Fan-Yan Wei

EIF2AK4 , which encodes the amino acid deficiency–sensing protein GCN2, has been implicated as a susceptibility gene for type 2 diabetes in the Japanese population. However, the mechanism by which GCN2 affects glucose homeostasis is unclear. Here, we show that insulin secretion is reduced in individuals harboring the risk allele of EIF2AK4 and that maintenance of GCN2-deficient mice on a high-fat diet results in a loss of pancreatic β cell mass. Our data suggest that GCN2 senses amino acid deficiency in β cells and limits signaling by mechanistic target of rapamycin complex 1 to prevent β cell failure during the consumption of a high-fat diet.

Background Information Cortactin contributes to growth cone morphogenesis by forming with dynamin, ring‐shaped complexes that mechanically bundle and stabilise F‐actin. However, the regulatory mechanism of cortactin action is poorly understood. Results Immunofluorescence microscopy revealed that protein kinase C (PKC) α colocalises with cortactin at growth cone filopodia in SH‐SY5Y neuroblastoma cells. PKC activation by phorbol 12‐myristate 13‐acetate causes cortactin phosphorylation, filopodial retraction and F‐actin‐bundle loss. Moreover, PKCα directly phosphorylates cortactin in vitro at S135/T145/S172, mitigating both cortactin's actin‐binding and actin‐crosslinking activity, whereas cellular expression of a phosphorylation‐mimetic cortactin mutant hinders filopodial formation with a significant decrease of actin bundles. Conclusions Our results indicate that PKC‐mediated cortactin phosphorylation might be implicated in the maintenance of growth cone.