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.