General Mechanisms of Cytokine Receptor Signaling

Taga, 1997, Gp130 and the interleukin-6 family of cytokines., Annu. Rev. Immunol., 15, 797, 10.1146/annurev.immunol.15.1.797 Hibi, 1996, IL-6 cytokine family and signal transduction: A model of the cytokine system., J Mol. Med., 74, 1, 10.1007/BF00202068 Stahl, 1997, IL6, IL11, LIF, OSM, Cardiotrophin-1, and CNTF, 2B, 777 Yamasaki, 1988, Cloning and expression of the human interleukin-6 (BSF-2/IFN/3 2) receptor., Science, 241, 825, 10.1126/science.3136546 Davis, 1991, The receptor for ciliary neurotrophic factor., Science, 253, 59, 10.1126/science.1648265 Taga, 1989, Interleukin-6 triggers the association of its receptor with a possible signal transducer, gpl30., Cell (Cambridge: Mass., 58, 573, 10.1016/0092-8674(89)90438-8 Hibi, 1990, Molecular cloning and expression of an IL6 signal transducer, gpl30. Cell, Cambridge, Mass., 63, 1149 Davis, 1993, Released form of CNTF receptor α component as a soluble mediator of CNTF responses., Science, 259, 1736, 10.1126/science.7681218 Robledo, 1997, Signaling of the cardiotrophin-1 receptor., J. Biol. Chem., 272, 4855, 10.1074/jbc.272.8.4855 Pennica, 1996, Cardiotrophin-1, a cytokine present in embryonic muscle, supports long-term survival of spinal motoneurons., Neuron, 17, 63, 10.1016/S0896-6273(00)80281-0 Nandurkar, 1996, The human IL-11 receptor requires gpl30 for signalling: Demonstration by molecular cloning of the receptor, Oncogene, 12, 585 Cherel, 1995, Molecular cloning of two isoforms of a receptor for the human hematopoietic cytokine interleukin-11., Blood, 86, 2534, 10.1182/blood.V86.7.2534.bloodjournal8672534 Neddermann, 1996, Functional expression of soluble human interleukin-11 (IL-11) receptor a and stoichiometry of in vitro IL-11 receptor complexes with gp 130., J. Biol. Chem., 271, 30986, 10.1074/jbc.271.48.30986 Baumann, 1996, Complex of the soluble IL-11 receptor and IL-11 acts as IL-6-type cytokine in hepatic and nonhepatic cells., J. Immunol., 157, 284 Gearing, 1991, Leukemia inhibitory factor receptor is structurally related to the IL-6 signal transducer, gpl30., EMBOJ., 10, 2839, 10.1002/j.1460-2075.1991.tb07833.x Gearing, 1992, The IL-6 signal transducer, gpl30: An oncostatin M receptor and affinity converter for the LIF receptor., Science, 255, 1434, 10.1126/science.1542794 Paonessa, 1995, Two distinct and independent sites on IL-6 trigger gpl30 dimer formation and signalling., EMBOJ., 14, 1942, 10.1002/j.1460-2075.1995.tb07186.x Sporeno, 1994, Oncostatin M binds directly to gpl30 and behaves as interleukin-6 antagonist on a cell line expressing gpl30 but lacking functional oncostatin M receptors., J. Biol. Chem., 269, 10991, 10.1016/S0021-9258(19)78081-8 Baumann, 1993, Reconstitution of the response to leukemia inhibitory factor, oncostatin M. and ciliary neurotrophic factor in hepatoma cells., J. Biol. Chem., 268, 8414, 10.1016/S0021-9258(18)52890-8 Gearing, 1994, Proliferative responses and binding properties of hematopoietic cells transfected with low-affinity receptors for leukemia inhibitory factor, oncostatin M. and ciliary neurotrophic factor., Proc. Natl. Acad. Sci. U.S.A., 91, 1119, 10.1073/pnas.91.3.1119 Davis, 1993, LIFR/3 and gpl30 as heterodimerizing signal transducers of the tripartite CNTF receptor., Science, 260, 1805, 10.1126/science.8390097 Stahl, 1993, The alphas, betas and kinases of cytokine receptor complexes. Cell, Cambridge, Mass., 74, 587 Murakami, 1993, IL6-induced homodimerization of gpl30 and associated activation of a tyrosine kinase., Science, 260, 1808, 10.1126/science.8511589 Mosley, 1996, Dual Oncostatin M (OSM) receptors., J. Biol. Chem., 271, 32635, 10.1074/jbc.271.51.32635 Pennica, 1995, Cardiotrophin-1. Biological activities and binding to the leukemia inhibitory factor receptor/gpl30 signaling complex., J. Biol. Chem., 270, 10915, 10.1074/jbc.270.18.10915 Ip, 1991, Ciliary neurotrophic factor enhances neuronal survival in rat hippocam-pal cultures., J. Neurosci., 11, 3124, 10.1523/JNEUROSCI.11-10-03124.1991 Stahl, 1994, The tripartite CNTF receptor complex: Activation and signaling involves components shared with other cytokines., J. Neurobiol., 25, 1454, 10.1002/neu.480251111 Ip, 1993, The a chain of the CNTF receptor is required for signalling and defines potential CNTF targets in the adult and during development., Neuron, 10, 89, 10.1016/0896-6273(93)90245-M Bellido, 1996, Detection of receptors for interleukin-6, interleukin-11, leukemia inhibitory factor, oncostatin M. and ciliary neurotrophic factor in bone marrow stromalJ. osteoblastic cells., J. Clin. Invest., 97, 431, 10.1172/JCI118432 Frieling, 1994, Soluble interleukin 6 receptor in biological fluids from human origin., Cytokine, 6, 376, 10.1016/1043-4666(94)90061-2 Narazaki, 1993, Soluble forms of the interleukin-6 signal-transducing receptor component gpl30 in human serum possessing a potential to inhibit signals through membrane-anchored gp130., Blood, 82, 1120, 10.1182/blood.V82.4.1120.1120 Gaillard, 1993, Increased and highly stable levels of functional soluble interleukin-6 receptor in sera of patients with monoclonal gammopathy., Eur. J. Immunol., 23, 820, 10.1002/eji.1830230408 Honda, 1992, Human soluble IL-6 receptor: Its detection and enhanced release by HIV infection., J. Immunol., 148, 2175 Frieling, 1995, Circulating interleukin-6 receptor in patients with sepsis syndrome., J. Infect. Dis., 171, 469, 10.1093/infdis/171.2.469 Kopf, 1994, Impaired immune and acute-phase responses in interleukin-6 deficient mice. Nature, London, 368, 339, 10.1038/368339a0 DeChiara, 1995, Mice lacking the CNTF receptor, unlike mice lacking CNTF, exhibit profound motor neuron deficits at birth. Cell, Cambridge, Mass., 83, 313 Yoshida, 1996, Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders., Proc. Natl. Acad. Sci. U.S.A., 93, 407, 10.1073/pnas.93.1.407 Ware, 1995, Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death. Development, Cambridge, UK, 121, 1283 Ward, 1994, High affinity interleukin-6 receptor is a hexameric complex consisting of two molecules each of interleukin-6, interleukin-6 receptor, and gp130., J. Biol. Chem., 269, 23286, 10.1016/S0021-9258(17)31651-4 Ward, 1996, Influence of interleukin-6 (IL-6) dimerization on formation of the high affinity hexameric IL-6-receptor complex., J. Biol. Chem., 271, 20138, 10.1074/jbc.271.33.20138 De Serio, 1995, In vitro binding of ciliary neurotrophic factor to its receptors: Evidence for the formation of an IL-6-type hexameric complex., J. Mol. Biol., 254, 795, 10.1006/jmbi.1995.0655 Simpson, 1997, Interleukin-6: Structure-function relationships., Protein Sci., 6, 929, 10.1002/pro.5560060501 de Vos, 1992, Human growth hormone and extracellular domain of its receptor: crystal structure of the complex., Science, 255, 306, 10.1126/science.1549776 Savino, 1994, Generation of interleukin-6 receptor antagonists by molecular-modeling guided mutagenesis of residues important for gpl30 activation., EMBOJ., 13, 1357, 10.1002/j.1460-2075.1994.tb06389.x Savino, 1993, Saturation mutagenesis of the human interleukin 6 receptor-binding site: Implications for its three-dimensional structure., Proc. Natl. Acad. Sci. U.S.A., 90, 4067, 10.1073/pnas.90.9.4067 Kruse, 1992, Conversion of human interleukin-4 into a high affinity antagonist by a single amino acid-replacement., EMBOJ., 11, 3237, 10.1002/j.1460-2075.1992.tb05401.x Panayotatos, 1993, Exchange of a single amino acid interconverts the specific activity and gel mobility of human and rat ciliary neurotrophic factors., J. Biol. Chem., 