Mitogen-activated protein kinases promote WNT/beta-catenin signaling via phosphorylation of LRP6.
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.
Institute of Experimental Biology, Faculty of Science, Masaryk University, CZ-611 37 Brno, Czech Republic.
Igor
I
Červenka
Joshua
J
Wolf
Jan
J
Mašek
Pavel
P
Krejci
William R
WR
Wilcox
Alois
A
Kozubík
Gunnar
G
Schulte
J Silvio
JS
Gutkind
Vítězslav
V
Bryja
D020816:Amino Acid Motifs; D000818:Animals; D002460:Cell Line; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D020935:MAP Kinase Signaling System; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011973:Receptors, LDL / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C495270:CTNNB1 protein, human; D026502:LDL-Receptor Related Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D034741:RNA, Small Interfering; D011973:Receptors, LDL; D051153:Wnt Proteins; D051176:beta Catenin; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases