Mitogen-Activated Protein Kinases Promote WNT/beta-CateninSignaling via Phosphorylation of LRP6
2011
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. On
the basis of a kinome-wide 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 phorbolesters 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 recruit not only one dedicated LRP6 kinase but
rather select their LRP6 kinase depending on cell type and the
external stimulus.
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