MECHWNTSIGNALS · Mechanisms of Wnt Signaling Initiation

Wnt proteins dictate critical cell growth and lineage decisions during development and in adult tissue homeostasis. Inappropriate activation of Wnt signalling is a frequent cause of cancer. The earliest events that occur after Wnts bind their receptors at the cell surface, such as receptor endocytosis and recruitment of cytoplasmic effectors, are decisive for downstream gene activation but the underlying mechanisms by which these events process and tune the Wnt signal remain poorly understood. The key objective of this proposal is to resolve critical molecular events that drive initiation of the Wnt cascade by focusing on two central questions: How does protein trafficking control Wnt signalling initiation? What molecular mechanisms underlie Wnt-induced formation and activation of multiprotein complexes? I will take a unique approach combining advanced live cell imaging and high resolution immuno-electron microscopy with sophisticated peptide chemistry, gene silencing and biochemistry to dissect early Wnt signalling events at the level of isolated molecules, in cultured cells and in complex tissues of living animals. With the proposed interdisciplinary work I expect to uncover where key Wnt signalling steps occur, which proteins are involved, how they direct protein complex assembly, trafficking and turnover and how these events control transmission of the Wnt signal. Mechanistic insight in how Wnt signals are transmitted is vital to understand how pathway specificity and sensitivity is controlled. Basic insight in these processes will be of utmost importance for the design of strategies to interfere with Wnt signalling in cancer.