Abstract
SOCS-1 (suppressor of cytokine signaling-1) is a representative of a family of negative regulators of cytokine signaling (SOCS-1 to SOCS-7 and CIS) characterized by a highly conserved C-terminal SOCS box preceded by an SH2 domain. This study comprehensively examined the ability of several SOCS family members to negatively regulate the gp130 signaling pathway. SOCS-1 and SOCS-3 inhibited both interleukin-6 (IL-6)- and leukemia inhibitory factor (LIF)-induced macrophage differentiation of murine monocytic leukemic M1 cells and LIF induction of a Stat3-responsive reporter construct in 293T fibroblasts. Deletion of amino acids 51-78 in the N-terminal region of SOCS-1 prevented inhibition of LIF signaling. The SOCS-1 and SOCS-3 N-terminal regions were functionally interchangeable, but this did not extend to other SOCS family members. Mutation of SH2 domains abrogated the ability of both SOCS-1 and SOCS-3 to inhibit LIF signal transduction. Unlike SOCS-1, SOCS-3 was unable to inhibit JAK kinase activity in vitro, suggesting that SOCS-1 and SOCS-3 act on the JAK-STAT pathway in different ways. Thus, although inhibition of signaling by SOCS-1 and SOCS-3 requires both the SH2 and N-terminal domains, their mechanisms of action appear to be biochemically different.
Full Text
The Full Text of this article is available as a PDF (730.0 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Briscoe J., Rogers N. C., Witthuhn B. A., Watling D., Harpur A. G., Wilks A. F., Stark G. R., Ihle J. N., Kerr I. M. Kinase-negative mutants of JAK1 can sustain interferon-gamma-inducible gene expression but not an antiviral state. EMBO J. 1996 Feb 15;15(4):799–809. [PMC free article] [PubMed] [Google Scholar]
- Chen M., Cheng A., Chen Y. Q., Hymel A., Hanson E. P., Kimmel L., Minami Y., Taniguchi T., Changelian P. S., O'Shea J. J. The amino terminus of JAK3 is necessary and sufficient for binding to the common gamma chain and confers the ability to transmit interleukin 2-mediated signals. Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6910–6915. doi: 10.1073/pnas.94.13.6910. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Endo T. A., Masuhara M., Yokouchi M., Suzuki R., Sakamoto H., Mitsui K., Matsumoto A., Tanimura S., Ohtsubo M., Misawa H. A new protein containing an SH2 domain that inhibits JAK kinases. Nature. 1997 Jun 26;387(6636):921–924. doi: 10.1038/43213. [DOI] [PubMed] [Google Scholar]
- Feng J., Witthuhn B. A., Matsuda T., Kohlhuber F., Kerr I. M., Ihle J. N. Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop. Mol Cell Biol. 1997 May;17(5):2497–2501. doi: 10.1128/mcb.17.5.2497. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Guschin D., Rogers N., Briscoe J., Witthuhn B., Watling D., Horn F., Pellegrini S., Yasukawa K., Heinrich P., Stark G. R. A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6. EMBO J. 1995 Apr 3;14(7):1421–1429. doi: 10.1002/j.1460-2075.1995.tb07128.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- He W., Rose D. W., Olefsky J. M., Gustafson T. A. Grb10 interacts differentially with the insulin receptor, insulin-like growth factor I receptor, and epidermal growth factor receptor via the Grb10 Src homology 2 (SH2) domain and a second novel domain located between the pleckstrin homology and SH2 domains. J Biol Chem. 1998 Mar 20;273(12):6860–6867. doi: 10.1074/jbc.273.12.6860. [DOI] [PubMed] [Google Scholar]
- Hilton D. J., Richardson R. T., Alexander W. S., Viney E. M., Willson T. A., Sprigg N. S., Starr R., Nicholson S. E., Metcalf D., Nicola N. A. Twenty proteins containing a C-terminal SOCS box form five structural classes. Proc Natl Acad Sci U S A. 1998 Jan 6;95(1):114–119. doi: 10.1073/pnas.95.1.114. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Horton R. M., Hunt H. D., Ho S. N., Pullen J. K., Pease L. R. Engineering hybrid genes without the use of restriction enzymes: gene splicing by overlap extension. Gene. 1989 Apr 15;77(1):61–68. doi: 10.1016/0378-1119(89)90359-4. [DOI] [PubMed] [Google Scholar]
