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J. Biol. Chem., Vol. 279, Issue 7, 5788-5801, February 13, 2004

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Identification of Two Distinct Pathways of Protein Kinase C Down-regulation in Intestinal Epithelial Cells^*

Olga V. Leontieva and Jennifer D. Black

From the Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263

Signal transduction pathways are controlled by desensitization mechanisms, which can affect receptors and/or downstream signal transducers. It has long been recognized that members of the protein kinase C (PKC) family of signal transduction molecules undergo down-regulation in response to activation. Previous reports have indicated that key steps in PKC desensitization include caveolar internalization, priming site dephosphorylation, ubiquitination of the dephosphorylated protein, and degradation by the proteasome. In the current study, comparative analysis of PKC processing induced by the PKC agonists phorbol 12-myristate 13-acetate and bryostatin 1 in IEC-18 rat intestinal epithelial cells demonstrates that: (a) at least two pathways of PKC down-regulation can co-exist within cells, and (b) a single PKC agonist can activate both pathways at the same time. Using a combined biochemical and morphological approach, we identify a novel pathway of PKC desensitization that involves ubiquitination of mature, fully phosphorylated activated enzyme at the plasma membrane and subsequent down-regulation by the proteasome. The phosphatase inhibitors okadaic acid and calyculin A accelerated PKC down-regulation and inhibitors of vesicular trafficking did not prevent degradation of the protein, indicating that neither internalization nor priming site dephosphorylation are requisite intermediate steps in this ubiquitin/proteasome dependent pathway of PKC down-regulation. Instead, caveolar trafficking and dephosphorylation are involved in a second, proteasome-independent mechanism of PKC desensitization in this system. Our findings highlight subcellular distribution and phosphorylation state as critical determinants of PKC desensitization pathways.

Received for publication, July 31, 2003 , and in revised form, November 5, 2003.

^* This work was supported by National Institutes of Health Grants DK 54909 and CA 16056 and by a grant from the Mae Stone Goode/Roswell Park Alliance Foundation. 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. Tel.: 716-845-5766; Fax: 716-845-8857; E-mail: jennifer.black{at}roswellpark.org.

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