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

doi:10.1371/journal.pone.0035826

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 journal › Article › peer-review

99 Scopus citations

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 language	English (US)
Article number	e35826
Journal	PLoS One
Volume	7
Issue number	4
DOIs	https://doi.org/10.1371/journal.pone.0035826
State	Published - Apr 27 2012
Externally published	Yes

ASJC Scopus subject areas

General Agricultural and Biological Sciences
General Biochemistry, Genetics and Molecular Biology
General Medicine

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Krejci, P., Aklian, A., Kaucka, M., Sevcikova, E., Prochazkova, J., Masek, J. K., Mikolka, P., Pospisilova, T., Spoustova, T., Weis, M., Paznekas, W. A., Wolf, J. H., Gutkind, J. S., Wilcox, W. R., Kozubik, A., Jabs, E. W., 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, 7(4), Article e35826. https://doi.org/10.1371/journal.pone.0035826

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

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

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.",

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

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AU - Krejci, Pavel

AU - Aklian, Anie

AU - Kaucka, Marketa

AU - Sevcikova, Eva

AU - Prochazkova, Jirina

AU - Masek, Jan Kukla

AU - Mikolka, Pavol

AU - Pospisilova, Tereza

AU - Spoustova, Tereza

AU - Weis, MaryAnn

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

PY - 2012/4/27

Y1 - 2012/4/27

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.

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

Abstract

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