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