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J. Biol. Chem., Vol. 281, Issue 49, 37705-37719, December 8, 2006

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Gastrointestinal Hormones Cause Rapid c-Met Receptor Down-regulation by a Novel Mechanism Involving Clathrin-mediated Endocytosis and a Lysosome-dependent Mechanism^*

K. Martin Hoffmann¹, Jose A. Tapia¹, Marc J. Berna, Michelle Thill^¶, Till Braunschweig^||, Samuel A. Mantey, Terry W. Moody, and Robert T. Jensen²

From the Digestive Diseases Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892-1804, the Departamento de Fisiología, Universidad de Extremadura, Cáceres 10071, Spain, the ^¶NEI, National Institutes of Health, Bethesda, Maryland 20892-1804, and the ^||Tissue Array Research Program, Laboratory of Pathology, NCI, National Institutes of Health, Bethesda, Maryland 20892-4605

The activated c-Met receptor has potent effects on normal tissues and tumors. c-Met levels are regulated by hepatocyte growth factor (HGF); however, it is unknown if they can be regulated by gastrointestinal (GI) hormones. c-Met is found in many GI tissues/tumors that possess GI hormone receptors. We studied the effect of GI hormones on c-Met in rat pancreatic acini, which possess both receptors. CCK-8, carbachol, and bombesin, but not VIP/secretin, decreased c-Met. CCK-8 caused rapid and potent c-Met down-regulation and abolished HGF-induced c-Met and Gab1 tyrosine phosphorylation, while stimulating c-Met serine phosphorylation. The effect of cholecystokinin (CCK) was also seen in intact acini using immunofluorescence, in a biotinylated fraction representing membrane proteins, in single acinar cells, in Panc-1 tumor cells, and in vivo in rats injected with CCK. CCK-8 did not decrease cell viability or overall responsiveness. GF109203X, thapsigargin, or their combination partially reversed the effect of CCK-8. In contrast to HGF-induced c-Met down-regulation, the effect of CCK was decreased by a lysosome inhibitor (concanamycin) but not the proteasome inhibitor lactacystin. Inhibitors of clathrin-mediated endocytosis blocked the effect of CCK. HGF but not CCK-8 caused c-Met ubiquitination. These results show CCK and other GI hormones can cause rapid c-Met down-regulation, which occurs by a novel mechanism. These results could be important for c-Met regulation in normal as well as in neoplastic tissue in the GI tract.

Received for publication, March 20, 2006 , and in revised form, August 29, 2006.

^* This was supported in part by the Intramural Research Program of the NIDDK, NCI, and NEI, 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.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Digestive Diseases Branch, NIDDK, National Institutes of Health, Bldg. 10, Rm. 9C-103, 10 Center Dr., MSC 1804, Bethesda, MD 20892-1804. Tel.: 301-496-4201; Fax: 301-402-0600; E-mail: robertj{at}bdg10.niddk.nih.gov.

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