Regulation of microtubule dynamics and function

Carsten Janke

Carsten Janke Team Leader Tel:

Microtubules are key cytoskeletal elements involved in a large number of functions in eukaryotic cells.

They assemble from a protein dimer of a- and b-tubulin, two highly similar and conserved proteins. Tubulins are subject to a large variety of posttranslational modifications (Fig. 1), which provide a rapid and reversible mechanism to diversify microtubule functions in cells. Our team is studying the mechanisms and functional roles of these modifications by using an interdisciplinary approach.

Figure 1 : Représentation schématique des modifications post traductionnelles de la tubuline Ce schéma représente les trois modifications post traductionnelles qui affectent directement la queue C-terminale de la tubuline, ainsi que leurs mécanismes et les enzymes impliquées. Polyglutamylation et polyglycylation ont lieu sur les tubulines et , alors que la détyrosination est limitée à la tubuline .
Figure 1: Schematic representation of tubulin post-translational modifications The three modifications that directly modify the C-terminal tail of tubulin, their mechanisms and enzymes involved in the modifications are depicted. Polyglutamylation and polyglycylation take place on both, α- and β-tubulin, whereas detyrosination is restricted to α-tubulin.

Our team has identified the enzymes involved in the posttranslational polyglutamylation (1, 2), deglutamylation (3, 4) and polyglycylation (5) of tubulin. Following the discovery of these enzymes, we are now investigating (i) the molecular mechanisms, and (ii) the biological functions of tubulin-modifying enzymes.

Polyglutamylation and polyglycylation take place within the C-terminal tails of the tubulin molecules. These tails are localized at the outer surface of the microtubule (Fig. 1), thus their posttranslational modification is most likely regulating the interactions of microtubules with their multiple binding partners, commonly known as microtubule-associated proteins (MAPs) and molecular motors. So far we have demonstrated that the microtubule-severing protein spastin is regulated by tubulin polyglutamylation (6), and that tubulin glycylation stabilizes ciliary axonemes by a yet unknown molecular mechanism (5, 7). Our functional studies have demonstrated an important role for both, polyglutamylation and polyglycylation for motile and primary cilia in mammals (7, 8), and we have found that polyglutamylation is directly linked to neurodegeneration in mice (4). We have further demonstrated a direct link between altered levels of a tubulin glycylase and colorectal cancer development (8).

In our ongoing projects, we are using biochemistry, biophysics and structural biology in conjunction with cell and mouse biology to identify the molecular mechanisms by which tubulin posttranslational modifications regulative microtubule behaviour and functions, and which are the cellular and developmental roles of these modifications and the corresponding enzymes. Our functional studies are focussed on the nervous system, cilia and flagella (including spermatogenesis), and cell division. Our team is closely collaborating with clinicians to delineate the implications of tubulin posttranlsational modifications in human pathologies.

Key publications

Year of publication 2014

Cecilia Rocha, Laura Papon, Wulfran Cacheux, Patricia Marques Sousa, Valeria Lascano, Olivia Tort, Tiziana Giordano, Sophie Vacher, Benedicte Lemmers, Pascale Mariani, Didier Meseure, Jan Paul Medema, Ivan Bièche, Michael Hahne, Carsten Janke (2014 Sep 1)

Tubulin glycylases are required for primary cilia, control of cell proliferation and tumor development in colon.

The EMBO journal : 2247-60 : DOI : 10.15252/embj.201488466
Olivia Tort, Sebastián Tanco, Cecilia Rocha, Ivan Bièche, Cecilia Seixas, Christophe Bosc, Annie Andrieux, Marie-Jo Moutin, Francesc Xavier Avilés, Julia Lorenzo, Carsten Janke (2014 Aug 7)

The cytosolic carboxypeptidases CCP2 and CCP3 catalyze posttranslational removal of acidic amino acids.

Molecular biology of the cell : 3017-27 : DOI : 10.1091/mbc.E14-06-1072

Year of publication 2013

Montserrat Bosch Grau, Gloria Gonzalez Curto, Cecilia Rocha, Maria M Magiera, Patricia Marques Sousa, Tiziana Giordano, Nathalie Spassky, Carsten Janke (2013 Jul 29)

Tubulin glycylases and glutamylases have distinct functions in stabilization and motility of ependymal cilia.

The Journal of cell biology : 441-51 : DOI : 10.1083/jcb.201305041

Year of publication 2010

Benjamin Lacroix, Juliette van Dijk, Nicholas D Gold, Julien Guizetti, Gudrun Aldrian-Herrada, Krzysztof Rogowski, Daniel W Gerlich, Carsten Janke (2010 Jun 7)

Tubulin polyglutamylation stimulates spastin-mediated microtubule severing.

The Journal of cell biology : 945-54 : DOI : 10.1083/jcb.201001024
Krzysztof Rogowski, Juliette van Dijk, Maria M Magiera, Christophe Bosc, Jean-Christophe Deloulme, Anouk Bosson, Leticia Peris, Nicholas D Gold, Benjamin Lacroix, Montserrat Bosch Grau, Nicole Bec, Christian Larroque, Solange Desagher, Max Holzer, Annie Andrieux, Marie-Jo Moutin, Carsten Janke (2010 Feb 2)

A family of protein-deglutamylating enzymes associated with neurodegeneration.

Cell : 564-78 : DOI : 10.1016/j.cell.2010.10.014

Year of publication 2009

Krzysztof Rogowski, François Juge, Juliette van Dijk, Dorota Wloga, Jean-Marc Strub, Nicolette Levilliers, Daniel Thomas, Marie-Hélène Bré, Alain Van Dorsselaer, Jacek Gaertig, Carsten Janke (2009 Jun 12)

Evolutionary divergence of enzymatic mechanisms for posttranslational polyglycylation.

Cell : 1076-87 : DOI : 10.1016/j.cell.2009.05.020
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