268, 19000, 10.1016/S0021-9258(17)46726-3 Murakami, 1991, Critical cytoplasmic region of the interleukin 6 signal transducer gp 130 is conserved in the cytokine receptor family., Proc. Natl. Acad. Sci. U.S.A., 88, 11349, 10.1073/pnas.88.24.11349 Ip, 1992, CNTF and LIF act on neuronal cells via shared signalling pathways that involve the IL-6 signal transducing receptor componentgpl30. Cell, Cambridge, Mass., 69, 1121 Stahl, 1993, Crosslinking of CNTF and LIF to endogenous and reconstructed receptor complexes identifies LIF binding protein as a CNTF receptor component., J. Biol. Chem., 268, 7628, 10.1016/S0021-9258(18)53001-5 Velazquez, 1992, A protein kinase in the interferon α/β signaling pathway. Cell, Cambridge, Mass., 70, 313 Watling, 1993, Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-γ signal transduction pathway. Nature, London, 366, 166, 10.1038/366166a0 Muller, 1993, The protein tyrosine kinase JAK1 complements defects in interferon-αβ and -γ signal transduction. Nature, London, 366, 129, 10.1038/366129a0 Witthuhn, 1993, JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell, Cambridge, Mass., 74, 227 Argetsinger, 1993, Identification ofJAK2 as a growth hormone receptor-associated tyrosine kinase. Cell, Cambridge, Mass., 74, 237 Stahl, 1994, Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL6 β receptor components., Science, 263, 92, 10.1126/science.8272873 Lutticken, 1994, Association of transcription factor APRF and protein kinase Jakl with the interleukin-6 signal transducer gp130., Science, 263, 89, 10.1126/science.8272872 Rui, 1994, Activation of receptor-associated tyrosine kinase Jak2 by prolactin., J. Biol. Chem., 269, 5364, 10.1016/S0021-9258(17)37695-0 Russell, 1994, Interaction of IL-2R/3 and γc chains with Jakl and Jak3: Implications for XSCID and XCID., Science, 266, 1042, 10.1126/science.7973658 Miyazaki, 1994, Functional activation of Jakl and Jak3 by selective association with IL-2 receptor subunits., Science, 266, 1045, 10.1126/science.7973659 Nicholson, 1994, Tyrosine kinase JAK1 is associated with the granulocyte-colony-stimulat-ing factor receptor and both become tyrosine-phosphorylated after receptor activation., Proc. Natl. Acad. Sci. U.S.A., 91, 2958, 10.1073/pnas.91.8.2985 Colamonici, 1994, P135tyk2 and interferon-α-activated tyrosine kinase, is physically associated with and interferon-α receptor., J. Biol. Chem., 269, 3518, 10.1016/S0021-9258(17)41893-X Ziemiecki, 1994, JAK protein tyrosine kinases: Their role in cytokine signalling., Trends Cell Biol., 4, 207, 10.1016/0962-8924(94)90143-0 Taniguchi, 1995, Cytokine signaling through nonreceptor protein tyrosine kinases., Science, 268, 251, 10.1126/science.7716517 Wilks, 1991, Two novel protein-tyrosine kinases, each with a second phosphotransferase-related catalytic domain, define a new class of protein kinase., Mol. Cell. Biol., 11, 2057, 10.1128/MCB.11.4.2057 Chen, 1997, The amino terminus of JAK3 is necessary and sufficient for binding to the common γ chain and confers the ability to transmit interleukin 2-mediated signals., Proc. Natl. Acad. Sci. U.S.A., 94, 6910, 10.1073/pnas.94.13.6910 Zhao, 1995, The amino-terminal portion of the JAK2 protein kinase is necessary for binding and phosphorylation of the granulocyte-macrophage colony-stimulating factor receptor ft, chain., J. Biol. Chem., 270, 13814, 10.1074/jbc.270.23.13814 Tanner, 1995, The conserved box 1 motif of cytokine receptors is required for association with JAK kinases., J. Biol. Chem., 270, 6523, 10.1074/jbc.270.12.6523 Murata, 1995, Receptors for interleukin (IL)-4 do not associate with the common gamma chain, and IL-4 induces the phosphorylation ofJAK2 tyrosine kinase in human colon carcinoma cells., J. Biol. Chem., 270, 30829, 10.1074/jbc.270.51.30829 Stahl, 