Figure 3.

Proposed c-Kit–IR interplay within the β-cell. (A) Transient receptor activation: c-Kit and IR both promote PI3K/Akt intracellular signaling, which leads to maintained insulin secretion. c-Kit receptor activation is proposed to promote upregulated IR/IRS signaling (via phosphorylation of tyrosine resides, green) through (i) direct activation and (ii) indirect activation through insulin secretion. Phosphorylation of IRS-1 tyrosine 608 in rodents and 612 in humans is linked to PI3K binding (74). (B) Chronic receptor activation: Sustained signaling through the PI3K/Akt pathway can lead to negative feedback through IRS-1 phosphorylation of serine residues (red) and impair insulin release. Multiple serine sites (e.g., Ser612) have been reported as phosphorylation targets from PI3K/Akt/mTOR/S6K1 signaling [for an extensive review, please see Copps and White (74)].