Microtubule plus-end tracking proteins (+TIPs) comprise a structurally and functionally diverse family of modular proteins that preferentially accumulate at microtubule (MT) growing ends. There, they regulate MT dynamics and mediate the anchorage of MTs to many other different cellular structures to control fundamental cellular processes including cell division, intracellular transport, cell adhesion and motility, and cell organization. +TIPs have a remarkable ability to form dynamic networks where most of the protein-protein interactions are mediated by End-Binding (EB) proteins. EBs are master regulators of all known +TIP networks; they are able to autonomously track MT tips independent of any binding partner while the rest of +TIPs generally require EB to efficiently track MT ends. Recently, a short linear sequence motif, denoted SxIP, used by numerous +TIPs for localization to MT ends in an EB-dependent manner, has been demonstrated to act as a general MT tip localization signal.The proposed research aims to obtain mechanistic insights into +TIP molecular recognition mechanisms and their modes of regulation, necessary to understand how +TIP dynamic and transient interactions translate into cellular functions. A major focus of the research project involves the identification of small-molecules that modulate these interactions and serve as a biological tool that allow the dissection with precise temporal control of the functional interplay between EBs and the broad number of proteins carrying a SxIP MT-tip localization signal. Furthermore, given the crucial role of this interplay in essential cellular processes, deregulated in neoplasia, such as MT-dynamics, mitosis or cell adhesion, and the proposed oncogenic roles of EB proteins, this research might also spur development of a new antitumoural therapeutic approach by blocking the EB-SxIP interaction.