Altered down regulation of the receptor tyrosine kinase Met in pancreatic adenocarcinoma cells

Kristen S. Hill, Marta Lorinczi, Lisa Elferink

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)297-312
Number of pages16
JournalJournal of Experimental Therapeutics and Oncology
Volume8
Issue number4
StatePublished - 2010

Fingerprint

Receptor Protein-Tyrosine Kinases
Adenocarcinoma
Down-Regulation
Ubiquitination
Cell Survival
Proto-Oncogene Proteins c-met
Ligands
Neoplasms
Ubiquitin-Protein Ligases
Hepatocyte Growth Factor
Gene Amplification
Recycling
Chemotaxis
Cell Movement
Carcinogenesis
Cell Membrane
Cell Line
Growth

Keywords

  • Cancer
  • Endocytosis
  • Hepatocyte Growth Factor
  • Met
  • Pancreatic
  • Receptor

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Cancer Research

Cite this

Altered down regulation of the receptor tyrosine kinase Met in pancreatic adenocarcinoma cells. / Hill, Kristen S.; Lorinczi, Marta; Elferink, Lisa.

In: Journal of Experimental Therapeutics and Oncology, Vol. 8, No. 4, 2010, p. 297-312.

Research output: Contribution to journalArticle

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