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Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL

Nature Cell Biology volume 5, pages 64–70 (2003)Cite this article

Abstract

Von Hippel-Lindau (VHL) tumour suppressor gene inactivation is linked to the development of haemangioblastomas in the central nervous system and retina, often in association with other tumours, such as clear-cell carcinomas of the kidney and phaeochromocytomas. Here we show that the VHL protein (pVHL) is a microtubule-associated protein that can protect microtubules from depolymerization in vivo. Both the microtubule binding and stabilization functions of pVHL depend on amino acids 95–123 of pVHL, a mutational 'hot-spot' in VHL disease. From analysis of naturally occurring pVHL mutants, it seems that only point mutations such as pVHLY98H and pVHLY112H (that predispose to haemangioblastoma and phaeochromocytoma, but not to renal cell carcinoma) disrupt pVHL's microtubule-stabilizing function. Our data identify a role for pVHL in the regulation of microtubule dynamics and potentially provide a link between this function of pVHL and the pathogenesis of haemangioblastoma and phaeochromocytoma in the context of VHL disease.

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Figure 1: pVHL30 associates with the microtubule network in vivo.
Figure 3: Amino acids 95–123 of pVHL are required for microtubule stabilization and binding.
Figure 2: Expression of pVHL prevents nocodazole-induced microtubule depolymerization.
Figure 4: Type 2A mutations of pVHL are defective in microtubule stabilization function.
Figure 5: Type 2A pVHL mutations fail to promote microtubule stabilization in VHL-deficient cells.

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Acknowledgements

We thank all members of our laboratory for discussions. We also thank H. Angliker and M. Pietrzak for sequencing, P. Mueller for synthesis of oligonucleotides, F. Fischer for peptide synthesis, A. Matus and J. Rohrer for Tu27b, anti-CLIMP63 and anti-ERGIC-53 antibodies, M. Heinlein for COS-7 cells and R. Bernards for PT67 cells. Special thanks go to P. Ratcliffe for providing pcDNA3-HA-VHL30-R82P, -P86H, -N90I, -Q96P and -Y112H plasmids. We are thankful to G. Thomas, U. Mueller, J. Paszkowski, F. Lehembre and P. Staller for careful reading of the manuscript. This work was supported by the Dr. Josef Steiner Foundation, the Robert Wenner Award and the Novartis Research Foundation.

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  1. Friedrich Miescher Institut, Maulbeerstrasse 66, Basel, CH-4058, Switzerland

    Alexander Hergovich, Joanna Lisztwan, Robert Barry, Pia Ballschmieter & Wilhelm Krek

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Correspondence to Wilhelm Krek.

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Figure S1. Schematic representation of the FKBP38 deletion derivatives. (PDF 1319 kb)

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Hergovich, A., Lisztwan, J., Barry, R. et al. Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL. Nat Cell Biol 5, 64–70 (2003). https://doi.org/10.1038/ncb899

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