| Mitogen-activated protein kinases promote WNT/beta-catenin signaling via phosphorylation of LRP6. | |
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MedLine Citation:
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PMID: 20974802 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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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Authors:
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Igor Červenka; Joshua Wolf; Jan Mašek; Pavel Krejci; William R Wilcox; Alois Kozubík; Gunnar Schulte; J Silvio Gutkind; Vítězslav Bryja |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't Date: 2010-10-25 |
Journal Detail:
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Title: Molecular and cellular biology Volume: 31 ISSN: 1098-5549 ISO Abbreviation: Mol. Cell. Biol. Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2010-12-14 Completed Date: 2011-01-27 Revised Date: 2011-08-01 |
Medline Journal Info:
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Nlm Unique ID: 8109087 Medline TA: Mol Cell Biol Country: United States |
Other Details:
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Languages: eng Pagination: 179-89 Citation Subset: IM |
Affiliation:
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Institute of Experimental Biology, Faculty of Science, Masaryk University, CZ-611 37 Brno, Czech Republic. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Motifs Animals Cell Line Humans LDL-Receptor Related Proteins / chemistry, genetics, metabolism* MAP Kinase Signaling System Mitogen-Activated Protein Kinase 8 / metabolism Mitogen-Activated Protein Kinases / antagonists & inhibitors, genetics, metabolism* Phosphorylation RNA, Small Interfering / genetics Rats Receptors, LDL / metabolism Signal Transduction Tumor Cells, Cultured Wnt Proteins / metabolism* beta Catenin / metabolism* p38 Mitogen-Activated Protein Kinases / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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5P01HD022657-21A/HD/NICHD NIH HHS; //Howard Hughes Medical Institute |
| Chemical | |
Reg. No./Substance:
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0/CTNNB1 protein, human; 0/LDL-Receptor Related Proteins; 0/RNA, Small Interfering; 0/Receptors, LDL; 0/Wnt Proteins; 0/beta Catenin; 0/lipoprotein receptor-related protein 6; EC 2.7.11.24/Mitogen-Activated Protein Kinase 8; EC 2.7.11.24/Mitogen-Activated Protein Kinases; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases |
| Comments/Corrections | |
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