Biological and clinical significance of the JAK-STAT pathway; lessons from knockout mice

Abstract. Originally described as the signal-transducing pathway of interferons, the JAK-STAT pathway soon turned out to participate in the signalling of numerous other immune and even non-immune mediators. Several murine knockout models have been described that underline the biological significance of this signalling system. Some human diseases (mainly neoplastic) are also known where malfunctioning of the JAK-STAT pathway is considered to participate in the pathogenesis. In this brief review article we will try to make a synopsis of its biological and clinical significance.

[1]  M. Aguet,et al.  Electrophoretically pure mouse interferon inhibits growth, induces liver and kidney lesions, and kills suckling mice. , 1981, The American journal of pathology.

[2]  D. Beier,et al.  Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene , 1993, Cell.

[3]  W. Leonard,et al.  Interleukin-2 receptor γ chain mutation results in X-linked severe combined immunodeficiency in humans , 1993, Cell.

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

[5]  J. Johnston,et al.  Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID) , 1995, Nature.

[6]  J. Darnell,et al.  Transcriptional responses to polypeptide ligands: the JAK-STAT pathway. , 1995, Annual review of biochemistry.

[7]  N. Copeland,et al.  A novel cytokine‐inducible gene CIS encodes an SH2‐containing protein that binds to tyrosine‐phosphorylated interleukin 3 and erythropoietin receptors. , 1995, The EMBO journal.

[8]  A. Fischer,et al.  Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[9]  W. Leonard,et al.  Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. , 1995, Immunity.

[10]  B. Groner,et al.  Mammary gland factor (MGF) is a novel member of the cytokine regulated transcription factor gene family and confers the prolactin response. , 1995, The EMBO journal.

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

[12]  H. Nakauchi,et al.  Developmental defects of lymphoid cells in Jak3 kinase-deficient mice. , 1995, Immunity.

[13]  J. Darnell,et al.  Maximal activation of transcription by statl and stat3 requires both tyrosine and serine phosphorylation , 1995, Cell.

[14]  P. Doherty,et al.  Defective Lymphoid Development in Mice Lacking Jak3 , 1995, Science.

[15]  W. Leonard,et al.  Mutation of Jak3 in a Patient with SCID: Essential Role of Jak3 in Lymphoid Development , 1995, Science.

[16]  M. Kaplan,et al.  Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice , 1996, Nature.

[17]  R. Schreiber,et al.  Targeted Disruption of the Stat1 Gene in Mice Reveals Unexpected Physiologic Specificity in the JAK–STAT Signaling Pathway , 1996, Cell.

[18]  Y. Fujio,et al.  Activation of JAK-STAT and MAP kinases by leukemia inhibitory factor through gp130 in cardiac myocytes. , 1996, Circulation.

[19]  K. Chien,et al.  Cardiotrophin-1: a multifunctional cytokine that signals via LIF receptor-gp 130 dependent pathways. , 1996, Cytokine & growth factor reviews.

[20]  D. Levy,et al.  Targeted Disruption of the Mouse Stat1 Gene Results in Compromised Innate Immunity to Viral Disease , 1996, Cell.

[21]  P. Nowell,et al.  Activation of Jak/STAT proteins involved in signal transduction pathway mediated by receptor for interleukin 2 in malignant T lymphocytes derived from cutaneous anaplastic large T-cell lymphoma and Sezary syndrome. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[22]  M. Heim,et al.  The Jak–STAT pathway: specific signal transduction from the cell membrane to the nucleus , 1996, European journal of clinical investigation.

[23]  A. Miyajima,et al.  Suppression of interleukin‐3‐induced gene expression by a C‐terminal truncated Stat5: role of Stat5 in proliferation. , 1996, The EMBO journal.

[24]  P. Doherty,et al.  Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells , 1996, Nature.

[25]  N. Tanaka,et al.  The interleukin-2 receptor gamma chain: its role in the multiple cytokine receptor complexes and T cell development in XSCID. , 1996, Annual review of immunology.

[26]  J. Darnell.  STATs and gene regulation. , 1997, Science.

