title: Receptor tyrosine kinases activate canonical WNT/β-catenin signaling via MAP kinase/LRP6 pathway and direct β-catenin phosphorylation.
abstract: Receptor tyrosine kinase signaling cooperates with WNT/β-catenin signaling in regulating many biological processes, but the mechanisms of their interaction remain poorly defined. We describe a potent activation of WNT/β-catenin by FGFR2, FGFR3, EGFR and TRKA kinases, which is independent of the PI3K/AKT pathway. Instead, this phenotype depends on ERK MAP kinase-mediated phosphorylation of WNT co-receptor LRP6 at Ser1490 and Thr1572 during its Golgi network-based maturation process. This phosphorylation dramatically increases the cellular response to WNT. Moreover, FGFR2, FGFR3, EGFR and TRKA directly phosphorylate β-catenin at Tyr142, which is known to increase cytoplasmic β-catenin concentration via release of β-catenin from membranous cadherin complexes. We conclude that signaling via ERK/LRP6 pathway and direct β-catenin phosphorylation at Tyr142 represent two mechanisms used by various receptor tyrosine kinase systems to activate canonical WNT signaling.
authors.affiliation: Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America. krejcip@sci.muni.cz
authors.forename: Pavel
authors.initials: P
authors.lastname: Krejci
authors.forename: Anie
authors.initials: A
authors.lastname: Aklian
authors.forename: Marketa
authors.initials: M
authors.lastname: Kaucka
authors.forename: Eva
authors.initials: E
authors.lastname: Sevcikova
authors.forename: Jirina
authors.initials: J
authors.lastname: Prochazkova
authors.forename: Jan Kukla
authors.initials: JK
authors.lastname: Masek
authors.forename: Pavol
authors.initials: P
authors.lastname: Mikolka
authors.forename: Tereza
authors.initials: T
authors.lastname: Pospisilova
authors.forename: Tereza
authors.initials: T
authors.lastname: Spoustova
authors.forename: MaryAnn
authors.initials: M
authors.lastname: Weis
authors.forename: William A
authors.initials: WA
authors.lastname: Paznekas
authors.forename: Joshua H
authors.initials: JH
authors.lastname: Wolf
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
authors.forename: William R
authors.initials: WR
authors.lastname: Wilcox
authors.forename: Alois
authors.initials: A
authors.lastname: Kozubik
authors.forename: Ethylin Wang
authors.initials: EW
authors.lastname: Jabs
authors.forename: Vitezslav
authors.initials: V
authors.lastname: Bryja
authors.forename: Lisa
authors.initials: L
authors.lastname: Salazar
authors.forename: Iva
authors.initials: I
authors.lastname: Vesela
authors.forename: Lukas
authors.initials: L
authors.lastname: Balek
mesh_terms: D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051153:Wnt Proteins; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3