Neurofibromatosis 2 (NF2) tumor suppressor merlin inhibits phosphatidylinositol 3-kinase through binding to PIKE-L.
Neurofibromatosis 2 (NF2) is a tumor suppressor, although the molecular mechanism accounting for this effect remains unknown. Here, we show that merlin exerts its activity by inhibiting phosphatidylinositol 3-kinase (PI3-kinase), through binding to PIKE-L. Wild-type merlin, but not patient-derived mutant (L64P), binds PIKE-L and inhibits PI3-kinase activity. This suppression of PI3-kinase activity results from merlin disrupting the binding of PIKE-L to PI3-kinase. In addition, merlin suppression of PI3-kinase activity as well as schwannoma cell growth is abrogated by a single PIKE-L point mutation (P187L) that cannot bind merlin but can still activate PI3-kinase. Knocking down PIKE-L with RNA interference abolishes merlin's tumor-suppressive activity. Our data support the hypothesis that PIKE-L is an important mediator of merlin growth suppression.
Rong
Rong
R
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.
Tang
Xiaoling
X
Gutmann
David H
DH
Ye
Keqiang
K
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D004396:Coloring Agents / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D007930:Leucine / Q000737:chemistry; D008856:Microscopy, Fluorescence; D009154:Mutation; D009442:Neurilemmoma / Q000378:metabolism; D016518:Neurofibromatosis 2 / Q000378:metabolism*; D025581:Neurofibromin 2 / Q000378:metabolism / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017354:Point Mutation; D011485:Protein Binding; D034622:RNA Interference; D051381:Rats; D013347:Subcellular Fractions; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors
D004396:Coloring Agents; D020690:GTPase-Activating Proteins; D025581:Neurofibromin 2; D013778:Tetrazolium Salts; D013844:Thiazoles; D005982:Glutathione Transferase; D019869:Phosphatidylinositol 3-Kinases; C485997:AGAP2 protein, human; D019204:GTP-Binding Proteins; C022616:thiazolyl blue; D007930:Leucine