Figure 5.

Cross-talk between Arf6 and Rho-GTPases in islet β-cell insulin secretion. Glucose metabolism leads to activation of Arf6, which initiates the activation of membrane associated phospholipase D (PLD) and phosphatidylinositol-4-phosphate 5-kinase (PIP5K) to generate fusogenic lipids such as phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidic acids (PA). The lipids generated facilitate the dissociation of Cdc42 from Cdc42/Caveolin-1 complex present in the insulin containing vesicle, when the caveolin-1 is phosphorylated by a Yes kinase, and subsequent activation by Cool/β-pix (GEF). The activated Cdc42 activates Pak1, which phosphorylates and activates Rac1/GDI. This leads to exchange of GDP/GTP to initiate cytoskeletal rearrangement for insulin granule mobilization and release.