The Journal of Experimental Medicine
StemCell Technologies
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Published online 16 January 2001.
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© The Rockefeller University Press, 0022-1007/2001/1/263/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 2, January 15, 2001 263-270

Brief Definitive Report

Signal Transducer and Activator of Transcription (STAT)-induced STAT Inhibitor 1 (SSI-1)/Suppressor of Cytokine Signaling 1 (SOCS1) Inhibits Insulin Signal Transduction Pathway through Modulating Insulin Receptor Substrate 1 (IRS-1) Phosphorylation

Yoshinori Kawazoea, Tetsuji Nakaa, Minoru Fujimotoa, Hidetsugu Kohzakia, Yoshiaki Moritaa, Masashi Narazakia, Kohichi Okumurae, Hiroshi Saitoha, Reiko Nakagawaa, Yasuo Uchiyamab, Shizuo Akirac, and Tadamitsu Kishimotod
a Department of Medicine III, Osaka 565-0871, Japan
b Department of Cell Biology and Anatomy I, Medical School, Osaka 565-0871, Japan
c Department of Host Defense, Research Institute for Microbial Diseases, Osaka 565-0871, Japan
d Osaka University, Osaka 565-0871, Japan
e Biomolecular Engineering Research Institute, Osaka 565-0871, Japan

Correspondence to: Tetsuji Naka, Department of Medicine III, Osaka University Medical School, 2-2 Yamada-oka, Suita-city, Osaka 565-0871, Japan. Tel:81-6-6879-4143 Fax:81-6-6879-4143 E-mail:naka{at}imed3.med.osaka-u.ac.jp.

Signal transducer and activator of transcription (STAT)-induced STAT inhibitor 1 (SSI-1) is known to function as a negative feedback regulator of cytokine signaling, but it is unclear whether it is involved in other biological events. Here, we show that SSI-1 participates and plays an important role in the insulin signal transduction pathway. SSI-1–deficient mice showed a significantly low level of blood sugar. While the forced expression of SSI-1 reduced the phosphorylation level of insulin receptor substrate 1 (IRS-1), SSI-1 deficiency resulted in sustained phosphorylation of IRS-1 in response to insulin. Furthermore, SSI-1 achieves this inhibition both by binding directly to IRS-1 and by suppressing Janus kinases. These findings suggest that SSI-1 acts as a negative feedback factor also in the insulin signal transduction pathway through the suppression of IRS-1 phosphorylation.

Key Words: insulin, IRS-1, SSI-1/SOCS1 signaling, Janus kinase, diabetes


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