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Molecular and Cellular Biology, August 2006, p. 5784-5796, Vol. 26, No. 15
0270-7306/06/$08.00+0     doi:10.1128/MCB.00232-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Priming-Dependent Phosphorylation and Regulation of the Tumor Suppressor pVHL by Glycogen Synthase Kinase 3{dagger}

Alexander Hergovich,{ddagger} Joanna Lisztwan ,§,¶ Claudio R. Thoma, Christiane Wirbelauer,{ddagger} Robert E. Barry,|| and Wilhelm Krek*

Institute for Cell Biology, ETH Zurich, 8093 Zurich, Switzerland

Received 8 February 2006/ Returned for modification 13 March 2006/ Accepted 14 May 2006

Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is linked to the development of tumors of the eyes, kidneys, and central nervous system. VHL encodes two gene products, pVHL30 and pVHL19, of which one, pVHL30, associates functionally with microtubules (MTs) to regulate their stability. Here we report that pVHL30 is a novel substrate of glycogen synthase kinase 3 (GSK3) in vitro and in vivo. Phosphorylation of pVHL on serine 68 (S68) by GSK3 requires a priming phosphorylation event at serine 72 (S72) mediated in vitro by casein kinase I. Functional analysis of pVHL species carrying nonphosphorylatable or phosphomimicking mutations at S68 and/or S72 reveals a central role for these phosphorylation events in the regulation of pVHL's MT stabilization (but not binding) activity. Taken together, our results identify pVHL as a novel priming-dependent substrate of GSK3 and suggest a dual-kinase mechanism in the control of pVHL's MT stabilization function. Since GSK3 is a component of multiple signaling pathways that are altered in human cancer, our results further imply that normal operation of the GSK3-pVHL axis may be a critical aspect of pVHL's tumor suppressor mechanism through the regulation of MT dynamics.

* Corresponding author. Mailing address: Institute for Cell Biology, ETH Zurich, CH-8093 Zurich, Switzerland. Phone: 41 01 633 33 38. Fax: 41 01 633 13 57. E-mail: wilhelm.krek{at}cell.biol.ethz.ch.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.

§ Present address: Novartis Institutes for Biomedical Research, CH-4002 Basel, Switzerland.

J.L. and C.R.T. contributed equally to this work.

|| Present address: UCD School of Medicine and Medical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.

Molecular and Cellular Biology, August 2006, p. 5784-5796, Vol. 26, No. 15
0270-7306/06/$08.00+0     doi:10.1128/MCB.00232-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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