The biochemistry, signalling and disease relevance of RYK and other WNT-binding receptor tyrosine kinases

Abstract

The receptor tyrosine kinases (RTKs) are a well-characterized family of growth factor receptors that have central roles in human disease and are frequently therapeutically targeted. The RYK, ROR, PTK7 and MuSK subfamilies make up an understudied subset of WNT-binding RTKs. Numerous developmental, stem cell and pathological roles of WNTs, in particular WNT5A, involve signalling via these WNT receptors. The WNT-binding RTKs have highly context-dependent signalling outputs and stimulate the β-catenin-dependent, planar cell polarity and/or WNT/Ca²⁺ pathways. RYK, ROR and PTK7 members have a pseudokinase domain in their intracellular regions. Alternative signalling mechanisms, including proteolytic cleavage and protein scaffolding functions, have been identified for these receptors. This review explores the structure, signalling, physiological and pathological roles of RYK, with particular attention paid to cancer and the possibility of therapeutically targeting RYK. The other WNT-binding RTKs are compared with RYK throughout to highlight the similarities and differences within this subset of WNT receptors.

Keywords: Cancer; WNT receptor; growth factor receptor; non-canonical WNT; pseudokinase; receptor signalling; receptor tyrosine kinase.