Gunnar Schulte - Pharmacology of the WNT Signaling System

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The WNT family of secreted lipoglycoproteins was discovered more than 35 years ago and it is established as a key player in embryonic development, tissue regeneration, and homeostasis as well as many devastating disorders such as developmental defects, diverse forms of tumors, bone disease, fibrosis, and neurodegenerative disorder (Willert and Nusse 2012). The 19 mammalian WNTs interact with a complex array of cell surface receptors, of which the Frizzleds (FZD110), members of the Class F of G protein-coupled receptors (GPCRs), present the main WNT receptors, which act either alone or in concert with coreceptors such as LRP5/6, ROR1/2, RYK, and PTK7 (Schulte 2010; van Amerongen 2012).

While many of the players of the WNT signaling system have been mapped and their biological functions are relatively well understood, mechanistic information on how WNT signals are molecularly interpreted by cells and translated into an intracellular response driving, for example, cell proliferation, migration of differentiation remains unclear. Since the field of WNT signaling has developed mainly with an origin in oncology and developmental biology, pharmacological aspects of this signaling system such as quantification of ligandreceptor binding and selectivity, molecular details of receptor activation and activation dynamics, and a quantitative understanding of ligandreceptor interaction in relationship to the amplitude of downstream effects are only slowly evolving.

Given the prominent association of WNT signaling with human disease, the concept of targeting this signaling system pharmacologically and therapeutically has been pursued intensively over the years in part with substantial success defining targetable components in the involved signaling cascades. However, it must be underlined that modulating a central signaling system that is absolutely essential for tissue renewal and homeostasis as most prominently exemplified by the rapid turnover of the intestinal epithelium, comes along with large risks for unwanted side effects.

In this Handbook of Experimental Pharmacology, international experts in the field provide a timely overview of molecular details of the signaling pathway ranging from WNT proteins themselves (Willert/Gross), cell surface receptors, such as Frizzleds (FZD; Schulte), LDL receptor-like proteins (LRPs; Davidson), and receptor tyrosine kinase-like orphan receptor (RORs; Mellstedt) over intracellular components such as the enigmatic scaffold protein Dishevelled (Bryja) to effector systems, such as the transcriptional regulator -catenin (van Amerongen). Emphasis is put on the details of molecular mechanisms of signal transduction in order to elucidate the molecular pharmacology of cellular communication. Furthermore, the reader is introduced to the druggability of different branches of the WNT signaling system including the planar cell polarity pathway (Gao) as well as the possibilities to screen for WNT system-targeting compounds from natural resources (Katanaev). While the potential indications for drugs modulating WNT signaling are numerous, only some important areas are exemplified here providing insight into the importance of FZD7 as a therapeutic target in intestinal cancers (Vincan), the use of WNT-derived peptides for anticancer therapy (Andersson), the opportunities of targeting lung disease (Gosens) and osteoarthritis (