title: M6P/IGF2R modulates the invasiveness of liver cells via its capacity to bind mannose 6-phosphate residues.
abstract: OBJECTIVE
  The mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R), a multifunctional protein, plays a central role in intracellular targeting of lysosomal enzymes and control of insulin-like growth factor II (IGF-II) bioactivity. Importantly, the gene encoding this receptor is frequently inactivated in a wide range of malignant tumors including hepatocellular carcinomas. Thus, M6P/IGF2R is considered a putative liver tumor suppressor. The aim of this study was to establish the impact of the receptor on the invasive properties of liver cells.
  
  
  METHODS
  Reconstitution experiments were performed by expression of wild type and mutant M6P/IGF2R in receptor-deficient FRL14 fetal rat liver cells. RNA interference was used to induce M6P/IGF2R downregulation in receptor-positive MIM-1-4 mouse hepatocytes.
  
  
  RESULTS
  We show that the M6P/IGF2R status exerts a strong impact on the invasiveness of tumorigenic rodent liver cells. M6P/IGF2R-deficient fetal rat liver cells hypersecrete lysosomal cathepsins and penetrate extracellular matrix barriers in a cathepsin-dependent manner. Forced expression of M6P/IGF2R restores intracellular transport of cathepsins to lysosomes and concomitantly reduces the tumorigenicity and invasive potential of these cells. Conversely, M6P/IGF2R knock-down in receptor-positive mouse hepatocytes causes increased cathepsin secretion as well as enhanced cell motility and invasiveness. We also demonstrate that functional M6P-binding sites are important for the anti-invasive properties of M6P/IGF2R, whereas the capacity to bind IGF-II is dispensable for the anti-invasive activity of the receptor in liver cells.
  
  
  CONCLUSIONS
  M6P/IGF2R restricts liver cell invasion by preventing the pericellular action of M6P-modified proteins.
authors.affiliation: Department of Applied Genetics and Cell Biology, University of Natural Resources and Life Sciences, Muthgasse 18, A-1190 Vienna, Austria.
authors.forename: Verena
authors.initials: V
authors.lastname: Puxbaum
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Nimmerfall
authors.forename: Christine
authors.initials: C
authors.lastname: Bäuerl
authors.forename: Nicole
authors.initials: N
authors.lastname: Taub
authors.forename: Pia-Maria
authors.initials: PM
authors.lastname: Blaas
authors.forename: Johannes
authors.initials: J
authors.lastname: Wieser
authors.forename: Mario
authors.initials: M
authors.lastname: Mikula
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mikulits
authors.forename: Ken M
authors.initials: KM
authors.lastname: Ng
authors.forename: George C T
authors.initials: GC
authors.lastname: Yeoh
authors.forename: Lukas
authors.initials: L
authors.lastname: Mach
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D022781:Hepatocytes / Q000473:pathology*; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008113:Liver Neoplasms / Q000473:pathology*; D008247:Lysosomes / Q000201:enzymology; D008360:Mannosephosphates / Q000378:metabolism*; D051379:Mice; D009361:Neoplasm Invasiveness; D011485:Protein Binding; D051381:Rats; D017527:Receptor, IGF Type 2 / Q000502:physiology*
chemical_list: D008360:Mannosephosphates; D017527:Receptor, IGF Type 2; C027693:mannose-6-phosphate; D007930:Leucine; C024974:E 64