Cytokine receptor signaling through the Jak-Stat-Socs pathway in disease.

The complexity of multicellular organisms is dependent on systems enabling cells to respond to specific stimuli. Cytokines and their receptors are one such system, whose perturbation can lead to a variety of disease states. This review represents an overview of our current understanding of the cytokine receptors, Janus kinases (Jaks), Signal transducers and activators of transcription (Stats) and Suppressors of cytokine signaling (Socs), focussing on their contribution to diseases of an immune or hematologic nature.

[1]  J. G. Zhang,et al.  The conserved SOCS box motif in suppressors of cytokine signaling binds to elongins B and C and may couple bound proteins to proteasomal degradation. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[2]  M. Freedman,et al.  Novel Point Mutation in the Extracellular Domain of the Granulocyte Colony-Stimulating Factor (G-Csf) Receptor in a Case of Severe Congenital Neutropenia Hyporesponsive to G-Csf Treatment , 1999, The Journal of experimental medicine.

[3]  Steven F. Ziegler,et al.  Defective IL7R expression in T-B+NK + severe combined immunodeficiency , 1998, Nature Genetics.

[4]  S. Frank.  Growth hormone signalling and its regulation: preventing too much of a good thing. , 2001, Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society.

[5]  L. Notarangelo,et al.  Jak3, severe combined immunodeficiency, and a new class of immunosuppressive drugs , 2005, Immunological reviews.

[6]  S. Chevalier,et al.  CLF associates with CLC to form a functional heteromeric ligand for the CNTF receptor complex , 2000, Nature Neuroscience.

[7]  S. Rafii,et al.  Interleukin-5 and the regulation of eosinophil production. , 1999, Current opinion in hematology.

[8]  J. Renauld.  Class II cytokine receptors and their ligands: Key antiviral and inflammatory modulators , 2003, Nature Reviews Immunology.

[9]  Y. Shima,et al.  Inadequate induction of suppressor of cytokine signaling-1 causes systemic autoimmune diseases. , 2004, International immunology.

[10]  I. Gery,et al.  Induction of suppressors of cytokine signaling (SOCS) in the retina during experimental autoimmune uveitis (EAU): Potential neuroprotective role of SOCS proteins , 2005, Journal of Neuroimmunology.

[11]  Nicola Gebbia,et al.  STAT proteins: From normal control of cellular events to tumorigenesis , 2003, Journal of cellular physiology.

[12]  M. Dolan,et al.  HIV-1 infection induces a selective reduction in STAT5 protein expression. , 1998, Journal of immunology.

[13]  J. Johnston,et al.  SOCS-3 regulates onset and maintenance of TH2-mediated allergic responses , 2003, Nature Medicine.

[14]  S. Constantinescu,et al.  A unique clonal JAK 2 mutation leading to constitutive signalling causes polycythaemia , 2005 .

[15]  W. Dietrich,et al.  A natural mutation in the Tyk2 pseudokinase domain underlies altered susceptibility of B10.Q/J mice to infection and autoimmunity , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[16]  A. Ward.  The role of the granulocyte colony-stimulating factor receptor (G-CSF-R) in disease. , 2007, Frontiers in bioscience : a journal and virtual library.

[17]  Sandra A. Moore,et al.  Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. , 2005, Cancer cell.

[18]  S. Pestka,et al.  Jak-Stat signal transduction pathway through the eyes of cytokine class II receptor complexes , 2000, Oncogene.

[19]  A. Yoshimura,et al.  The Jak-Stat pathway in normal and perturbed hematopoiesis. , 2000, Blood.

[20]  T. Taniguchi,et al.  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. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[21]  A. Lewis-Antes,et al.  IFN-λs mediate antiviral protection through a distinct class II cytokine receptor complex , 2003, Nature Immunology.

[22]  Jan-Gowth Chang,et al.  Epigenetic alteration of the SOCS1 gene in chronic myeloid leukaemia , 2003, British journal of haematology.

[23]  W. Leonard,et al.  Cytokine receptor signaling pathways. , 2000, The Journal of allergy and clinical immunology.

[24]  A. de la Chapelle,et al.  Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[25]  J. Thompson,et al.  Multiple sequence alignment with Clustal X. , 1998, Trends in biochemical sciences.

[26]  D. Barber,et al.  Turning cells red: signal transduction mediated by erythropoietin. , 2005, Trends in cell biology.

