The C. elegans ROR Receptor Tyrosine Kinase, CAM-1, Regulates Wnt Signaling by Two Distinct Mechanisms

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The ROR (receptor orphan) family of receptor tyrosine kinase, which is required for human skeletal development and has been implicated in human cancer, is one of the few classes of RTK whose activity remains elusive. Although the mechanism is unknown, there is evidence that ROR proteins inhibit signaling by Wnts, a conserved class of secreted glycoproteins. We have studied how ROR proteins interact with Wnt signaling during C. elegans vulval development, a classic model used to study cell-signaling pathways. Wnt/β-catenin signaling controls cell-fate decisions of the vulval precursor cells (VPCs). We found that loss and over-expression of the C. elegans ROR homolog, cam-1, caused reciprocal defects in Wnt-mediated cell-fate specification. Our molecular and genetic analysis revealed that during vulval induction the CAM-1 extracellular domain (ECD) is sufficient to non-autonomously antagonize multiple Wnts, implying that the CAM-1 ECD sequesters Wnts. Our finding that the CAM-1 ECD specifically binds Wnts in vitro supports a sequestration model. Thus, CAM-1/ROR regulates Wnt signaling by modifying the spatial profile of Wnt activity. In addition to regulating cell-fate specification, Wnt signaling also determines VPC polarity. The mirror symmetry of the C. elegans vulva is achieved by the opposite division orientation of the VPCs flanking the axis of symmetry. We characterized the molecular mechanisms by which opposing Wnts establish this division pattern and how CAM-1 contributes to VPC orientation. Wnts MOM-2 and LIN-44 are expressed at the axis of symmetry and orient the VPCs towards the center. We show that these Wnts, via Fz/LIN-17 and Ryk/LIN-18, control β-catenin localization and activate gene transcription. In addition, we found that VPCs on both sides of the axis of symmetry possess a uniform underlying “ground” polarity, established by the instructive activity of Wnt/EGL-20. EGL-20 establishes ground polarity via a novel type of signaling involving CAM-1 and the Planar Cell Polarity component Van Gogh/VANG-1. CAM-1 activity during ground polarity signaling requires the CAM-1 intracellular domain and is thus likely to be a cell-autonomous function. Therefore, CAM-1 interacts with Wnts by two distinct mechanisms: it sequesters Wnts and it transmits directional information from Wnts to individual cells.