J 2011

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

ČERVENKA, Igor, Joshua WOLF, Jan MAŠEK, Pavel KREJČÍ, William R. WILCOX et. al.

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

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30105 Physiology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

Impact factor

Impact factor: 5.527

RIV identification code

RIV/00216224:14310/11:00058652

Organization unit

Faculty of Science

DOI

UT WoS

000285093600014

Keywords in English

Wnt; beta-catenin; LRP6; MAPKs

Tags

Změněno: 12/4/2013 09:39, Ing. Andrea Mikešková

Abstract

V originále

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