title: Context-dependent activation or inhibition of Wnt-beta-catenin signaling by Kremen.
abstract: Wnt-beta-catenin signaling controls critical events in metazoan development, and its dysregulation leads to cancers and developmental disorders. Binding of a Wnt ligand to its transmembrane co-receptors Frizzled (Fz) and low-density lipoprotein (LDL) receptor-related protein (LRP) 5 or LRP6 inhibits the degradation of the transcriptional coactivator beta-catenin, which translocates to the nucleus to regulate gene expression. The secreted protein Dickkopf1 (Dkk1) inhibits Wnt signaling by binding to LRP5 and LRP6 and blocking their interaction with Wnt and Fz. Kremen 1 and 2 (Krm1 and 2, collectively termed Krms) are single-pass transmembrane Dkk1 receptors that synergize with Dkk1 to inhibit Wnt signaling by promoting the endocytosis of LRP5 and LRP6. A study now suggests that Krms, in the absence of Dkk1, potentiate Wnt signaling by maintaining LRP5 and LRP6 at the plasma membrane. It is proposed that the absence or presence of Dkk1 determines whether Krms will activate or inhibit Wnt-beta-catenin signaling, respectively. Here, we speculate that the proposed context-dependent positive and negative roles for Krms could promote biphasic Wnt signaling in response to a shallow gradient of Dkk1, resulting in the generation of precise and robust borders between cells during development. Identification of a context-dependent role for Krms in Wnt-beta-catenin signaling offers insight into the mechanism of Wnt signaling and has important developmental implications.
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University Medical Center, 465 21st Avenue South, U-4225 MRBIII, Nashville, TN 37232-8240, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Cselenyi
authors.forename: Ethan
authors.initials: E
authors.lastname: Lee
mesh_terms: D000818:Animals; D004705:Endocytosis; D051157:Frizzled Receptors / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000502:physiology*; D011485:Protein Binding; D011973:Receptors, LDL / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000378:metabolism*; D014981:Xenopus; D029867:Xenopus Proteins / Q000378:metabolism / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051157:Frizzled Receptors; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011973:Receptors, LDL; D051153:Wnt Proteins; D029867:Xenopus Proteins; D051176:beta Catenin; C110182:dkk1 protein, Xenopus; C471149:kremen2 protein, Xenopus