Cell Division and Cytoskeleton

Microtubules are key components of cytoskeleton that enable intracellular transport, thus contributing to essential cellular functions, including cell division and migration. Microtubules are important drug target of anticancer agents, such as the vinca alkaloids and taxane. However, due to various side effects, such as neuropathies and neurotoxicity, as well as due to the development of drug resistance, the efficacy of these drugs are often challenged in clinical settings.

Consequently, specific targeting of other molecules or molecular properties involved in microtubule-related functions is of great interest. These include tubulin PTMs and tubulin isotypes, which together compose the so-called “tubulin-code”. Tubulin detyrosination is one of the tubulin PTMs that is altered in different cancers and its dysregulation is associated with tumor aggressiveness and poor prognosis in patients, making it a highly promising “molecular target”. In addition, numerous motor proteins are deregulated in cancer and the inhibitors of some of those are involved in advanced phases of clinical trials. Because of the impact of tubulin PTMs on the activity of motor proteins, as well as their association with cancer, this still underexplored field is a particularly attractive platform for the quest for potential anticancer therapeutics.

Current work in the Cell Division and Cytoskeleton (CDC) group is focused on investigation of molecular mechanisms of chromosomal and cytoskeletal dynamics, whose alterations during the cell cycle promote aneuploidy and metastasis, and consequently facilitate tumorigenesis.

Our research is highly based on investigation of

• mechanisms of chromosome congression and segregation during mitosis
• regulation of microtubule dynamics
• the impact of tubulin PTMs on the activity of cytoskeletal motor proteins and their roles in chromosomal and cellular movements

Recently, our work contributed to solving the first structure and elucidating the mitotic role of a recently identified tubulin carboxypeptidase, the vasohibin-SVBP complex (Liao, Rajendraprasad et al., Cell Res 2019). We also established the long-sought molecular mechanism and role of microtubule poleward flux (Steblyanko et al., EMBO J 2020).

Selected publications:

Steblyanko Y, Rajendraprasad G, Osswald M, Eibes S, Jacome A, Geley S, Pereira AJ, Maiato H, Barisic M: Microtubule poleward flux in human cells is driven by the coordinated action of four kinesins. EMBO J 2020;e105432

Liao S, Rajendraprasad G, Wang N, Eibes S, Gao J, Yu H, Wu G, Tu X, Huang H, Barisic M, Xu C: Molecular basis of vasohibins-mediated detyrosination and its impact on spindle function and mitosis. Cell Res 2019;29(7):533-547

Barisic M, Silva e Sousa R, Tripathy SK, Magiera MM, Zaytsev AV, Pereira AL, Janke C, Grishchuk EL, Maiato H: Microtubule detyrosination guides chromosomes during mitosis. Science 2015;348(6236):799-803

Barisic M, Aguiar P, Geley S, Maiato H: Kinetochore motors drive congression of peripheral polar chromosomes by overcoming random arm-ejection forces. Nat Cell Biol 2014;16(12):1249-1256

Barisic M, Sohm B, Mikolcevic P, Wandke C, Rauch V, Ringer T, Hess M, Bonn G, Geley S: Spindly/CCDC99 is required for efficient chromosome congression and mitotic checkpoint regulation. Mol Biol Cell 2010;21(12):1968-1981