Tumor Suppression by the von Hippel-Lindau Protein Requires Phosphorylation of the Acidic Domain

• Published in: The Journal of biological chemistry Vol. 280; no. 23; pp. 22205 - 22211
• Main Authors: Lolkema, Martijn P., Gervais, Michelle L., Snijckers, Cristel M., Hill, Richard P., Giles, Rachel H., Voest, Emile E., Ohh, Michael
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.06.2005; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cell Line; Chromatography, Gel; DNA-Binding Proteins - metabolism; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Enzyme-Linked Immunosorbent Assay; Fibronectins - metabolism; Humans; Hypoxia - metabolism; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Immunoblotting; Immunoprecipitation; Mice; Mice, SCID; Mutation; Neoplasm Transplantation; Nuclear Proteins - metabolism; Phosphorylation; Plasmids - metabolism; Protein Binding; Protein Processing, Post-Translational; Protein Structure, Tertiary; Time Factors; Transcription Factors - metabolism; Transfection; Tumor Suppressor Proteins - chemistry; Tumor Suppressor Proteins - metabolism; Tumor Suppressor Proteins - physiology; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - chemistry; Ubiquitin-Protein Ligases - metabolism; Ubiquitin-Protein Ligases - physiology; Von Hippel-Lindau Tumor Suppressor Protein
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M503220200

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.