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

Abstract

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.

ACKNOWLEDGMENTS

This study was supported by grants from the Czech Science Foundation (204/09/0498, 204/09/J030, 204/09/H058, 301/09/0587; V.B. and P.K.), the EMBO Installation Grant (V.B.), and the Ministry of Education Youth and Sports of the Czech Republic (MSM 0021622430; V.B.); by the Academy of Sciences of the Czech Republic (AVOZ50040507, AVOZ50040702); and by grants from the Karolinska Institutet, the Swedish Medical Research Council (K2008-68P-20810-01-4, K2008-68X-20805-01-4), the Knut and Alice Wallenberg Foundation, the Swedish Cancer Foundation, the Swedish Foundation for the International Cooperation in Research and Higher Education (STINT) (G.S.), the National Institutes of Health (NIH 5P01HD022657-21A; W.R.W.), the Intramural Program, the National Institute of Dental and Craniofacial Research (J.W. and J.S.G.), and the Howard Hughes Medical Institute Research Scholars Program (J.W.).

We thank S. Yanagawa (Kyoto University, Kyoto, Japan), Mikhail Semenov and Xe He (Harvard Medical School, Boston, MA), Randy Moon (University of Washington, Seattle, WA), J. M. Graff (University of Texas, Dallas, TX), S. Byers (Georgetown University, Washington, DC), and Bart Williams (Van Andel Institute, Grand Rapids, MI) for providing plasmids.

We declare no competing interests.