[27]  I. Adcock,et al.  STAT4 activation in smokers and patients with chronic obstructive pulmonary disease , 2004, European Respiratory Journal.

[28]  V. Gouilleux-Gruart,et al.  Constitutive activation of STAT proteins in primary lymphoid and myeloid leukemia cells and in Epstein-Barr virus (EBV)-related lymphoma cell lines. , 1996, Blood.

[29]  A. Svejgaard,et al.  Constitutive STAT3 Activation in Intestinal T Cells from Patients with Crohn's Disease* , 2003, The Journal of Biological Chemistry.

[30]  J. Kere,et al.  Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. , 2005, American journal of human genetics.

[31]  P. Campbell,et al.  Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders , 2005, The Lancet.

[32]  H. Lodish,et al.  The N-terminal domain of Janus kinase 2 is required for Golgi processing and cell surface expression of erythropoietin receptor. , 2001, Molecular cell.

[33]  M. Kubo,et al.  The Control of Allergic Conjunctivitis by Suppressor of Cytokine Signaling (SOCS)3 and SOCS5 in a Murine Model1 , 2005, The Journal of Immunology.

[34]  R. Gascoyne,et al.  Signal transducer and activator of transcription 6 is frequently activated in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. , 2002, Blood.

[35]  T. Kishimoto,et al.  Cytokine Signal Transduction through a Homo‐or Heterodimer of gp130 , 1995, Annals of the New York Academy of Sciences.

[36]  Mario Cazzola,et al.  A gain-of-function mutation of JAK2 in myeloproliferative disorders. , 2005, The New England journal of medicine.

[37]  R. Ray,et al.  Hepatitis C virus NS5A mediated STAT3 activation requires co-operation of Jak1 kinase. , 2004, Virology.

[38]  G. Lutfalla,et al.  Alpha and beta interferons and their receptor and their friends and relations. , 1995, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[39]  R Berger,et al.  A TEL-JAK2 fusion protein with constitutive kinase activity in human leukemia. , 1997, Science.

[40]  S. Becker,et al.  Structure of the Unphosphorylated STAT5a Dimer* , 2005, Journal of Biological Chemistry.

[41]  P. Heinrich,et al.  Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. , 1998, The Biochemical journal.

[42]  P. Marynen,et al.  Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15;12) in a myeloid leukemia. , 1997, Blood.

[43]  T. Naoe,et al.  Differential constitutive activation between STAT‐related proteins and MAP kinase in primary acute myelogenous leukaemia , 1998, British journal of haematology.

[44]  K. Shiota,et al.  Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[45]  C. Ware,et al.  Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death. , 1995, Development.

[46]  W. Alexander,et al.  Defective Gp130-Mediated Signal Transducer and Activator of Transcription (Stat) Signaling Results in Degenerative Joint Disease, Gastrointestinal Ulceration, and Failure of Uterine Implantation , 2001, The Journal of experimental medicine.

[47]  Rene Devos,et al.  Identification and expression cloning of a leptin receptor, OB-R , 1995, Cell.

[48]  W. Leonard,et al.  Cytokine and Cytokine Receptor Pleiotropy and Redundancy* , 2002, The Journal of Biological Chemistry.

[49]  G. Lutfalla,et al.  α and α Interferons and Their Receptor and Their Friends and Relations , 1995 .

[50]  Shu-Wha Lin,et al.  SOCS1 methylation in patients with newly diagnosed acute myeloid leukemia , 2003, Genes, chromosomes & cancer.

[51]  M. Tymms,et al.  A null mutation in the gene encoding a type I interferon receptor component eliminates antiproliferative and antiviral responses to interferons alpha and beta and alters macrophage responses. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[52]  R. Buckley.  Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution. , 2004, Annual review of immunology.

[53]  J. Bazan,et al.  Structural design and molecular evolution of a cytokine receptor superfamily. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[54]  Steven M. Holland,et al.  Impairment of Mycobacterial But Not Viral Immunity by a Germline Human STAT1 Mutation , 2001, Science.

[55]  Peter Beighton,et al.  de la Chapelle, A. , 1997 .

[56]  N. Sato,et al.  Multimeric cytokine receptors: common versus specific functions. , 1994, Current opinion in cell biology.

