title: Essential role of flotillin-1 palmitoylation in the intracellular localization and signaling function of IGF-1 receptor.
abstract: Here, we explored flotillin-1-mediated regulation of insulin-like growth factor-1 (IGF-1) signaling. Flotillin-1-deficient cells exhibited a reduction in the activation of IGF-1 receptor (IGF-1R), ERK1/2 and Akt pathways, and the transcriptional activation of Elk-1 and the proliferation in response to IGF-1 were reduced in these cells. We found that IGF-1-independent flotillin-1 palmitoylation at Cys34 in the endoplasmic reticulum (ER) was required for the ER exit and the plasma membrane localization of flotillin-1 and IGF-1R. IGF-1-dependent depalmitoylation and repalmitoylation of flotillin-1 sustained tyrosine kinase activation of the plasma-membrane-targeted IGF-1R. Dysfunction and blocking the turnover of flotillin-1 palmitoylation abrogated cancer cell proliferation after IGF-1R signaling activation. Our data show that flotillin-1 palmitoylation is a new mechanism by which the intracellular localization and activation of IGF-1R are controlled.
authors.affiliation: Division of Life Science, Graduate School of Applied Life Science (BK21 Plus Program), PMBBRC, Gyeongsang National University, Jinju 660-701, Korea.
authors.forename: Donghwan
authors.initials: D
authors.lastname: Jang
authors.affiliation: Division of Life Science, Graduate School of Applied Life Science (BK21 Plus Program), PMBBRC, Gyeongsang National University, Jinju 660-701, Korea.
authors.forename: Hayeong
authors.initials: H
authors.lastname: Kwon
authors.affiliation: Division of Life Science, Graduate School of Applied Life Science (BK21 Plus Program), PMBBRC, Gyeongsang National University, Jinju 660-701, Korea.
authors.forename: Kyuho
authors.initials: K
authors.lastname: Jeong
authors.affiliation: Division of Life Science, Graduate School of Applied Life Science (BK21 Plus Program), PMBBRC, Gyeongsang National University, Jinju 660-701, Korea.
authors.forename: Jaewoong
authors.initials: J
authors.lastname: Lee
authors.affiliation: Division of Life Science, Graduate School of Applied Life Science (BK21 Plus Program), PMBBRC, Gyeongsang National University, Jinju 660-701, Korea ybpak@gnu.ac.kr.
authors.forename: Yunbae
authors.initials: Y
authors.lastname: Pak
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D054878:Lipoylation / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; C106354:flotillins; D007334:Insulin-Like Growth Factor I; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt
keywords: Flotillin-1; Flotillin-2; IGF-1 receptor; Palmitoylation