title: CD44 functions in Wnt signaling by regulating LRP6 localization and activation.
abstract: Wnt reception at the membrane is complex and not fully understood. CD44 is a major Wnt target gene in the intestine and is essential for Wnt-induced tumor progression in colorectal cancer. Here we show that CD44 acts as a positive regulator of the Wnt receptor complex. Downregulation of CD44 expression decreases, whereas CD44 overexpression increases Wnt activity in a concentration-dependent manner. Epistasis experiments place CD44 function at the level of the Wnt receptor LRP6. Mechanistically, CD44 physically associates with LRP6 upon Wnt treatment and modulates LRP6 membrane localization. Moreover, CD44 regulates Wnt signaling in the developing brain of Xenopus laevis embryos as shown by a decreased expression of Wnt targets tcf-4 and en-2 in CD44 morphants.
authors.affiliation: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Campus North, Postfach 3640, Karlsruhe 76021, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schmitt
authors.affiliation: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Campus North, Postfach 3640, Karlsruhe 76021, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Metzger
authors.affiliation: Zoological Institute II, Karlsruhe Institute of Technology, Campus South, Postfach 6980, Karlsruhe 76128, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Gradl
authors.affiliation: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Campus North, Postfach 3640, Karlsruhe 76021, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Davidson
authors.affiliation: Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Campus North, Postfach 3640, Karlsruhe 76021, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Orian-Rousseau
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000737:chemistry / Q000378:metabolism; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D014982:Xenopus laevis / Q000254:growth & development / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D000099149:Ezrin
chemical_list: D000199:Actins; D003598:Cytoskeletal Proteins; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D051176:beta Catenin; D000099149:Ezrin; C555475:LRP6 protein, human