DOC2b Enhances β-Cell Function via a Novel Tyrosine Phosphorylation-Dependent Mechanism.
Journal
Diabetes
ISSN: 1939-327X
Titre abrégé: Diabetes
Pays: United States
ID NLM: 0372763
Informations de publication
Date de publication:
01 06 2022
01 06 2022
Historique:
received:
02
08
2021
accepted:
13
03
2022
pubmed:
5
4
2022
medline:
25
5
2022
entrez:
4
4
2022
Statut:
ppublish
Résumé
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 and human and rodent clonal β-cells revealed that DOC2b is tyrosine phosphorylated within 2 min 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. Coimmunoprecipitation 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 posttranslational modification of DOC2b in β-cells, pinpointing the kinase, site of action, and downstream signaling events and 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.
Identifiants
pubmed: 35377441
pii: 144972
doi: 10.2337/db21-0681
pmc: PMC9163558
doi:
Substances chimiques
Calcium-Binding Proteins
0
Insulin
0
Nerve Tissue Proteins
0
Tyrosine
42HK56048U
Glucose
IY9XDZ35W2
Banques de données
figshare
['10.2337/figshare.19411307']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1246-1260Subventions
Organisme : NCI NIH HHS
ID : P30 CA033572
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK067912
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK102233
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK112917
Pays : United States
Informations de copyright
© 2022 by the American Diabetes Association.
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