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Medline ® Abstract for Reference 16

of 'Molecular biology and pathogenesis of von Hippel-Lindau disease'

16
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Tumor suppression by the von Hippel-Lindau protein requires phosphorylation of the acidic domain.
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Lolkema MP, Gervais ML, Snijckers CM, Hill RP, Giles RH, Voest EE, Ohh M
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J Biol Chem. 2005 Jun;280(23):22205-11. Epub 2005 Apr 11.
 
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.
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Department of Medical Oncology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
PMID