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.
Lolkema
Martijn P
MP
Department of Medical Oncology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Gervais
Michelle L
ML
Snijckers
Cristel M
CM
Hill
Richard P
RP
Giles
Rachel H
RH
Voest
Emile E
EE
Ohh
Michael
M
D000818:Animals; D002460:Cell Line; D002850:Chromatography, Gel; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D051794:Von Hippel-Lindau Tumor Suppressor Protein
D004268:DNA-Binding Proteins; D005353:Fibronectins; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human