- Masuhara M., Sakamoto H., Matsumoto A., Suzuki R., Yasukawa H., Mitsui K., Wakioka T., Tanimura S., Sasaki A., Misawa H. Cloning and characterization of novel CIS family genes. Biochem Biophys Res Commun. 1997 Oct 20;239(2):439–446. doi: 10.1006/bbrc.1997.7484. [DOI] [PubMed] [Google Scholar]
- Matsumoto A., Masuhara M., Mitsui K., Yokouchi M., Ohtsubo M., Misawa H., Miyajima A., Yoshimura A. CIS, a cytokine inducible SH2 protein, is a target of the JAK-STAT5 pathway and modulates STAT5 activation. Blood. 1997 May 1;89(9):3148–3154. [PubMed] [Google Scholar]
- Mayer B. J., Jackson P. K., Van Etten R. A., Baltimore D. Point mutations in the abl SH2 domain coordinately impair phosphotyrosine binding in vitro and transforming activity in vivo. Mol Cell Biol. 1992 Feb;12(2):609–618. doi: 10.1128/mcb.12.2.609. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Metcalf D. Actions and interactions of G-CSF, LIF, and IL-6 on normal and leukemic murine cells. Leukemia. 1989 May;3(5):349–355. [PubMed] [Google Scholar]
- Naka T., Narazaki M., Hirata M., Matsumoto T., Minamoto S., Aono A., Nishimoto N., Kajita T., Taga T., Yoshizaki K. Structure and function of a new STAT-induced STAT inhibitor. Nature. 1997 Jun 26;387(6636):924–929. doi: 10.1038/43219. [DOI] [PubMed] [Google Scholar]
- Nakajima K., Yamanaka Y., Nakae K., Kojima H., Ichiba M., Kiuchi N., Kitaoka T., Fukada T., Hibi M., Hirano T. A central role for Stat3 in IL-6-induced regulation of growth and differentiation in M1 leukemia cells. EMBO J. 1996 Jul 15;15(14):3651–3658. [PMC free article] [PubMed] [Google Scholar]
- Nicholson S. E., Novak U., Ziegler S. F., Layton J. E. Distinct regions of the granulocyte colony-stimulating factor receptor are required for tyrosine phosphorylation of the signaling molecules JAK2, Stat3, and p42, p44MAPK. Blood. 1995 Nov 15;86(10):3698–3704. [PubMed] [Google Scholar]
- Ogilvy S., Elefanty A. G., Visvader J., Bath M. L., Harris A. W., Adams J. M. Transcriptional regulation of vav, a gene expressed throughout the hematopoietic compartment. Blood. 1998 Jan 15;91(2):419–430. [PubMed] [Google Scholar]
- Ohya K. i., Kajigaya S., Yamashita Y., Miyazato A., Hatake K., Miura Y., Ikeda U., Shimada K., Ozawa K., Mano H. SOCS-1/JAB/SSI-1 can bind to and suppress Tec protein-tyrosine kinase. J Biol Chem. 1997 Oct 24;272(43):27178–27182. doi: 10.1074/jbc.272.43.27178. [DOI] [PubMed] [Google Scholar]
- Rayner J. R., Gonda T. J. A simple and efficient procedure for generating stable expression libraries by cDNA cloning in a retroviral vector. Mol Cell Biol. 1994 Feb;14(2):880–887. doi: 10.1128/mcb.14.2.880. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rodig S. J., Meraz M. A., White J. M., Lampe P. A., Riley J. K., Arthur C. D., King K. L., Sheehan K. C., Yin L., Pennica D. Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell. 1998 May 1;93(3):373–383. doi: 10.1016/s0092-8674(00)81166-6. [DOI] [PubMed] [Google Scholar]
- Starr R., Willson T. A., Viney E. M., Murray L. J., Rayner J. R., Jenkins B. J., Gonda T. J., Alexander W. S., Metcalf D., Nicola N. A. A family of cytokine-inducible inhibitors of signalling. Nature. 1997 Jun 26;387(6636):917–921. doi: 10.1038/43206. [DOI] [PubMed] [Google Scholar]
- Waksman G., Kominos D., Robertson S. C., Pant N., Baltimore D., Birge R. B., Cowburn D., Hanafusa H., Mayer B. J., Overduin M. Crystal structure of the phosphotyrosine recognition domain SH2 of v-src complexed with tyrosine-phosphorylated peptides. Nature. 1992 Aug 20;358(6388):646–653. doi: 10.1038/358646a0. [DOI] [PubMed] [Google Scholar]
- Yamanaka Y., Nakajima K., Fukada T., Hibi M., Hirano T. Differentiation and growth arrest signals are generated through the cytoplasmic region of gp130 that is essential for Stat3 activation. EMBO J. 1996 Apr 1;15(7):1557–1565. [PMC free article] [PubMed] [Google Scholar]
- Yoshimura A., Ohkubo T., Kiguchi T., Jenkins N. A., Gilbert D. J., Copeland N. G., Hara T., Miyajima A. A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors. EMBO J. 1995 Jun 15;14(12):2816–2826. doi: 10.1002/j.1460-2075.1995.tb07281.x. [DOI] [PMC free article] [PubMed] [Google Scholar]