[57]  P. Marynen,et al.  Genomic imbalances including amplification of the tyrosine kinase gene JAK2 in CD30+ Hodgkin cells. , 2000, Cancer research.

[58]  S. Gaffen.  Signaling domains of the interleukin 2 receptor. , 2001, Cytokine.

[59]  W. Alexander,et al.  Suppressor of cytokine signaling-1 regulates acute inflammatory arthritis and T cell activation. , 2003, The Journal of clinical investigation.

[60]  F. Dong,et al.  Severe congenital neutropenia terminating in acute myeloid leukemia: disease progression associated with mutations in the granulocyte-colony stimulating factor receptor gene. , 1996, Leukemia research.

[61]  A. Khwaja,et al.  A truncated isoform of the human beta chain common to the receptors for granulocyte-macrophage colony-stimulating factor, interleukin-3 (IL-3), and IL-5 with increased mRNA expression in some patients with acute leukemia. , 1998, Blood.

[62]  David L Rimm,et al.  Tissue microarray analysis of signal transducers and activators of transcription 3 (Stat3) and phospho-Stat3 (Tyr705) in node-negative breast cancer shows nuclear localization is associated with a better prognosis. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[63]  H. Saito,et al.  Measles virus suppresses interferon-alpha signaling pathway: suppression of Jak1 phosphorylation and association of viral accessory proteins, C and V, with interferon-alpha receptor complex. , 2003, Virology.

[64]  W. Alexander,et al.  Thrombopoietin Signalling in Physiology and Disease , 2004, Growth factors.

[65]  K. Welte,et al.  Mutations in the gene for the granulocyte colony-stimulating-factor receptor in patients with acute myeloid leukemia preceded by severe congenital neutropenia. , 1995, The New England journal of medicine.

[66]  A. Yoshimura,et al.  CIS, a cytokine inducible SH2 protein, is a target of the JAK-STAT5 pathway and modulates STAT5 activation. , 1997, Blood.

[67]  A. Lewis-Antes,et al.  IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. , 2003, Nature immunology.

[68]  S. H. Lee,et al.  The JAK2 V617F mutation in de novo acute myelogenous leukemias , 2006, Oncogene.

[69]  P. Coffer,et al.  Regulation of proliferation, differentiation and survival by the IL-3/IL-5/GM-CSF receptor family. , 1998, Cellular signalling.

[70]  P. Kelly,et al.  Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. , 1998, Endocrine reviews.

[71]  P. Brousset,et al.  The t(8;9)(p22;p24) translocation in atypical chronic myeloid leukaemia yields a new PCM1-JAK2 fusion gene , 2005, Oncogene.

[72]  R. Levine,et al.  The JAK 2 V 617 F activating tyrosine kinase mutation is an infrequent event in both “ atypical ” myeloproliferative disorders and myelodysplastic syndromes , 2005 .

[73]  W. Paul,et al.  Molecular phylogeny within type I cytokines and their cognate receptors. , 2003, Immunity.

[74]  Scott R. Presnell,et al.  Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function , 2000, Nature.

[75]  D. Choubey,et al.  Type-I Interferon Receptor Deficiency Reduces Lupus-like Disease in NZB Mice , 2003, The Journal of experimental medicine.

[76]  Mangi Mh,et al.  Interleukin-3 in hematology and oncology: current state of knowledge and future directions. , 1999 .

[77]  Thomas S. Lin,et al.  STAT signaling in the pathogenesis and treatment of leukemias , 2000, Oncogene.

[78]  C. Sawyers,et al.  Constitutive activation of STAT5 by the BCR-ABL oncogene in chronic myelogenous leukemia. , 1996, Oncogene.

[79]  J. Johnston,et al.  Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[80]  A. Kraft,et al.  The Amino-terminal Portion of the JAK2 Protein Kinase Is Necessary For Binding and Phosphorylation of the Granulocyte-Macrophage Colony-stimulating Factor Receptor β Chain (*) , 1995, The Journal of Biological Chemistry.

[81]  O. Silvennoinen,et al.  Regulation of the Jak2 Tyrosine Kinase by Its Pseudokinase Domain , 2000, Molecular and Cellular Biology.

[82]  H. Anaguchi,et al.  Evidence for the ligand‐induced conversion from a dimer to a tetramer of the granulocyte colony‐stimulating factor receptor , 1994, FEBS letters.

