MT-TIP INHIBITORS · Mechanisms and functions of microtubule plus end tracking proteins in mammalian cells: development of inhibitory strategies

Microtubule plus end tracking proteins are a group of factors that accumulate specifically at the ends of growing microtubules where they control microtubule dynamics and the interactions with different structures, such as mitotic kinetochores, actin cytoskeleton and the cell cortex. The core components of the microtubule plus end tracking machinery are End Binding (EB) proteins, such as EB1, which autonomously track the growing ends of microtubules and recruit to microtubule tips multiple functionally diverse proteins. The aim of this proposal is to use a wide range of microtubule-targeting anti-cancer compounds to systematically probe their effects on the microtubule-EB binding and thus gain insight into the basis of the enigmatic plus end recognition mechanism by the EBs. We also intend to use the detailed knowledge of the mechanisms underlying the interactions of EB proteins with their partners to develop novel reagents to inhibit microtubule plus end tracking of a broad range of proteins and thus probe the general significance of this phenomenon. In addition, we plan to use this knowledge to develop new tools to efficiently visualize growing microtubule ends in different cellular settings.