Mitogen-Activated Protein Kinases Promote WNT/β-Catenin Signaling via Phosphorylation of LRP6
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LDL-related protein 6 (LRP6) is a coreceptor of WNTs and a key regulator of the WNT/β-catenin pathway. Upon activation, LRP6 is phosphorylated within its intracellular PPPS/TP motifs. These phosphorylated motifs are required to recruit axin and to inhibit glycogen synthase kinase 3 (GSK3), two basic components of the β-catenin destruction complex. On the basis of a kinome-wide small interfering RNA (siRNA) screen and confirmative biochemical analysis, we show that several proline-directed mitogen-activated protein kinases (MAPKs), such as p38, ERK1/2, and JNK1 are sufficient and required for the phosphorylation of PPPS/TP motifs of LRP6. External stimuli, which control the activity of MAPKs, such as phorbol esters and fibroblast growth factor 2 (FGF2) control the choice of the LRP6-PPPS/TP kinase and regulate the amplitude of LRP6 phosphorylation and WNT/β-catenin-dependent transcription. Our findings suggest that cells not only recruit one dedicated LRP6 kinase but rather select their LRP6 kinase depending on cell type and the external stimulus. Moreover, direct phosphorylation of LRP6 by MAPKs provides a unique point for convergence between WNT/β-catenin signaling and mitogenic pathways.
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Multiple studies provide evidence that MAPK modulates the activities of the Wnt/β-catenin pathway.
“Furthermore, multiple studies have provided evidence of the involvement of MAPK in modulating the activities of the Wnt/β-catenin pathway.”
From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [133]
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- Authors
- Červenka, I., Wolf, J., Mašek, J., Krejci, P., Wilcox, W. R., Kozubík, A., Schulte, G., Gutkind, J. S., & Bryja, V.
- Affiliations
- National Institutes of Health (US)
- Institute of Experimental Biology, Faculty of Science, Masaryk University, Kotlářská 2, 611 37 Brno, Czech Republic
- Cedars-Sinai Medical Center (US)
- Corresponding author
- Gutkind, J. Silvio
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2011-01-01
- Volume
- 31
- Issue
- 1
- Pages
- 179-189
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC3019858
- OpenAlex
- W2149682914
- Cited by
- 117
- References
- 37
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 2 · 2022: 7 · 2021: 10 · 2020: 7 · 2019: 9 · 2018: 7 · 2017: 5 · 2016: 6 · 2015: 12 · 2014: 13 · 2013: 13 · 2012: 14
- FWCI
- 4.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ASEP (submittedVersion, public-domain)
- Funders
- Howard Hughes Medical Institute
- University of Washington
- Georgetown University
- Swedish Cancer Foundation
- Swedish Foundation for International Cooperation in Research and Higher Education
- Grantová Agentura České Republiky (GD204/09/H058, GA204/09/0498, AVOZ50040507)
- Karolinska Institutet
- Knut och Alice Wallenbergs Stiftelse
- Akademie Věd České Republiky (AVO Z5 004 0507, AVOZ50040702)
- National Institutes of Health
- Medical Research Council
- National Institute of Dental and Craniofacial Research
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD022657, 5P01HD022657-21A)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- LRP6, Wnt/β-catenin signaling, mitogen-activated protein kinase, MAPK phosphorylation, p38 MAPK, ERK1/2, JNK1, Axin, glycogen synthase kinase-3, β-catenin destruction complex, FGF2, phorbol ester, transcriptional regulation
- MeSH terms
- Animals, Cell Line, Humans, Phosphorylation, Receptors, LDL, Tumor Cells, Cultured, Signal Transduction, Amino Acid Motifs, Mitogen-Activated Protein Kinases, MAP Kinase Signaling System, LDL-Receptor Related Proteins, RNA, Small Interfering, p38 Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase 8, Wnt Proteins, beta Catenin, Rats, Low Density Lipoprotein Receptor-Related Protein-6
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