MyRIP interaction with MyoVa on secretory granules is controlled by the cAMP-PKA pathway

Mol Biol Cell. 2012 Nov;23(22):4444-55. doi: 10.1091/mbc.E12-05-0369. Epub 2012 Sep 19.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Glucose / pharmacology
  • Insulin-Secreting Cells / metabolism*
  • Islets of Langerhans / metabolism
  • Mice
  • Models, Biological
  • Myosin Heavy Chains / metabolism*
  • Myosin Type V / metabolism*
  • Phosphorylation
  • Rats
  • Secretory Vesicles / metabolism*
  • Vesicular Transport Proteins / metabolism*


  • MYRIP protein, mouse
  • Myo5a protein, mouse
  • Vesicular Transport Proteins
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Myosin Type V
  • Myosin Heavy Chains
  • Glucose