The product of the von Hippel-Lindau tumor suppressor gene stabilizes microtubules by inhibiting GTPase activity

Alexandre Matov

Chen

Christian R. Hoerner

Claudio R. Thoma

Crossey

Dimitrov

Frew

Gallou

Gaudenz Danuser

Hergovich

Hesterberg

Hoffman

Iliopoulos

Jaqaman

Kaelin

Katrin L. Gutbrodt

Keller

Kishida

Knauth

Kondo

Matov

Mitchison

Perez

Rosa

Schek

Schermer

Schrijver

Stepanova

Thoma

Vasquez

Weisenberg

Wilhelm Krek

Zlatko Smole

English

PubMed

Crossref

Von Hippel-Lindau (VHL) tumor suppressor gene mutations predispose carriers to kidney cancer. The protein pVHL has been shown to interact with microtubules (MTs), which is critical to cilia maintenance and mitotic spindle orientation. However, the function for pVHL in the regulation of MT dynamics is unknown. We tracked MT growth via the plus end marker EB3 (end-binding protein 3)-GFP and inferred additional parameters of MT dynamics indirectly by spatiotemporal grouping of growth tracks from live cell imaging. Our data establish pVHL as a near-optimal MT-stabilizing protein: it attenuates tubulin turnover, both during MT growth and shrinkage, inhibits catastrophe, and enhances rescue frequencies. These functions are mediated, in part, by inhibition of tubulin guanosine triphosphatase activity in vitro and at MT plus ends and along the MT lattice in vivo. Mutants connected to the VHL cancer syndrome are differentially compromised in these activities. Thus, single cell–level analysis of pVHL MT regulatory function allows new predictions for genotype to phenotype associations that deviate from the coarser clinically defined mutant classifications.ISSN:0021-9525ISSN:1540-814

Thoma, Claudio R.

Matov, Alexandre

Gutbrodt, Katrin L.

Hoerner, Christian R.

Smole, Zlatko

Krek, Wilhelm

Danuser, Gaudenz

Repository for Publications and Research Data

Quantitative image analysis identifies pVHL as a key regulator of microtubule dynamic instability

Von Hippel-Lindau (VHL) tumor suppressor gene mutations predispose carriers to kidney cancer. The protein pVHL has been shown to interact with microtubules (MTs), which is critical to cilia maintenance and mitotic spindle orientation. However, the function for pVHL in the regulation of MT dynamics is unknown. We tracked MT growth via the plus end marker EB3 (end-binding protein 3)-GFP and inferred additional parameters of MT dynamics indirectly by spatiotemporal grouping of growth tracks from live cell imaging. Our data establish pVHL as a near-optimal MT-stabilizing protein: it attenuates tubulin turnover, both during MT growth and shrinkage, inhibits catastrophe, and enhances rescue frequencies. These functions are mediated, in part, by inhibition of tubulin guanosine triphosphatase activity in vitro and at MT plus ends and along the MT lattice in vivo. Mutants connected to the VHL cancer syndrome are differentially compromised in these activities. Thus, single cell–level analysis of pVHL MT regulatory function allows new predictions for genotype to phenotype associations that deviate from the coarser clinically defined mutant classifications.</jats:p

The Journal of Cell Biology

Detection of GTP-tubulin conformation in vivo reveals a role for GTP remnants in microtubule rescues.

doi:10.1126/science.11654011003 pVHL regulates microtubule dynamic instability •

Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype.

Microtubule assembly dynamics at the nanoscale.

pVHL and GSK3beta are components of a primary cilium-maintenance signalling network.

Survivin modulates microtubule dynamics and nucleation throughout the cell cycle.

The von HippelLindau tumor suppressor protein controls ciliogenesis by orienting microtubule growth.

Tubulin-nucleotide interactions during the polymerization and depolymerization of microtubules.

VHL loss causes spindle misorientation and chromosome instability.

Visualization of microtubule growth in cultured neurons via the use of EB3-GFP (end-binding protein 3-green fluorescent protein).

http://rupress.org/jcb/article-pdf/190/6/991/1348453/jcb_201006059.pdf

Quantitative image analysis identifies pVHL as a key regulator of microtubule dynamic instability

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