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^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
Department of Medicine III, Osaka University Medical School, 2-2 Yamada-oka, Suita-city, Osaka 565-0871, Japan.81-6-6879-414381-6-6879-4143

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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