Essential role of flotillin-1 palmitoylation in the intracellular localization and signaling function of IGF-1 receptor

• Published in: Journal of cell science Vol. 128; no. 11; pp. 2179 - 2190
• Main Authors: Jang, Donghwan, Kwon, Hayeong, Jeong, Kyuho, Lee, Jaewoong, Pak, Yunbae
• Format: Journal Article
• Language: English
• Published: England 01.06.2015
• Subjects: Cell Line, Tumor; Cell Proliferation - physiology; Endoplasmic Reticulum - metabolism; HEK293 Cells; HeLa Cells; Humans; Insulin-Like Growth Factor I - metabolism; Lipoylation - physiology; MAP Kinase Signaling System - physiology; Membrane Proteins - metabolism; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Receptor, IGF Type 1 - metabolism; Signal Transduction - physiology; Flotillin-1; Palmitoylation; Flotillin-2; IGF-1 receptor
• ISSN: 0021-9533; 1477-9137
• DOI: 10.1242/jcs.169409

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.