title: Altered down regulation of the receptor tyrosine kinase met in pancreatic adenocarcinoma cells.
abstract: Increased signaling from Met, the receptor for Hepatocyte Growth Factor, promotes pancreatic tumorigenesis and poor patient prognosis by enhancing tumor cell growth, survival and motility. Increased Met levels can result from gene amplification or increased transcription. However, receptor down regulation--a process that normally functions to attenuate Met signaling in vivo--could if impaired, amplify Met signaling in pancreatic tumor cells. Here we report that the lysosomal down regulation of Met is uncoupled in pancreatic adenocarcinoma cell lines. Interestingly, different endocytic mechanisms are employed to escape receptor down regulation and prolong Met signaling. Specifically, ligand treatment does not result in Met retention on the plasma membrane. Rather impaired binding of the E3 ubiquitin ligase Cbl to internalized Met in pancreatic Suit-2 cells causes reduced receptor ubiquitination and enhances Met recycling to the cell surface. Conversely, transient ligand-induced Met ubiquitination in pancreatic BxPC-3 cells correlates with prolonged Met stability and signaling. Moreover, increased Met stability and signaling enhances Suit-2 and BxPC-3 cell viability and chemotaxis towards Hepatocyte Growth Factor. Together our data indicate that uncoupled Met down regulation likely functions to amplify the oncogenic signaling of Met in pancreatic tumor cells.
authors.affiliation: Department of Neuroscience and Cell Biology, Sealy Center for Cancer Cell Biology, University of Texas Medical Branch, Galveston, TX 77555-1074, USA.
authors.forename: Kristen S
authors.initials: KS
authors.lastname: Hill
authors.forename: Marta
authors.initials: M
authors.lastname: Lorinczi
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Elferink
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D004705:Endocytosis; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D021381:Protein Transport; D050721:Proto-Oncogene Proteins c-cbl / Q000502:physiology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D054875:Ubiquitination
chemical_list: D017978:Receptors, Growth Factor; D017228:Hepatocyte Growth Factor; D050721:Proto-Oncogene Proteins c-cbl; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C067419:CBL protein, human