title: Agonistic and antagonistic roles for TNIK and MINK in non-canonical and canonical Wnt signalling.
abstract: Wnt signalling is a key regulatory factor in animal development and homeostasis and plays an important role in the establishment and progression of cancer. Wnt signals are predominantly transduced via the Frizzled family of serpentine receptors to two distinct pathways, the canonical ß-catenin pathway and a non-canonical pathway controlling planar cell polarity and convergent extension. Interference between these pathways is an important determinant of cellular and phenotypic responses, but is poorly understood. Here we show that TNIK (Traf2 and Nck-interacting kinase) and MINK (Misshapen/NIKs-related kinase) MAP4K signalling kinases are integral components of both canonical and non-canonical pathways in Xenopus. xTNIK and xMINK interact and are proteolytically cleaved in vivo to generate Kinase domain fragments that are active in signal transduction, and Citron-NIK-Homology (CNH) Domain fragments that are suppressive. The catalytic activity of the Kinase domain fragments of both xTNIK and xMINK mediate non-canonical signalling. However, while the Kinase domain fragments of xTNIK also mediate canonical signalling, the analogous fragments derived from xMINK strongly antagonize this signalling. Our data suggest that the proteolytic cleavage of xTNIK and xMINK determines their respective activities and is an important factor in controlling the balance between canonical and non-canonical Wnt signalling in vivo.
authors.affiliation: Laboratory of Growth and Development, Cancer Research Centre, Laval University, Quebec City, Québec, Canada.
authors.forename: Alexander
authors.initials: A
authors.lastname: Mikryukov
authors.forename: Tom
authors.initials: T
authors.lastname: Moss
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D055162:Biocatalysis; D019521:Body Patterning; D016764:Cell Polarity; D000072261:Dishevelled Proteins; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000201:enzymology; D054262:Gastrulation; D055785:Gene Knockdown Techniques; D000081410:Germinal Center Kinases; D006801:Humans; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D054259:Neural Tube / Q000166:cytology / Q000196:embryology / Q000201:enzymology; D009672:Notochord / Q000166:cytology / Q000196:embryology; D010455:Peptides / Q000378:metabolism; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D017384:Sequence Deletion; D013347:Subcellular Fractions / Q000201:enzymology; D020825:T-Box Domain Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D014981:Xenopus / Q000196:embryology / Q000378:metabolism*; D029867:Xenopus Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; D000081410:Germinal Center Kinases; D050505:Mutant Proteins; D010455:Peptides; D010750:Phosphoproteins; D020825:T-Box Domain Proteins; C116765:TBXT protein, Xenopus; C000631453:TNIK protein, Xenopus; D029867:Xenopus Proteins; C578778:MINK1 protein, Xenopus; D017346:Protein Serine-Threonine Kinases; C000631454:TNIK protein, human