1. Receptor Tyrosine Kinases Activate Canonical WNT/?-Catenin Signaling via MAP Kinase/LRP6 Pathway and Direct Beta-Catenin Phosphorylation
- Author
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Krejci, Pavel, Aklian, Anie, Kaucka, Marketa, Sevcikova, Eva, Prochazkova, Jirina, Masek, Jan Kukla, Mikolka, Pavol, Pospisilova, Tereza, Spoustova, Tereza, Weis, MaryAnn, Paznekas, William A., Wolf, Joshua H., Gutkind, J. Silvio, Wilcox, William R., Kozubik, Alois, Jabs, Ethylin Wang, Bryja, Vitezslav, Salazar, Lisa, Vesela, Iva, and Balek, Lukas
- Subjects
wnt ,insulin ,fgfr3 ,lrp6 ,mutations ,dysplasia ,mechanism ,cancer - 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.
- Published
- 2012