1995, Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors., Science, 267, 1349, 10.1126/science.7871433 Noguchi, 1993, Interleukin-2 receptor γ chain mutation results in X-linked severe combined immunodeficiency in humans. Cell, Cambridge, Mass., 73, 147 Kitamura, 1991, Expression cloning of the human IL-3 receptor cDNA reveals a shared β subunit for the human IL-3 and GM-CSF receptors. Cell, Cambridge, Mass., 66, 1165 Nicholson, 1995, Distinct regions of the granulocyte colon-stimulating factor receptor are required for tyrosine phosphorylation of the signaling molecules JAK2, Stat3, and p42, p44MAPK., Blood, 86, 3698, 10.1182/blood.V86.10.3698.bloodjournal86103698 Tanaka, 1994, Physical association of JAK1 andJAK2 tyrosine kinases with the interleukin 2 receptor beta and gamma chains., Proc. Natl. Acad. Sci. U.S.A., 91, 7271, 10.1073/pnas.91.15.7271 Yin, 1994, JAK1 kinase forms complexes with interleukin-4 receptor and 4PS/Insulin receptor substrate-1-like protein and is activated by interleukin-4 and interleukin-9 in T lymphocytes., J. Biol. Chem., 269, 26614, 10.1016/S0021-9258(18)47061-5 van der Geer, 1994, Receptor protein-tyrosine kinases and their signal transduction pathways., Annu. Rev. Cell Biol., 10, 251, 10.1146/annurev.cb.10.110194.001343 Glass, 1996, Agrin acts via a MuSK receptor complex. Cell, Cambridge, Mass., 85, 513 Sanicola, 1997, Glial cell line-derived neurotrophic factor-dependent RET activation can be mediated by two different cell-surface accessory proteins., Proc. Natl. Acad. Sci. U.S.A., 94, 6238, 10.1073/pnas.94.12.6238 Darnell, 1994, Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins., Science, 264, 1415, 10.1126/science.8197455 Decker, 1991, Cytoplasmic activation of GAF, an IFTSPy-regulated DNA-binding factor., EMBOJ., 10, 927, 10.1002/j.1460-2075.1991.tb08026.x Schindler, 1992, Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor., Science, 257, 809, 10.1126/science.1496401 Shuai, 1992, Activation of transcription by IFN-γ: Tyrosine phosphorylation of a 91-kDa binding protein., Science, 258, 1808, 10.1126/science.1281555 Fu, 1992, The proteins of ISGF-3, the interferon ct-induced transcriptional activator, define a gene family involved in signal transduction., Proc. Natl. Acad. Sci. U.S.A., 89, 7840, 10.1073/pnas.89.16.7840 Schindler, 1992, Proteins of transcription factor ISGF-3: One encodes the 91- and 84-kDa ISGF-3 proteins that are activated by interferon, A. Proc. Natl. Acad. Sci. U.S.A., 89, 7836, 10.1073/pnas.89.16.7836 Zhong, 1994, Stat3: A STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6., Science, 264, 95, 10.1126/science.8140422 Shuai, 1994, Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions. Cell, Cambridge, Mass., 76, 821 Schindler, 1995, Transcriptional responses to polypeptide ligands: The JAK-STAT pathway., Annu. Rev. Biochem., 64, 621, 10.1146/annurev.bi.64.070195.003201 Akira, 1994, Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gpl30-mediated signaling pathway. Cell, Cambridge, Mass., 77, 63 Yamamoto, 1994, Stat4, a novel gamma interferon activation site-binding protein expressed in early myeloid differentiation., Mol. Cell. Biol., 14, 4342, 10.1128/MCB.14.7.4342 Wakao, 1994, Mammary gland factor (MGF) is a novel member of the cytokine regulated transcription factor gene family and confers the prolactin response., EMBOJ., 13, 2182, 10.1002/j.1460-2075.1994.tb06495.x Hou, 1994, An interleukin-4-induced transcription factor: IL-4 Stat., Science, 265, 1701, 10.1126/science.8085155 Pawson, 1992, SH2 and SH3 domains: From structure to function. Cell, Cambridge, Mass., 71, 359 Wegenka, 1994, The interleukin-6-activated acute-phase response factor is antigenically and functionally related to members of the signal transducer and activator of transcription (STAT) family., Mol. Cell. Biol., 14, 3186, 10.1128/MCB.14.5.3186 Tian, 1994, Rapid activation of the STAT3 transcription factor by granulocyte colony-stimulating factor., Blood, 84, 1760, 10.1182/blood.V84.6.1760.1760 Baumann, 1996, The full-length leptin receptor has signaling capabilities of interleukin-6 cytokine receptors., Proc. Natl. Acad. Sci. U.S.A., 93, 8374, 10.1073/pnas.93.16.8374 Thierfelder, 1996, Requirement for Stat4 in interleukin-12 mediated responses of natural killer and T cells. Nature, London, 382, 171, 10.1038/382171a0 Ihle, 1996, STATs: Signal transducers and activators of transcription. Cell, Cambridge, Mass., 84, 331 Takeda, 1996, Essential role of Stat6 in IL-4 signalling, Nature London, 380, 627, 10.1038/380627a0 Durbin, 1996, Targeted disruption of the mouse Statl gene results in compromised innate immunity to viral disease. Cell, Cambridge, Mass., 84, 443 Meraz, 1996, Targeted disruption of the Statl gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell, Cambridge, Mass., 84, 431 Heim, 1995, Contribution of STAT SH2 groups to specific interferon signaling by the Jak-STAT pathway., Science, 267, 1347, 10.1126/science.7871432 Seidel, 1995, Spacing of palindromic half sites as a determinant of selective STAT (signal transducers and activators of transcription) DNA binding and transcriptional activity., Proc. Natl. Acad. Sci. U.S.A., 92, 3041, 10.1073/pnas.92.7.3041 Kotanides, 1996, Interleukin-4-induced STAT6 recognizes and activates a target site in the promoter of the interleukin-4 receptor gene., J. Biol. Chem., 271, 25555, 10.1074/jbc.271.41.25555 Schindler, 1995, Components of Stat recognition code: Evidence for two layers of molecular selectivity., Immunity, 2, 689, 10.1016/1074-7613(95)90013-6 Boulton, 1995, STAT3 activation by cytokines utilizing gpl30 and related transducers involves a secondary modification requiring an H7-sensitive kinase., Proc. Natl. Acad. Sci. U.S.A., 92, 6915, 10.1073/pnas.92.15.6915 Zhang, 1995, Requirement of serine phosphorylation for formation of STAT-promoter complexes., Science, 267, 1990, 10.1126/science.7701321 Wen, 1995, Maximal activation of transcription by Statl and Stat3 requires both tyrosine and serine phosphorylation. Cell, Cambridge, Mass., 82, 241 Boulton, 1994, Ciliary neurotrophic factorJ. leukemia inhibitory factor/interleukin 6/oncostatin M family of cytokines induces tyrosine phosphorylation of a common set of proteins overlapping those induced by other cytokines and growth factors., J. Biol. Chem., 269, 11648, 10.1016/S0021-9258(19)78174-5 David, 1995, Requirement for MAP kinase (ERK2) activity in interferon a-and interferon β-stimulated gene expression through STAT proteins., Science, 269, 1721, 10.1126/science.7569900 Korzus, 1997, The mitogen-activated protein kinase and JAK-STAT signaling pathways are required for an oncostatin M-responsive element-mediated activation of matrix metalloproteinase 1 gene expression., J. Biol. Chem., 272, 1188, 10.1074/jbc.272.2.1188 Fukuda, 1996, Two signals are necessary for cell proliferation induced by a cytokine receptor gpl30: Involvement of STAT3 in anti-apoptosis., Immunity, 5, 449, 10.1016/S1074-7613(00)80501-4 Greenlund, 1994, Ligand induced IFNy receptor tyrosine phosphorylation couples the receptor to its signal transduction system (p91)., EMBOJ., 13, 1591, 10.1002/j.1460-2075.1994.tb06422.x Tartaglia, 1995, Identification and expression cloning of a leptin receptor, OB-R. Cell, Cambridge, Mass., 83, 1263 DrachmanJ, 1997, Dissecting the thrombopoietin receptor: Functional elements of the Mpl cytoplasmic domain., Proc. Natl. Acad. Set. U.S.A., 94, 2350, 10.1073/pnas.94.6.2350 Greenlund, 1995, Stat recruitment by tyrosine-phosphorylated cytokine receptors: An ordered reversible affinity-driven