Cdk5 phosphorylates PLD2 to mediate EGF-dependent insulin secretion

Hye Young Lee, Hyuntae Jung, Il Ho Jang, Pann Ghill Suh, Sung Ho Ryu

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Insulin secretion from pancreatic β-cells is an important process that affects the regulation of glucose level in the blood. In our previous study, we suggested that epidermal growth factor (EGF) stimulates insulin secretion by activating phospholipase D2 (PLD2) [H.Y. Lee, K. Yea, J. Kim, B.D. Lee, Y.C. Chae, H.S. Kim, D.W. Lee, S.H. Kim, J.H. Cho, C.J. Jin, D.S. Koh, K.S. Park, P.G. Suh, S.H. Ryu, 2007. Epidermal Growth Factor Increases Insulin Secretion and Lowers Blood Glucose in Diabetic Mice. J. Cell. Mol. Med. 5:5]. However, the specific mechanism by which PLD2 activation leads to insulin secretion was not determined. In this study, we suggest that the phosphorylation and activation of PLD2 by cyclin-dependent kinase 5 (Cdk5) is critical for EGF-dependent insulin secretion. We found that a Cdk5 inhibitor, roscovitine, and dominant-negative Cdk5 inhibited EGF-dependent PLD2 activation and insulin secretion. EGF stimulation activated Cdk5 activity in rat insulinoma RINm5F cells, and PLD2 phosphorylation by Cdk5 was observed in vitro and in cells. The kinetics of PLD2 phosphorylation correlates with the interaction between PLD2 and Cdk5 and its effect on EGF signaling. We determined that the phosphorylation site of PLD2 was located at Ser134. PLD2-S134A did not show EGF-dependent phosphorylation and activation by Cdk5. Furthermore, this mutant was unable to mediate EGF-dependent insulin secretion in pancreatic β cell lines, suggesting that the phosphorylation of PLD2 at Ser134 by Cdk5 is critical for this process. The study results suggest that PLD2 is a new substrate of Cdk5 and that the phosphorylation of PLD2 by Cdk5 is involved in EGF-dependent insulin secretion.

Original languageEnglish (US)
Pages (from-to)1787-1794
Number of pages8
JournalCellular Signalling
Volume20
Issue number10
DOIs
StatePublished - Oct 1 2008
Externally publishedYes

Keywords

  • Cyclin-dependent kinase 5
  • Epidermal growth factor
  • Insulin secretion
  • Phospholipase D2

ASJC Scopus subject areas

  • Cell Biology

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