The role of protein kinase D in neurotensin secretion mediated by protein kinase C-α/-δ and Rho/Rho kinase

Jing Li, Kathleen L. O'Connor, Mark R. Hellmich, George H Greeley, Courtney M. Townsend, B. Mark Evers

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Neurotensin (NT) is a gut peptide that plays an important role in gastrointestinal (GI) secretion, motility, and growth as well as the proliferation of NT receptor positive cancers. Secretion of NT is regulated by phorbol ester-sensitive protein kinase C (PKC) isoforms-α and -δ and may involve protein kinase D (PKD). The purpose of our present study was: (i) to define the role of PKD in NT release from BON endocrine cells and (ii) to delineate the upstream signaling mechanisms mediating this effect. Here, we demonstrate that small interfering RNA (siRNA) targeted against PKD dramatically inhibited both basal and PMA-stimulated NT secretion; NT release is significantly increased by overexpression of PKD. PKC-α and -δ siRNA attenuated PKD activity, whereas overexpression of PKC-α and -δ enhanced PKD activity. Rho kinase (ROK) siRNA significantly inhibited NT secretion, whereas overexpression of ROKα effectively increased NT release. Rho protein inhibitor C3 dramatically inhibited both NT secretion and PKD activity. In conclusion, our results demonstrate that PKD activation plays a central role in NT peptide secretion; upstream regulators of PKD include PKC-α and -δ and Rho/ROK. Importantly, our results identify novel signaling pathways, which culminate in gut peptide release.

Original languageEnglish (US)
Pages (from-to)28466-28474
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number27
DOIs
StatePublished - Jul 2 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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