Receptor tyrosine kinases activate canonical WNT/?-catenin signaling via MAP kinase/LRP6 pathway and direct ?-catenin phosphorylation.

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

SUBMITTER: Krejci P 

PROVIDER: S-EPMC3338780 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature