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Published 5 June 2006. doi:10.1083/jcb.200601065
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 173, Number 5, 665-671
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 Myosin motor Myo1c and its receptor NEMO/IKK-{gamma} promote TNF-{alpha}–induced serine307 phosphorylation of IRS-1

Yoshitaka Nakamori1, Masahiro Emoto1, Naofumi Fukuda1, Akihiko Taguchi1, Shigeru Okuya1, Michiko Tajiri2,3, Makoto Miyagishi4, Kazunari Taira4, Yoshinao Wada2,3, and Yukio Tanizawa1

1 Division of Molecular Analysis of Human Disorders, Department of Bio-Signal Analysis, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan
2 Core Research for Evolution Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan
3 Department of Molecular Medicine, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka 594-1101, Japan
4 Department of Chemistry and Biotechnology, University of Tokyo, Bunkyo-ku, Tokyo 113-8656, Japan

Correspondence to Masahiro Emoto: emotom{at}yamaguchi-u.ac.jp

Tumor necrosis factor-{alpha} (TNF-{alpha}) signaling through the I{kappa}B kinase (IKK) complex attenuates insulin action via the phosphorylation of insulin receptor substrate 1 (IRS-1) at Ser307. However, the precise molecular mechanism by which the IKK complex phosphorylates IRS-1 is unknown. In this study, we report nuclear factor {kappa}B essential modulator (NEMO)/IKK-{gamma} subunit accumulation in membrane ruffles followed by an interaction with IRS-1. This intracellular trafficking of NEMO requires insulin, an intact actin cytoskeletal network, and the motor protein Myo1c. Increased Myo1c expression enhanced the NEMO–IRS-1 interaction, which is essential for TNF-{alpha}– induced phosphorylation of Ser307–IRS-1. In contrast, dominant inhibitory Myo1c cargo domain expression diminished this interaction and inhibited IRS-1 phosphorylation. NEMO expression also enhanced TNF-{alpha}–induced Ser307–IRS-1 phosphorylation and inhibited glucose uptake. In contrast, a deletion mutant of NEMO lacking the IKK-ß–binding domain or silencing NEMO blocked the TNF-{alpha} signal. Thus, motor protein Myo1c and its receptor protein NEMO act cooperatively to form the IKK–IRS-1 complex and function in TNF-{alpha}–induced insulin resistance.

Abbreviations used in this paper: eGFP, enhanced GFP; IKK, I{kappa}B kinase; IR, insulin receptor; IRS-1, IR substrate 1; NEMO, nuclear factor {kappa}B essential modulator; shRNA, short hairpin RNA; WT, wild type.


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