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The JAK-inhibitor, JAB/SOCS-1 selectively inhibits cytokine-induced, but not v-Src induced JAK–STAT activation

Oncogene volume 19, pages 4795–4801 (2000)Cite this article

Abstract

Recently, constitutive activation of JAK kinases (JAKs) and/or signal transducers and activators of transcription (STATs) has been reported in growing numbers of human cancer cells as well as oncogene-transformed cells. JAB/SOCS-1 has been shown to be an intrinsic JAK tyrosine kinase inhibitor and to suppress the cytokine-dependent JAK–STAT pathway. In this report, we investigated the effect of ectopic expression of JAB on v-Src-induced JAK–STAT activation. Forced expression of JAB in v-Src-transformed NIH3T3 cells neither suppressed phosphorylation of STAT3 and JAK1/JAK2 nor blocked STAT3-reporter gene activation. Colony forming assay also showed that JAB did not suppress v-Src-induced transformation of NIH3T3 cells, while dominant negative STAT3 suppressed it. In contrast, JAB could downregulate phosphorylation of STAT1 and STAT3 induced by interferon gamma (IFNγ) and interleukin-6 (IL-6) plus soluble IL6 receptor (sIL-6R), respectively. Furthermore, in vitro kinase assay indicated that JAB suppressed hyperactivation of JAK1/JAK2 and JAK1 induced by INFγ and IL-6 plus sIL-6R respectively, but not v-Src-induced basal JAK1/JAK2 activity. Nevertheless, both JAK1/JAK2 activated by v-Src and that activated by IL-6 plus sIL-6R could similarly bind JAB. These results clearly demonstrate that JAB distinguishes cytokine-induced JAK–STAT signaling from v-Src-induced one and can not suppress the transformation with v-Src.

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Acknowledgements

We thank Dr Toshio Hirano for STAT3 plasmid and Dr Izumi Nakashima for critical reading of the manuscript. IL-6 is a gift from Kirin Brewer Co. Ltd. This work was supported by grant-in-aids for COE Research from the Ministry of Education, Science and Culture of Japan and for Scientific Research of Japan Society for Promotion of Science.

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Authors and Affiliations

  1. Department of Ophthalmology, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-Ku, Nagoya, 466-8550, Japan

    Takashi Iwamoto & Yozo Miyake

  2. Department of Molecular Pathogenesis, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-Ku, Nagoya, 466-8550, Japan

    Takeshi Senga, Yuko Naito, Satoru Matsuda & Michinari Hamaguchi

  3. Institute of Life Science, Kurume University, Aikawa-machi 2432-3, Kurume, 839-0861, Japan

    Akihiko Yoshimura

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Iwamoto, T., Senga, T., Naito, Y. et al. The JAK-inhibitor, JAB/SOCS-1 selectively inhibits cytokine-induced, but not v-Src induced JAK–STAT activation. Oncogene 19, 4795–4801 (2000). https://doi.org/10.1038/sj.onc.1203829

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