The protein Double C2 domain B (DOC2b) is essential for glucose-stimulated insulin secretion (GSIS) in β-cells. However, the underlying mechanism was unknown. Using primary human islets and human and rodent clonal β-cells, researchers discovered that DOC2b is tyrosine phosphorylated within 2 minutes of glucose stimulation and that Src family kinase member YES is essential for the process. Biochemical and functional investigation of DOC2bY301 mutants indicated that Y301 phosphorylation is required for DOC2b association with YES kinase and increased plasma membrane (PM) content of VAMP2, a protein on insulin secretory granules, coincident with DOC2b-mediated augmentation of GSIS in β-cells. Following glucose stimulation or pervanadate administration, coimmunoprecipitation experiments revealed an enhanced interaction of DOC2b with ERM family proteins in β-cells. 

ERM protein knockdown hindered DOC2b-mediated GSIS boosting, indicating that tyrosine-phosphorylated DOC2b controls GSIS via ERM-mediated granule localization to the PM. In addition, the findings showed that glucose induces posttranslational modification of DOC2b in β-cells, identifying the kinase, site of action, and downstream signaling events and demonstrating a regulatory role for YES kinase at distinct stages of GSIS. The research aided in the development of new treatment options for restoring glucose homeostasis in diabetics.