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J. Biol. Chem., Vol. 280, Issue 9, 8351-8357, March 4, 2005

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Myristoylated Alanine-rich C Kinase Substrate-mediated Neurotensin Release via Protein Kinase C- Downstream of the Rho/ROK Pathway^*

Jing Li, Kathleen L. O'Connor, George H. Greeley, Jr., Perry J. Blackshear¶, 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 and the ^¶Office of Clinical Research and Laboratory of Neurobiology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709

Myristoylated alanine-rich protein kinase C substrate (MARCKS) is a cellular substrate for protein kinase C (PKC). Recently, we have shown that PKC isoforms- and -, as well as the Rho/Rho kinase (ROK) pathway, play a role in phorbol 12-myristate 13-acetate (PMA)-mediated secretion of the gut peptide neurotensin (NT) in the BON human endocrine cell line. Here, we demonstrate that activation of MARCKS protein is important for PMA- and bombesin (BBS)-mediated NT secretion in BON cells. Small interfering RNA (siRNA) to MARCKS significantly inhibited, whereas overexpression of wild-type MARCKS significantly increased PMA-mediated NT secretion. Endogenous MARCKS and green fluorescent protein-tagged wild-type MARCKS were translocated from membrane to cytosol upon PMA treatment, further confirming MARCKS activation. MARCKS phosphorylation was inhibited by PKC- siRNA, ROK siRNA, and C3 toxin (a Rho protein inhibitor), suggesting that the PKC- and the Rho/ROK pathways are necessary for MARCKS activation. The phosphorylation of PKC- was inhibited by C3 toxin, demonstrating that the role of MARCKS in NT secretion was regulated by PKC- downstream of the Rho/ROK pathway. BON cell clones stably transfected with the receptor for gastrin releasing peptide, a physiologic stimulant of NT, and treated with BBS, the amphibian equivalent of gastrin releasing peptide, demonstrated a similar MARCKS phosphorylation as noted with PMA. BBS-mediated NT secretion was attenuated by MARCKS siRNA. Collectively, these findings provide evidence for novel signaling pathways, including the sequential regulation of MARCKS activity by Rho/ROK and PKC- proteins, in stimulated gut peptide secretion.

Received for publication, August 17, 2004 , and in revised form, December 16, 2004.

^* This work was supported by National Institutes of Health Grants 2R37 AG10885, RO1 DK48489, PO1 DK35608, and R21 CA10212. This paper was presented, in part, at the annual meeting of the American Gastroenterological Association (May 18-24, 2004, New Orleans, LA) and was previously published in abstract form (64). 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.

^|| 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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