title: Rab6-mediated retrograde transport regulates inner nuclear membrane targeting of caveolin-2 in response to insulin.
abstract: Here, we have identified a retrograde transport pathway of caveolin-2 (cav-2) for its regulatory function in the nucleus. Confocal microscopy analysis, photoactivation experiments and subcellular fractionation revealed that cav-2 localized in the Golgi was transported to the inner nuclear membrane (INM) in response to insulin. Exogenous caveolin-1 (cav-1) and P132L-cav-1 expression did not affect the Golgi localization and insulin-induced INM targeting of cav-2. Cav-2(DKV)  mutant in the endoplasmic reticulum (ER) was unable to translocate to the INM in response to insulin. The GTP-bound form of Rab6 promoted, but Rab6 siRNA and the GDP-bound form of Rab6 abrogated, retrograde trafficking of cav-2 from the Golgi to ER. Colchicine or nocodazole treatment abolished insulin-induced INM targeting of cav-2. Knock down of gp210 inhibited insulin-induced import of cav-2 from ER/outer nuclear membrane (ONM) to the INM. The INM-targeted cav-2 prevented heterochromatinization and promoted transcriptional activation of Elk-1 and signal transducer and activator of transcription 3 (STAT3). The results provide molecular mechanisms for insulin-induced INM translocation of cav-2 initiated (i) by Golgi-to-ER retrograde trafficking of cav-2 via microtubule-based Rab6-GTP-dependent transport and subsequently processed (ii) by gp210-mediated import of cav-2 from ER/ONM to INM.
authors.affiliation: Department of Biochemistry, Division of Applied Life Science (BK21 Program), PMBBRC, Gyeongsang National University, Jinju 660-701, Korea.
authors.forename: Kyuho
authors.initials: K
authors.lastname: Jeong
authors.forename: Hayeong
authors.initials: H
authors.lastname: Kwon
authors.forename: Jaewoong
authors.initials: J
authors.lastname: Lee
authors.forename: Donghwan
authors.initials: D
authors.lastname: Jang
authors.forename: Eun Mi
authors.initials: EM
authors.lastname: Hwang
authors.forename: Jae-Yong
authors.initials: JY
authors.lastname: Park
authors.forename: Yunbae
authors.initials: Y
authors.lastname: Pak
mesh_terms: D000818:Animals; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D051243:Caveolin 2 / Q000235:genetics / Q000378:metabolism*; D003078:Colchicine / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D015739:Nocodazole / Q000494:pharmacology; D009685:Nuclear Envelope / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D021381:Protein Transport / Q000187:drug effects; D034741:RNA, Small Interfering; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015533:Transcriptional Activation; D050257:Tubulin Modulators / Q000494:pharmacology; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C495537:Cav1 protein, rat; C495546:Cav2 protein, rat; D051242:Caveolin 1; D051243:Caveolin 2; C494114:Elk1 protein, rat; D007328:Insulin; D028861:Nuclear Pore Complex Proteins; C522336:Nup210 protein, rat; D034741:RNA, Small Interfering; C094135:Rab6 protein; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D050257:Tubulin Modulators; D050807:ets-Domain Protein Elk-1; D020691:rab GTP-Binding Proteins; D015739:Nocodazole; D003078:Colchicine