title: Regulation of folliculin (the BHD gene product) phosphorylation by Tsc2-mTOR pathway.
abstract: The Birt-Hogg-Dubé gene (BHD) encodes the tumor suppressor protein folliculin (FLCN). The function of FLCN has recently been implicated in the regulation of rapamycin-sensitive mTOR complex (mTORC1). Reciprocally, the mTORC1-dependent phosphorylation of FLCN was reported. However, precise mechanism of FLCN phosphorylation and functional interaction of FLCN with tuberin, the product of tuberous sclerosis 2 gene (TSC2) which is a negative regulator of mTORC1, are unclear. Here we report that multiple phosphorylation in FLCN are evoked by downregulation of tuberin as well as by Rheb expression. We found that phosphorylation at Ser62 and Ser302 are differently regulated by mTORC1-dependent pathway. Some unknown kinases downstream of tuberin-mTORC1 are thought to directly phosphorylate FLCN. Interestingly, our results also suggest that the complex formation of FLCN with AMPK is modulated by FLCN phosphorylation. These results suggest that FLCN is involved in a novel mechanism of signal transduction downstream of tuberin.
authors.affiliation: Department of Pathology and Oncology, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo 113-8421, Japan.
authors.forename: Xianghua
authors.initials: X
authors.lastname: Piao
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Shiono
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Takagi
authors.forename: Guodong
authors.initials: G
authors.lastname: Sun
authors.forename: Masaaki
authors.initials: M
authors.lastname: Abe
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Hagiwara
authors.forename: Danqing
authors.initials: D
authors.lastname: Zhang
authors.forename: Kazuo
authors.initials: K
authors.lastname: Okimoto
authors.forename: Mami
authors.initials: M
authors.lastname: Kouchi
authors.forename: Izumi
authors.initials: I
authors.lastname: Matsumoto
authors.forename: Okio
authors.initials: O
authors.lastname: Hino
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D019943:Amino Acid Substitution; D000818:Animals; D045744:Cell Line, Tumor; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D000076205:Ras Homolog Enriched in Brain Protein; D051381:Rats; D012694:Serine / Q000235:genetics / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C545700:CRTC2 protein, rat; C519510:Crtc1 protein, rat; C482582:Flcn protein, rat; D009479:Neuropeptides; D011506:Proteins; D000076205:Ras Homolog Enriched in Brain Protein; C087693:Rheb protein, rat; D015534:Trans-Activators; D014157:Transcription Factors; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D012694:Serine; D011494:Protein Kinases; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D020559:Monomeric GTP-Binding Proteins