Receptor Tyrosine Kinases Activate Canonical WNT/β-Catenin Signaling via MAP Kinase/LRP6 Pathway and Direct β-Catenin Phosphorylation
Open Access
- 27 April 2012
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 7 (4), e35826
- https://doi.org/10.1371/journal.pone.0035826
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.Keywords
This publication has 24 references indexed in Scilit:
- Fibroblast growth factors and their receptors in cancerBiochemical Journal, 2011
- Mechanisms underlying differential responses to FGF signalingCytokine & Growth Factor Reviews, 2005
- Essential role of BCL9-2 in the switch between β-catenin's adhesive and transcriptional functionsGenes & Development, 2004
- A Mechanism for Wnt Coreceptor ActivationMolecular Cell, 2004
- p120 Catenin-Associated Fer and Fyn Tyrosine Kinases Regulate β-Catenin Tyr-142 Phosphorylation and β-Catenin-α-Catenin InteractionMolecular and Cellular Biology, 2003
- Differential Regulation of Glycogen Synthase Kinase 3β by Insulin and Wnt SignalingJournal of Biological Chemistry, 2000
- Suppression of Glycogen Synthase Kinase Activity Is Not Sufficient for Leukemia Enhancer Factor-1 ActivationJournal of Biological Chemistry, 1999
- Frequent activating mutations of FGFR3 in human bladder and cervix carcinomasNature Genetics, 1999
- Molecular, radiologic, and histopathologic correlations in thanatophoric dysplasiaAmerican Journal of Medical Genetics, 1998
- Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase BNature, 1995