M6P/IGF2R Modulates the Invasiveness of Liver Cells Via Its Capacity to Bind Mannose 6-phosphate Residues

Overview

Journal J Hepatol

Publisher Elsevier

Specialty Gastroenterology

Date 2012 Apr 24

PMID 22521359

Citations 15

Authors

Verena Puxbaum

Elisabeth Nimmerfall

Christine Bauerl

Nicole Taub

Pia-Maria Blaas

Johannes Wieser

Mario Mikula

Wolfgang Mikulits

Ken M Ng

George C T Yeoh

Lukas Mach

Affiliations

Soon will be listed here.

Abstract

Background & Aims: 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.

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