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

  • Author(s): 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
  • Balek, Lukas
  • et al.
Creative Commons Attribution 4.0 International Public License
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.

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