process., Immunity, 2, 677, 10.1016/1074-7613(95)90012-8 Gerhartz, 1996, Differential activation of acute phase response factor/STAT3 and STAT1 via the cytoplasmic domain of the interleu-kin 6 signal transducer gpl30. II. Src homology SH2 domains define the specificity of STAT factor activation., J. Biol. Chem., 271, 12991, 10.1074/jbc.271.22.12999 Klingmuller, 1995, Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation ofJak2 and termination of proliferative signals., Cell {Cambridge, Mass., 80, 729, 10.1016/0092-8674(95)90351-8 D'Ambrosio, 1995, Recruitment and activation of PTP1C in negative regulation of antigen receptor signaling by FcγRIIBl., Science, 268, 293, 10.1126/science.7716523 Ali, 1996, PTP1D is a positive regulator of the prolactin signal leading to /3-casein promoter activation., EMBOJ., 15, 135, 10.1002/j.1460-2075.1996.tb00341.x Lechleider, 1993, Tyrosyl phosphorylation and growth factor association of the human corkscrew homologue, SH-PTP2., J. Biol. Chem., 268, 13434, 10.1016/S0021-9258(19)38668-5 Kharitonenkov, 1995, Adapter function of protein-tyrosine phosphatase ID in insulin receptor/insulin receptor substrate-1 interaction., J. Biol. Chem., 270, 29189, 10.1074/jbc.270.49.29189 David, 1996, The SH2 domain-containing tyrosine phosphatase PTP1D is required for interferon α/β-induced gene expression., J. Biol. Chem., 271, 15862, 10.1074/jbc.271.27.15862 Lechleider, 1993, Tyrosyl phosphorylation and growth factor receptor association of the human corkscrew homologue, SH-PTP2., J. Biol. Chem., 268, 13434, 10.1016/S0021-9258(19)38668-5 Li, 1994, A new function for a phosphotyrosine phosphatase: Linking GRB2-Sos to a receptor tyrosine kinase., Mol. Cell. Biol., 14, 509, 10.1128/MCB.14.1.509 Pluskey, 1995, Potent stimulation of SH-PTP2 phosphatase activity by simultaneous occupancy of both SH2 domains., J. Biol. Chem., 270, 2897, 10.1074/jbc.270.7.2897 Symes, 1997, The protein tyrosine phosphatase SHP-2 negatively regulates ciliary neurotrophic factor induction of gene expression., Curr. Biol., 7, 697, 10.1016/S0960-9822(06)00298-3 Carpenter, 1997, Enhancing leptin response by preventing SHP-2 interaction with ObR., Proc. Natl. Acad. Sci. U.S.A., 95, 6061, 10.1073/pnas.95.11.6061 Servidei, 1998, Coordinate regulation of STAT signaling and c-fos expression by the tyrosine phosphatase SHP-2., J. Biol. Chem., 273, 6233, 10.1074/jbc.273.11.6233 Starr, 1997, A family of cytokine-inducible inhibitors of signalling. Nature, London, 387, 917, 10.1038/43206 Endo, 1997, A new protein containing an SH2 domain that inhibits JAK kinases. Nature, London, 387, 921, 10.1038/43213 Naka, 1997, Structure and function of a new STAT-induced STAT inhibitor. Nature, London, 387, 924, 10.1038/43219 Kim, 1996, Regulation of interferon-gamma-activated STATl by the ubiquitin-proteasome pathway., Science, 273, 1714, 10.1126/science.273.5282.1717 Haspel, 1996, The rapid inactiva-tion of nuclear tyrosine phosphorylated Statl depends upon a protein tyrosine phosphatase., EMBOJ., 15, 6262, 10.1002/j.1460-2075.1996.tb01016.x Yu, 1997, Involvement of proteasomes in regulating Jak-STAT pathways upon interleukin-2 stimulation., J. Biol. Chem., 272, 14017, 10.1074/jbc.272.22.14017 Fountoulakis, 1995, Interferon y receptor extracellular domain expressed as IgG fusion protein in Chinese hamster ovary cells., J. Biol. Chem., 270, 3958, 10.1074/jbc.270.8.3958 Economides, A., Yancopoulos, G. D., and Stahl, N. (1997). Unpublished data. Livnah, 1996, Functional mimicry of a protein hormone by a peptide agonist: The EPO receptor complex at 2.8 A., Science, 273, 464, 10.1126/science.273.5274.464 Cwirla, 1997, Peptide agonist of the thrombopoietin receptor as potent as the natural cytokine., Science, 276, 1696, 10.1126/science.276.5319.1696