[27]  J. Ritz,et al.  B lymphocytes from patients with chronic lymphocytic leukemia contain signal transducer and activator of transcription (STAT) 1 and STAT3 constitutively phosphorylated on serine residues. , 1997, The Journal of clinical investigation.

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

[29]  D. Alexander,et al.  The role of phosphotyrosine phosphatases in haematopoietic cell signal transduction , 1997, BioEssays : news and reviews in molecular, cellular and developmental biology.

[30]  P. Rothman,et al.  Constitutive activation of JAKs and STATs in BCR-Abl-expressing cell lines and peripheral blood cells derived from leukemic patients. , 1997, Journal of immunology.

[31]  R. Snell,et al.  Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[32]  A. Deisseroth,et al.  Potential role of bcr-abl in the activation of JAK1 kinase. , 1997, Clinical cancer research : an official journal of the American Association for Cancer Research.

[33]  T. Waldmann,et al.  Proliferation of adult T cell leukemia/lymphoma cells is associated with the constitutive activation of JAK/STAT proteins. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[34]  L. Berg,et al.  The role of Jak3 in lymphoid development, activation, and signaling. , 1997, Current opinion in immunology.

[35]  S. Akira,et al.  Structure and function of a new STAT-induced STAT inhibitor , 1997, Nature.

[36]  L. Hennighausen,et al.  Stat5a is mandatory for adult mammary gland development and lactogenesis. , 1997, Genes & development.

[37]  S. Akira,et al.  Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Warren S. Alexander,et al.  A family of cytokine-inducible inhibitors of signalling , 1997, Nature.

[39]  S. Ogawa,et al.  Role of angiotensin II in activation of the JAK/STAT pathway induced by acute pressure overload in the rat heart. , 1997, Circulation research.

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

[41]  W. Leonard,et al.  An indirect effect of Stat5a in IL-2-induced proliferation: a critical role for Stat5a in IL-2-mediated IL-2 receptor alpha chain induction. , 1997, Immunity.

[42]  A. Cumano,et al.  Jak2 Deficiency Defines an EssentialDevelopmental Checkpoint in DefinitiveHematopoiesis , 1998, Cell.

[43]  W. Leonard,et al.  Stat5b Is Essential for Natural Killer Cell–mediated Proliferation and Cytolytic Activity , 1998, The Journal of experimental medicine.

[44]  D. Chang,et al.  Inhibition of Stat1-mediated gene activation by PIAS1. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[45]  M. Wills-Karp,et al.  Signal Transducer and Activator of Transcription Factor 6 (Stat6)-deficient Mice Are Protected from Antigen-induced Airway Hyperresponsiveness and Mucus Production , 1998, The Journal of experimental medicine.

[46]  Michael P. Brown,et al.  Stat5a and Stat5b Proteins Have Essential and Nonessential, or Redundant, Roles in Cytokine Responses , 1998, Cell.

[47]  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.

[48]  Y. Uchiyama,et al.  Accelerated apoptosis of lymphocytes by augmented induction of Bax in SSI-1 (STAT-induced STAT inhibitor-1) deficient mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

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

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

[51]  S. Govoni,et al.  Members of the JAK/STAT proteins are expressed and regulated during development in the mammalian forebrain , 1998, Journal of neuroscience research.

[52]  S. Ogawa,et al.  Biphasic activation of the JAK/STAT pathway by angiotensin II in rat cardiomyocytes. , 1998, Circulation research.

[53]  S. Akira,et al.  Abrogation of Bronchial Eosinophilic Inflammation and Airway Hyperreactivity in Signal Transducers and Activators of Transcription (STAT)6-deficient Mice , 1998, The Journal of experimental medicine.

[54]  A. Elefanty,et al.  Liver degeneration and lymphoid deficiencies in mice lacking suppressor of cytokine signaling-1. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[55]  J. Marine,et al.  Jak2 Is Essential for Signaling through a Variety of Cytokine Receptors , 1998, Cell.

[56]  R. Schreiber,et al.  Disruption of the Jak1 Gene Demonstrates Obligatory and Nonredundant Roles of the Jaks in Cytokine-Induced Biologic Responses , 1998, Cell.

