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J. Biol. Chem., Vol. 279, Issue 27, 28466-28474, July 2, 2004

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The Role of Protein Kinase D in Neurotensin Secretion Mediated by Protein Kinase C-/- and Rho/Rho Kinase^*

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

From the Department of Surgery and Sealy Center for Cancer Cell Biology, The University of Texas Medical Branch, Galveston, Texas 77555-0536

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- and - 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- and - siRNA attenuated PKD activity, whereas overexpression of PKC- and - enhanced PKD activity. Rho kinase (ROK) siRNA significantly inhibited NT secretion, whereas overexpression of ROK 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- and - and Rho/ROK. Importantly, our results identify novel signaling pathways, which culminate in gut peptide release.

Received for publication, December 30, 2003 , and in revised form, April 22, 2004.

^* This work was supported by Grants 2R37 AG10885, RO1 DK48489, PO1 DK35608, R21 CA10212, and RO1 DK58119 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a Supplementary Video.

^¶ To whom correspondence should be addressed: The University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-0536. Tel.: 409-772-5612; Fax: 409-747-4819; E-mail: mevers{at}utmb.edu.

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