Medizinische Universität Graz - Research portal
Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Hoffmann, KM; Tapia, JA; Berna, MJ; Thill, M; Braunschweig, T; Mantey, SA; Moody, TW; Jensen, RT.
Gastrointestinal hormones cause rapid c-Met receptor down-regulation by a novel mechanism involving clathrin-mediated endocytosis and a lysosome-dependent mechanism.
J Biol Chem. 2006; 281(49):37705-37719
Doi: 10.1074/jbc.M602583200
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- Leading authors Med Uni Graz
- Hoffmann Karl Martin
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- Abstract:
- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Bombesin - pharmacology
- Calcium - metabolism
- Carbachol - pharmacology
- Cell Line -
- Clathrin - metabolism
- Down-Regulation - drug effects
- Endocytosis -
- Gastrointestinal Hormones - pharmacology
- Hepatocyte Growth Factor - pharmacology
- Lysosomes - metabolism
- Male -
- Pancreas - drug effects
- Protein Kinase C - antagonists & inhibitors
- Proto-Oncogene Proteins c-met - metabolism
- Rats -
- Rats, Sprague-Dawley -
- Sincalide - pharmacology