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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Gene Expression Regulation*
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 / metabolism
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HEK293 Cells
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Humans
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Low Density Lipoprotein Receptor-Related Protein-6 / genetics
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Low Density Lipoprotein Receptor-Related Protein-6 / metabolism
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MAP Kinase Signaling System / genetics*
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Receptor Protein-Tyrosine Kinases
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Wnt Proteins / genetics
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Wnt Proteins / metabolism
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Wnt Signaling Pathway / genetics*
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beta Catenin / genetics
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beta Catenin / metabolism
Substances
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LRP6 protein, human
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Low Density Lipoprotein Receptor-Related Protein-6
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Wnt Proteins
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beta Catenin
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Phosphatidylinositol 3-Kinases
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Receptor Protein-Tyrosine Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinases
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Glycogen Synthase Kinase 3