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

Časopis: PLOS ONE 7
Autoři: Krejci, P., Aklian, A., Kaucka, M., Sevcikova, E., Prochazkova, J., Masek, JK., Mikolka, P., Pospisilova, T., Spoustova, T., Weis, M., Paznekas, WA., Wolf, JH., Gutkind, JS., Wilcox, WR., Kozubik, A., Jabs, EW., Bryja, V., Salazar, L., Vesela, I., Balek, L.
Rok: 2012


Receptor tyrosine kinase signaling cooperates with WNT/beta-catenin signaling in regulating many biological processes, but the mechanisms of their interaction remain poorly defined. We describe a potent activation of WNT/beta-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 beta-catenin at Tyr142, which is known to increase cytoplasmic beta-catenin concentration via release of beta-catenin from membranous cadherin complexes. We conclude that signaling via ERK/LRP6 pathway and direct beta-catenin phosphorylation at Tyr142 represent two mechanisms used by various receptor tyrosine kinase systems to activate canonical WNT signaling.