Tumor suppression by the von Hippel-Lindau protein requires phosphorylation of the acidic domain.
The tumor suppressor function of the von Hippel-Lindau protein (pVHL) has previously been linked to its role in regulating hypoxia-inducible factor levels. However, VHL gene mutations suggest a hypoxia-inducible factor-independent function for the N-terminal acidic domain in tumor suppression. Here, we report that phosphorylation of the N-terminal acidic domain of ... pVHL by casein kinase-2 is essential for its tumor suppressor function. This post-translational modification did not affect the levels of hypoxia-inducible factor; however, it did change the binding of pVHL to another known binding partner, fibronectin. Cells expressing phospho-defective mutants caused improper fibronectin matrix deposition and demonstrated retarded tumor formation in mice. We propose that phosphorylation of the acidic domain plays a role in the regulation of proper fibronectin matrix deposition and that this may be relevant for the development of VHL-associated malignancies.
Mesh Terms:
Animals, Anoxia, Cell Line, Chromatography, Gel, DNA-Binding Proteins, Dose-Response Relationship, Drug, Electrophoresis, Polyacrylamide Gel, Enzyme-Linked Immunosorbent Assay, Fibronectins, Humans, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Immunoblotting, Immunoprecipitation, Mice, Mice, SCID, Mutation, Neoplasm Transplantation, Nuclear Proteins, Phosphorylation, Plasmids, Protein Binding, Protein Processing, Post-Translational, Protein Structure, Tertiary, Time Factors, Transcription Factors, Transfection, Tumor Suppressor Proteins, Ubiquitin, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein
Animals, Anoxia, Cell Line, Chromatography, Gel, DNA-Binding Proteins, Dose-Response Relationship, Drug, Electrophoresis, Polyacrylamide Gel, Enzyme-Linked Immunosorbent Assay, Fibronectins, Humans, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Immunoblotting, Immunoprecipitation, Mice, Mice, SCID, Mutation, Neoplasm Transplantation, Nuclear Proteins, Phosphorylation, Plasmids, Protein Binding, Protein Processing, Post-Translational, Protein Structure, Tertiary, Time Factors, Transcription Factors, Transfection, Tumor Suppressor Proteins, Ubiquitin, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein
J. Biol. Chem.
Date: Jun. 10, 2005
PubMed ID: 15824109
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