Mitogen-Activated Protein Kinases Promote WNT/beta-Catenin Signaling via Phosphorylation of LRP6

ČERVENKA, Igor, Joshua WOLF, Jan MAŠEK, Pavel KREJČÍ, William R. WILCOX, Alois KOZUBÍK, Gunnar SCHULTE, Silvio J. GUTKIND and Vítězslav BRYJA. Mitogen-Activated Protein Kinases Promote WNT/beta-Catenin Signaling via Phosphorylation of LRP6. Molecular and cellular biology. 2011, vol. 31, No 1, p. 179-189. ISSN 0270-7306. Available from: https://dx.doi.org/10.1128/MCB.00550-10.

Basic information

• Original name: Mitogen-Activated Protein Kinases Promote WNT/beta-Catenin Signaling via Phosphorylation of LRP6
• Authors: ČERVENKA, Igor (703 Slovakia, belonging to the institution), Joshua WOLF (840 United States of America), Jan MAŠEK (203 Czech Republic, belonging to the institution), Pavel KREJČÍ (203 Czech Republic, belonging to the institution), William R. WILCOX (840 United States of America), Alois KOZUBÍK (203 Czech Republic, belonging to the institution), Gunnar SCHULTE (276 Germany), Silvio J. GUTKIND (840 United States of America) and Vítězslav BRYJA (203 Czech Republic, guarantor, belonging to the institution).
• Edition: Molecular and cellular biology, 2011, 0270-7306.

Other information

• Original language: English
• Type of outcome: Article in a journal
• Field of Study: 30105 Physiology
• Country of publisher: United States of America
• Confidentiality degree: is not subject to a state or trade secret
• Impact factor: Impact factor: 5.527
• RIV identification code: RIV/00216224:14310/11:00058652
• Organization unit: Faculty of Science
• Doi: http://dx.doi.org/10.1128/MCB.00550-10
• UT WoS: 000285093600014
• Keywords in English: Wnt; beta-catenin; LRP6; MAPKs
• Tags: AKR, rivok

Abstract

LDL-related protein 6 (LRP6) is a coreceptor of WNTs and a key regulator of the WNT/beta-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 beta-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/beta-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/beta-catenin signaling and mitogenic pathways.

Links

• GA301/09/0587, research and development project: Name: Nové dráhy FGFR3 signalingu v achondroplázii

Investor: Czech Science Foundation, Novel pathway of FGFR3 signaling in achondroplasia

• GD204/09/H058, research and development project: Name: Mezibuněčná signalizace ve vývoji organismu a vzniku onemocnění

Investor: Czech Science Foundation, Intercellular signalling in development and disease

• MSM0021622430, plan (intention): Name: Funkční a molekulární charakteristiky nádorových a normálních kmenových buněk - identifikace cílů pro nová terapeutika a terapeutické strategie

Investor: Ministry of Education, Youth and Sports of the CR, Functional and molecular characteristics of cancer and normal stem cells - identification of targets for novel therapeutics and therapeutic strategies

• 1658, interní kód MU: Name: EMBO Young Investigator Programme (Acronym: EMBO)

Investor: EMBO (European Molecular Biology Organization), EMBO Young Investigator Programme