Journal
TRAFFIC
Volume 13, Issue 9, Pages 1218-1233Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1600-0854.2012.01378.x
Keywords
caveolin-2; gp210; heterochromatinization; inner nuclear membrane; insulin; microtubules; Rab6; retrograde transport; transcriptional activation
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Funding
- National Research Foundation of Korea
- Ministry of Education, Science and Technology (MEST) [2010-0007897]
- BK21 Program (MEST)
- Gyeongsang National University
- National Research Foundation of Korea [2010-0007897] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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-2DKV 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.
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