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

Pavel Krejci, Anie Aklian, Marketa Kaucka, Eva Sevcikova, Jirina Prochazkova, Jan Kukla Masek, Pavol Mikolka, Tereza Pospisilova, Tereza Spoustova, MaryAnn Weis, William A. Paznekas, Joshua H. Wolf, J. Silvio Gutkind, William R. Wilcox, Alois Kozubik, Ethylin Wang Jabs, Vitezslav Bryja, Lisa Salazar, Iva Vesela, Lukas Balek

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere35826
JournalPLoS One
Volume7
Issue number4
DOIs
StatePublished - Apr 27 2012
Externally publishedYes

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Catenins
Phosphorylation
Receptor Protein-Tyrosine Kinases
mitogen-activated protein kinase
tyrosine
phosphorylation
phosphotransferases (kinases)
Phosphotransferases
receptors
cadherins
phosphatidylinositol 3-kinase
Biological Phenomena
phenotype
MAP Kinase Signaling System
Extracellular Signal-Regulated MAP Kinases
Cadherins
Phosphatidylinositol 3-Kinases
Chemical activation
Phenotype

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

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

In: PLoS One, Vol. 7, No. 4, e35826, 27.04.2012.

Research output: Contribution to journalArticle

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 2012, 'Receptor tyrosine kinases activate canonical WNT/β-catenin signaling via MAP kinase/LRP6 pathway and direct β-catenin phosphorylation', PLoS One, vol. 7, no. 4, e35826. https://doi.org/10.1371/journal.pone.0035826
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. / Receptor tyrosine kinases activate canonical WNT/β-catenin signaling via MAP kinase/LRP6 pathway and direct β-catenin phosphorylation. In: PLoS One. 2012 ; Vol. 7, No. 4.
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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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AU - Sevcikova, Eva

AU - Prochazkova, Jirina

AU - Masek, Jan Kukla

AU - Mikolka, Pavol

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AU - Paznekas, William A.

AU - Wolf, Joshua H.

AU - Gutkind, J. Silvio

AU - Wilcox, William R.

AU - Kozubik, Alois

AU - Jabs, Ethylin Wang

AU - Bryja, Vitezslav

AU - Salazar, Lisa

AU - Vesela, Iva

AU - Balek, Lukas

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N2 - 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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