Merlin inhibits Wnt/β-catenin signaling by blocking LRP6 phosphorylation.
Merlin, encoded by the NF2 gene, is a tumor suppressor that acts by inhibiting mitogenic signaling and is mutated in Neurofibromatosis type II (NF2) disease, although its molecular mechanism is not fully understood. Here, we observed that Merlin inhibited Wnt/β-catenin signaling by blocking phosphorylation of LRP6, which is necessary for Wnt signal transduction, whereas mutated Merlin in NF2 patients did not. Treatment with Wnt3a enhanced phosphorylation of Ser518 in Merlin via activation of PAK1 in a PIP2-dependent manner. Phosphorylated Merlin dissociated from LRP6, allowing for phosphorylation of LRP6. Tissues from NF2 patients exhibited higher levels of β-catenin, and proliferation of RT4-D6P2T rat schwannoma cells was significantly reduced by treatment with chemical inhibitors of Wnt/β-catenin signaling. Taken together, our findings suggest that sustained activation of Wnt/β-catenin signaling due to abrogation of Merlin-mediated inhibition of LRP6 phosphorylation may be a cause of NF2 disease.
Department of Life Science, University of Seoul, Seoul 130-743, Republic of Korea.
M
M
Kim
Department of Life Science, University of Seoul, Seoul 130-743, Republic of Korea.
S
S
Kim
Department of Biochemistry, Institute of Cell Differentiation and Aging, College of Medicine, Hallym University, Chuncheon 200-702, Republic of Korea.|Division of Bioconvergence Analysis, Korea Basic Science Institute (KBSI), Daejeon, Republic of Korea.
S-H
SH
Lee
Department of Life Science, University of Seoul, Seoul 130-743, Republic of Korea.
W
W
Kim
Department of Neurosurgery, Inje University Ilsan Paik Hospital, College of Medicine, Goyang 411-706, Republic of Korea.
M-J
MJ
Sohn
Department of Pathology, Inje University Ilsan Paik Hospital, College of Medicine, Goyang 411-706, Republic of Korea.
H-S
HS
Kim
Department of Biochemistry, Institute of Cell Differentiation and Aging, College of Medicine, Hallym University, Chuncheon 200-702, Republic of Korea.
J
J
Kim
Department of Life Science, University of Seoul, Seoul 130-743, Republic of Korea.
E-H
EH
Jho
D000328:Adult; D000818:Animals; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D025581:Neurofibromin 2 / Q000378:metabolism*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects; D060509:Wnt3A Protein / Q000494:pharmacology; D014981:Xenopus / Q000196:embryology; D055815:Young Adult; D054462:p21-Activated Kinases / Q000378:metabolism
D017077:Culture Media, Conditioned; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D050505:Mutant Proteins; D025581:Neurofibromin 2; D019269:Phosphatidylinositol 4,5-Diphosphate; D060509:Wnt3A Protein; C515903:PAK1 protein, human; D054462:p21-Activated Kinases