The C. elegans ROR receptor tyrosine kinase, CAM-1, non-autonomously inhibits the Wnt pathway.
Inhibitors of Wnt signaling promote normal development and prevent cancer by restraining when and where the Wnt pathway is activated. ROR proteins, a class of Wnt-binding receptor tyrosine kinases, inhibit Wnt signaling by an unknown mechanism. To clarify how RORs inhibit the Wnt pathway, we examined the relationship between Wnts and the sole C. elegans ROR homolog, cam-1, during C. elegans vulval development, a Wnt-regulated process. We found that loss and overexpression of cam-1 causes reciprocal defects in Wnt-mediated cell-fate specification. Our molecular and genetic analyses revealed that the CAM-1 extracellular domain (ECD) is sufficient to non-autonomously antagonize multiple Wnts, suggesting that the CAM-1/ROR ECD sequesters Wnts. A sequestration model is supported by our findings that the CAM-1 ECD binds to several Wnts in vitro. These results demonstrate how ROR proteins help to refine the spatial pattern of Wnt activity in a complex multicellular environment.
Green
Jennifer L
JL
Division of Biology, California Institute of Technology, Mail Code 156-29, Pasadena, CA 91125, USA.
Inoue
Takao
T
Sternberg
Paul W
PW
D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000196:embryology / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004625:Embryo, Nonmammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006023:Glycoproteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008954:Models, Biological; D009024:Morphogenesis / Q000235:genetics; D011485:Protein Binding; D017434:Protein Structure, Tertiary / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014844:Vulva / Q000196:embryology; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
C526268:CWN-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; C117259:Egl-20 protein, C elegans; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; C518000:MOM-2 protein, C elegans; D051153:Wnt Proteins; C526267:CAM-1 protein, C elegans; D020794:Receptor Protein-Tyrosine Kinases; D057050:Receptor Tyrosine Kinase-like Orphan Receptors