[83]  C. Peschle,et al.  Interleukin-3 receptor in acute leukemia , 2004, Leukemia.

[84]  R. Döffinger,et al.  In a novel form of IFN-gamma receptor 1 deficiency, cell surface receptors fail to bind IFN-gamma. , 2000, The Journal of clinical investigation.

[85]  S. Kotenko,et al.  Full house: 12 receptors for 27 cytokines. , 2004, International immunopharmacology.

[86]  D. White,et al.  Ligand-independent Dimerization of the Extracellular Domain of the Leptin Receptor and Determination of the Stoichiometry of Leptin Binding* , 1997, The Journal of Biological Chemistry.

[87]  Hiroaki Ito.  IL-6 and Crohn's disease. , 2003, Current drug targets. Inflammation and allergy.

[88]  T. Fry,et al.  The Many Faces of IL-7: From Lymphopoiesis to Peripheral T Cell Maintenance , 2005, The Journal of Immunology.

[89]  W. Renner,et al.  A functional single-nucleotide polymorphism of the G-CSF receptor gene predisposes individuals to high-risk myelodysplastic syndrome. , 2005, Blood.

[90]  D. Conklin,et al.  Interleukin 20 Discovery, Receptor Identification, and Role in Epidermal Function , 2001, Cell.

[91]  I. Touw,et al.  Multiple pathways contribute to the hyperproliferative responses from truncated granulocyte colony-stimulating factor receptors , 2006, Leukemia.

[92]  David P Steensma,et al.  The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both "atypical" myeloproliferative disorders and myelodysplastic syndromes. , 2005, Blood.

[93]  M. Cathcart,et al.  IL‐13 signal transduction in human monocytes: phosphorylation of receptor components, association with Jaks, and phosphorylation/activation of Stats , 2002, Journal of leukocyte biology.

[94]  W. Leonard,et al.  Cytokines and immunodeficiency diseases: critical roles of the γc‐dependent cytokines interleukins 2, 4, 7, 9, 15, and 21, and their signaling pathways , 2004, Immunological reviews.

[95]  A R Dunn,et al.  Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization. , 1994, Blood.

[96]  P. Conti,et al.  IL-10 subfamily members: IL-19, IL-20, IL-22, IL-24 and IL-26. , 2003, Immunology letters.

[97]  D. Sampath,et al.  Constitutive activation of an epithelial signal transducer and activator of transcription (STAT) pathway in asthma. , 1999, The Journal of clinical investigation.

[98]  I. Wilson,et al.  Erythropoietin receptor activation by a ligand-induced conformation change. , 1999, Science.

[99]  U. Dirksen,et al.  Human pulmonary alveolar proteinosis associated with a defect in GM-CSF/IL-3/IL-5 receptor common beta chain expression. , 1997, The Journal of clinical investigation.

[100]  K. Tokuyama,et al.  Linkage and Association Studies of STAT6 Gene Polymorphisms and Allergic Diseases , 2003, International Archives of Allergy and Immunology.

[101]  W. Paul.  Interleukin 4: signalling mechanisms and control of T cell differentiation. , 1997, Ciba Foundation symposium.

[102]  Yuka Kanno,et al.  Signaling by IL‐12 and IL‐23 and the immunoregulatory roles of STAT4 , 2004, Immunological reviews.

[103]  Takaho A. Endo,et al.  A new protein containing an SH2 domain that inhibits JAK kinases , 1997, Nature.

[104]  C. Heldin,et al.  Dimerization of cell surface receptors in signal transduction , 1995, Cell.

[105]  H. Saito,et al.  Measles virus suppresses interferon-α signaling pathway: suppression of Jak1 phosphorylation and association of viral accessory proteins, C and V, with interferon-α receptor complex , 2003 .

[106]  W. Alexander,et al.  Twenty proteins containing a C-terminal SOCS box form five structural classes. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[107]  J. Turkson,et al.  Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. , 1999, Immunity.

[108]  S. Akira,et al.  Cytokine signal transduction , 1994, Cell.

[109]  R. Nussenblatt,et al.  SOCS5 mRNA levels in peripheral blood mononuclear cells (PBMC): a potential bio-marker for monitoring response of uveitis patients to Daclizumab therapy. , 2005, Journal of autoimmunity.

[110]  D. Sheppard,et al.  Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma , 2002, Nature Medicine.