Publication details

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

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Authors

ČERVENKA Igor WOLF Joshua MAŠEK Jan KREJČÍ Pavel WILCOX William R. KOZUBÍK Alois SCHULTE Gunnar GUTKIND Silvio J. BRYJA Vítězslav

Year of publication 2011
Type Article in Periodical
Magazine / Source Molecular and cellular biology
MU Faculty or unit

Faculty of Science

Citation
Doi http://dx.doi.org/10.1128/MCB.00550-10
Field Physiology
Keywords Wnt; beta-catenin; LRP6; MAPKs
Description 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.
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