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Double C2 Domain Β (DOC2b) protein is required for glucose-stimulated insulin secretion (GSIS) in β-cells, the underlying mechanism of which remains unresolved. Our biochemical analysis using primary human islets, human and rodent clonal β-cells revealed that DOC2b is tyrosine phosphorylated within 2 minutes of glucose stimulation, and Src family kinase member YES is required for this process. Biochemical and functional analysis using DOC2bY301 mutants revealed the requirement of Y301 phosphorylation for the interaction of DOC2b with YES kinase and increased content of VAMP2, a protein on insulin secretory granules, at the plasma membrane (PM), concomitant with DOC2b-mediated enhancement of GSIS in β-cells. Co-immunoprecipitation studies demonstrated an increased association of DOC2b with ERM family proteins in β-cells following glucose stimulation or pervanadate-treatment. Y301 phosphorylation-competent DOC2b was required to increase ERM protein activation, and ERM protein knockdown impaired DOC2b-mediated boosting of GSIS, suggesting that tyrosine-phosphorylated DOC2b regulates GSIS via ERM-mediated granule localization to the PM. Taken together, these results demonstrate the glucose-induced post-translational modification of DOC2b in β-cells, pinpointing the kinase, site of action, and downstream signaling events revealing a regulatory role of YES kinase at various steps in GSIS. This work will enhance the development of novel therapeutic strategies to restore glucose homeostasis in diabetes

DOC2b Enhances β-Cell Function via a Novel Tyrosine Phosphorylation-Dependent Mechanism