[57]  A. Yoshimura,et al.  SOCS1 Deficiency Causes a Lymphocyte-Dependent Perinatal Lethality , 1999, Cell.

[58]  H. Pendeville,et al.  SOCS3 Is Essential in the Regulation of Fetal Liver Erythropoiesis , 1999, Cell.

[59]  A. Elefanty,et al.  Aberrant hematopoiesis in mice with inactivation of the gene encoding SOCS-1 , 1999, Leukemia.

[60]  S. Pellegrini,et al.  The Janus kinase family of protein tyrosine kinases and their role in signaling , 1999, Cellular and Molecular Life Sciences CMLS.

[61]  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.

[62]  D. Levy,et al.  Physiological significance of STAT proteins: investigations through gene disruption in vivo , 1999, Cellular and Molecular Life Sciences CMLS.

[63]  A. Yoshimura,et al.  The JAK‐binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop , 1999, The EMBO journal.

[64]  G. Butti,et al.  Expression of the JAK and STAT superfamilies in human meningiomas. , 1999, Journal of neurosurgery.

[65]  R. Jove,et al.  Constitutive Activation of the JAK 2 / STAT 5 Signal Transduction Pathway Correlates With Growth Factor Independence of Megakaryocytic Leukemic Cell Lines , 1999 .

[66]  MotoakiSano,et al.  Mechanical Stretch Activates the JAK/STAT Pathway in Rat Cardiomyocytes , 1999 .

[67]  Levy De,et al.  Physiological significance of STAT proteins: investigations through gene disruption in vivo. , 1999 .

[68]  T. Decker,et al.  Transcription factor activity of STAT proteins: structural requirements and regulation by phosphorylation and interacting proteins , 1999, Cellular and Molecular Life Sciences CMLS.

[69]  A. Mui,et al.  The role of STATs in proliferation, differentiation, and apoptosis , 1999, Cellular and Molecular Life Sciences CMLS.

[70]  J. Ihle,et al.  Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells. , 1999, Immunity.

[71]  Paul J Hertzog,et al.  SOCS1 Is a Critical Inhibitor of Interferon γ Signaling and Prevents the Potentially Fatal Neonatal Actions of this Cytokine , 1999, Cell.

[72]  R. Jove,et al.  Constitutive activation of the JAK2/STAT5 signal transduction pathway correlates with growth factor independence of megakaryocytic leukemic cell lines. , 1999, Blood.

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

[74]  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.

[75]  J. Darnell,et al.  Stat3 as an Oncogene , 1999, Cell.

[76]  C. Geisler,et al.  Inhibition of constitutively activated Stat3 correlates with altered Bcl-2/Bax expression and induction of apoptosis in mycosis fungoides tumor cells , 1999, Leukemia.

[77]  D. Hilton,et al.  Negative regulators of cytokine signal transduction , 1999, Cellular and Molecular Life Sciences CMLS.

[78]  D. Hilton,et al.  Negative regulation of the JAK/STAT pathway , 1999, BioEssays : news and reviews in molecular, cellular and developmental biology.

[79]  W. Alexander,et al.  Suppressors of cytokine signaling (SOCS): negative regulators of signal transduction , 1999, Journal of leukocyte biology.

[80]  G. Feng,et al.  Genetic evidence that Shp-2 tyrosine phosphatase is a signal enhancer of the epidermal growth factor receptor in mammals. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[81]  D. Hilton,et al.  SOCS: physiological suppressors of cytokine signaling. , 2000, Journal of cell science.

[82]  J. G. Zhang,et al.  Suppressor of cytokine signaling-3 preferentially binds to the SHP-2-binding site on the shared cytokine receptor subunit gp130. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[83]  C. Schindler,et al.  Immune response in Stat2 knockout mice. , 2000, Immunity.

[84]  D. Metcalf,et al.  The development of fatal myocarditis and polymyositis in mice heterozygous for IFN-gamma and lacking the SOCS-1 gene. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[85]  W. Alexander,et al.  Gigantism in mice lacking suppressor of cytokine signalling-2 , 2000, Nature.