Hrs Is Associated with STAM, a Signal-transducing Adaptor Molecule
ITS SUPPRESSIVE EFFECT ON CYTOKINE-INDUCED CELL GROWTH*
- Hironobu Asao‡§,
- Yoshiteru Sasaki‡§,
- Tomikazu Arita‡,
- Nobuyuki Tanaka‡,
- Kazuhiro Endo‡,
- Hirotake Kasai‡,
- Toshikazu Takeshita‡,
- Yuichi Endo¶,
- Teizo Fujita¶ and
- Kazuo Sugamura‡‖
- From the ‡Department of Microbiology and Immunology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-77 and the ¶Department of Biochemistry, Fukushima Medical College, 1 Hikarigaoka, Fukushima 960-12, Japan
Abstract
We previously reported a new type of signal-transducing adaptor molecule, STAM, which was shown to be involved in cytokine-mediated intracellular signal transduction. In this study, we molecularly cloned a 110-kDa phosphotyrosine protein inducible by stimulation with interleukin 2 (IL-2). The 110-kDa molecule was found to be a human counterpart of mouse Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate) and to be associated with STAM. Tyrosine phosphorylation of Hrs is induced rapidly after stimulation with IL-2 and granulocyte-macrophage colony-stimulating factor as well as hepatocyte growth factor. The mutual association sites of Hrs and STAM include highly conserved coiled-coil sequences, suggesting that their association is mediated by the coiled-coil structures. Exogenous introduction of the wild-type Hrs significantly suppressed DNA synthesis upon stimulation with IL-2 and granulocyte-macrophage colony-stimulating factor, while the Hrs mutant deleted of the STAM-binding site lost such suppressive ability. These results suggest that Hrs counteracts the STAM function which is critical for cell growth signaling mediated by the cytokines.
Footnotes
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↵* This work was supported by Core Research for Evolutional Science and Technology (CREST) of the Japan Science and Technology Corporation; by a grant-in-aid for scientific research on priority areas from the Ministry of Education, Science, Sport, and Culture of Japan; and by a grant from special coordination funds of the Science and Technology Agency of Japan.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBank™/EMBL Data Bank with accession number(s) U43895.
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↵§ These workers contributed equally to this work.
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↵‖ To whom correspondence should be addressed. Tel.: 81-22-717-8096; Fax: 81-22-273-2787; E-mail:sugamura{at}mail.cc.tohoku.ac.jp.
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↵1 The abbreviations used are: Stat, signal transducer and activator of transcription; SH, Src homology; IL, interleukin; GM-CSF, granulocyte-macrophage colony-stimulating factor; ITAM, immunoreceptor tyrosine-based activation motif; HGF, hepatocyte growth factor; EGF, epidermal growth factor; PDGF, platelet-derived growth factor; NTPase, nucleotide triphosphatase; PBL, peripheral blood leukocytes; PHA, phytohemagglutinin; mAb, monoclonal antibody; HA, hemagglutinin; FISH, fluorescence in situ hybridization; PAGE, polyacrylamide gel electrophoresis; PCR, polymerase chain reaction; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; FCS, fetal calf serum; bp, base pair(s); kb, kilobase pair(s).
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- Received August 25, 1997.
