected convergence of the two pathways, and show that the localization of atypical protein kinase C (PKCζ/λ) to specific lipid raft microdomains confers specificity on the system.

Previous work had suggested that PI3K could activate PKCζ/λ or protein kinase B, but the relative importance of these downstream effectors was controversial. In the new study, the authors found that both the PI3K and TC10 pathways can activate PKCζ/λ in adipocytes, but only the TC10 pathway recruits PKCζ/λ to TC10-containing lipid raft microdomains. The localization is directed by Par6 and Par3, proteins that are known to link GTPases to PKCs in the worm C. elegans.

PI3K activation is a common result of many signaling pathways and thus has many readouts, some of them inapropriate for insulin signaling. Kanzaki et al. believe that insulin stimulates PI3K to levels that are by themselves insufficient to generate all downstream events, either desirable or undesirable. But the convergence of the TC10 stimulation on raft-localized PKCζ/λ pushes the stimulation to a level sufficient to turn on only the few desirable downstream events, such as the recruitment of glucose transporters, that function in raft microdomains. ▪