Receptor Tyrosine Kinases Activate Canonical WNT/beta-Catenin Signaling via MAP Kinase/LRP6 Pathway and Direct beta-Catenin Phosphorylation

• Type of Material: Article
• Authors: Pavel Krejci, Cedars-Sinai Medical Center; Anie Aklian, Cedars-Sinai Medical Center; Marketa Kaucka, Masaryk University; Eva Sevcikova, Masaryk University; Jirina Prochazkova, Masaryk University; Jan Kukla Masek, Masaryk University; Pavol Mikolka, Masaryk University; Tereza Pospisilova, Masaryk University; Tereza Spoustova, Masaryk University; MaryAnn Weis, University of Washington; William A. Paznekas, Mount Sinai School of Medicine; Joshua H. Wolf, National Institutes of Health; J. Silvio Gutkind, National Institutes of Health; William R. Wilcox, Emory University; Alois Kozubik, Masaryk University; Ethylin Wang Jabs, Mount Sinai School of Medicine; Vitezslav Bryja, Masaryk University; Lisa Salazar, University of California Irvine; Iva Vesela, Masaryk University; Lukas Balek, Masaryk University
• Language: English
• Date: 2012-04-27
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2012 Krejci et al.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0035826
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 7
• Issue: 4
• Start Page: e35826
• End Page: e35826
• Grant/Funding Information: This work was supported by: National Institutes of Health (NIH) 5P01HD022657-21A, NIH GCRC Grant M01-RR00425 (www.nih.gov/); Ministry of Education, Youth and Sports of the Czech Republic (MSM0021622430) (www.msmt.cz/); Grant Agency of the Czech Republic (301/09/0587, 204/09/H058, 204/09/J030, 305/11/0752) (www.gacr.cz); Winnick Family Research Scholars award (WRW) (www.winnickfamilyfoundation.com); and EMBO Installation grant (VB) (www.embo.org).
• Keywords: LRP6; FGFR3; Science & Technology - Other Topics; WNT; Science & Technology; MUTATIONS; CANCER; DYSPLASIA; MECHANISM; Multidisciplinary Sciences; INSULIN
• Research Categories: Biology, Genetics; Health Sciences, Immunology

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.