Microtubules play a vital role in cell functions, including division, intracellular transport and cell migration. Microtubule plus-end–tracking proteins (+TIPs) control microtubule dynamics and their interactions with, amongst others, mitotic kinetochores, the actin cytoskeleton and the cell cortex. +TIPs are a specialised group of microtubule-associated factors that bind to the growing ends of microtubules and regulate their functions. EB proteins are the core proteins of the +TIP interaction network. They help to link other +TIPs to the growing plus-ends of the microtubules. Most of the +TIPs have a short conserved SXIP motif, which is involved in EB-dependent microtubule plus-end localisation. The main goal of the EU-funded MT-TIP INHIBITORS project was to use various inhibitory strategies to gain insight into the actions of microtubule-targeting agents (MTAs). These drugs are widely used for the treatment of cancer and other diseases. However, the effects of +TIPs on MTA actions are much less studied. This project used a reconstituted microtubule model in vitro to investigate the influence of EB proteins on the effects that MTAs exert on microtubule plus-end growth. Researchers found that EBs sensitise microtubules to the action of drugs both in cells and in vitro by promoting catastrophes (rapid shrinkage). This effect occurred regardless of the nature of the binding site and the molecular mechanism of action of the MTAs tested. It was found that some MTAs not only induce catastrophes but might also induce microtubule rescue and reverse the microtubule ageing process. The scientists also developed peptides to inhibit the interaction and functions of endogenous +TIP proteins. Efficiently tracking the plus-ends of the microtubules, they affected cell division by arresting the cells at mitosis. In general, this project provided important insights into EB proteins' effects on various drugs at physiological concentrations. It also analysed the role of these proteins in regulating microtubule functions.
Mechanisms and functions of microtubule plus end tracking proteins in mammalian cells: development of inhibitory strategies
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8 February 2021