期刊
MOLECULAR BIOLOGY OF THE CELL
卷 23, 期 22, 页码 4444-4455出版社
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E12-05-0369
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资金
- Biotechnology and Biological Sciences Research Council UK
- Wellcome Trust
- Medical Research Council UK [G0601509]
- Biotechnology and Biological Sciences Research Council UK [BB/F011326/1, BB/J015938/1]
- Biotechnology and Biological Sciences Research Council [BB/F011326/1, BB/E021050/1] Funding Source: researchfish
- Medical Research Council [G0601509] Funding Source: researchfish
- BBSRC [BB/F011326/1, BB/E021050/1] Funding Source: UKRI
- MRC [G0601509] Funding Source: UKRI
Myosin- and Rab-interacting protein (MyRIP), which belongs to the protein kinase A (PKA)-anchoring family, is implicated in hormone secretion. However, its mechanism of action is not fully elucidated. Here we investigate the role of MyRIP in myosin Va (MyoVa)-dependent secretory granule (SG) transport and secretion in pancreatic beta cells. These cells solely express the brain isoform of MyoVa (BR-MyoVa), which is a key motor protein in SG transport. In vitro pull-down, coimmunoprecipitation, and colocalization studies revealed that MyRIP does not interact with BR-MyoVa in glucose-stimulated pancreatic beta cells, suggesting that, contrary to previous notions, MyRIP does not link this motor protein to SGs. Glucose-stimulated insulin secretion is augmented by incretin hormones, which increase cAMP levels and leads to MyRIP phosphorylation, its interaction with BR-MyoVa, and phosphorylation of the BR-MyoVa receptor rabphilin-3A (Rph-3A). Rph-3A phosphorylation on Ser-234 was inhibited by small interfering RNA knockdown of MyRIP, which also reduced cAMP-mediated hormone secretion. Demonstrating the importance of this phosphorylation, nonphosphorylatable and phosphomimic Rph-3A mutants significantly altered hormone release when PKA was activated. These data suggest that MyRIP only forms a functional protein complex with BR-MyoVa on SGs when cAMP is elevated and under this condition facilitates phosphorylation of SG-associated proteins, which in turn can enhance secretion.
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