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Jaks, STATs, Cytokine Signal Transduction, and Immunoregulation: Are We There Yet?

1997; Cell Press; Volume: 7; Issue: 1 Linguagem: Inglês

10.1016/s1074-7613(00)80505-1

1097-4180

John J. O’Shea,

interferon and immune responses

The impatient refrain "Are we there yet?," echoing from the back seat, is a familiar one to any parent. The question, though, is a valid one for the impatient immunologist struggling to understand the regulation of the immune response. That is, abundant data exist to substantiate the role of various cytokines in immunoregulation (84Paul W.E Seder R.A Lymphocyte responses and cytokines.Cell. 1994; 76: 241-251Abstract Full Text PDF PubMed Scopus (1369) Google Scholar, 1Abbas A.K Murphy K.M Sher A Functional diversity of helper T lymphocytes.Nature. 1996; 383: 787-793Crossref PubMed Scopus (3201) Google Scholar). Concomitantly, striking advances have been made recently in understanding cytokine signaling. But do these advances provide a satisfactory molecular explanation for cytokine actions and the processes involved in regulating the immune response? The discoveries of Janus kinases (Jaks) (Figure 1 and Figure 2) and signal transducers and activators of transcription (STATs) (Figure 3) have explained a great deal about signaling by cytokine receptors. One appeal of the Jak/STAT pathway is that the trail from membrane to gene regulation is remarkably direct. In addition, although the Jaks do not provide an explanation for the specificity of cytokine signaling, cytokine receptors and STATs do. This review focuses on the relationship of cytokine signaling to immunoregulation. In particular, humans and mice that lack specific Jaks and STATs are discussed (Table 1), because these examples provide clear illustrations of the importance of the Jak/STAT pathway in controlling the immune response.Figure 2A Model for the Role of Jaks and STATs in Cytokine Signal TransductionShow full captionCytokine binding to receptor subunits induces homo- or heterodimerization resulting in the apposition of Jaks that are bound to the receptor chains. The N terminus of the Jaks is probably important for receptor association. Bringing the Jaks into proximity allows the Jaks to become activated, likely through transphosphorylation. Like other tyrosine kinases, phosphorylation of tyrosine residues within the activation loop of the kinase domain is probably an essential part of this activation. The activated Jaks phosphorylate the cytokine receptor subunits providing docking sites for proteins with SH2 domains. The STAT family of transcription factors is one important class. STATs bound to cytokine receptors are themselves phosphorylated on a C-terminal tyrosine residue. This site in turn is recognized by the SH2 domain of another STAT molecule allowing dimerization to occur. Homo- and hetero-dimerized STATs translocate to the nucleus and bind DNA, thereby regulating gene expression. Other mechanisms may be involved in STAT–receptor interactions and alternative means for STAT activation may exist. Aside from their role as transcription factors, STATs may also function as adapter molecules for coupling receptors to other signaling pathways. That is, STAT3 has been reported to bind phosphatidylinositol 3-kinase.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3Structure of STATsShow full captionThe signal transducer and activator of transcription (STAT) family of transcription factors are notable structurally by the presence of a central DNA binding domain, an SH3-like domain, and an SH2 domain. C-terminal to the SH2 domain there is a conserved tyrosine residue that is phosphorylated upon cytokine stimulation and that is essential for STAT dimerization. The STAT SH2 domain serves both to bind to the phosphorylated cytokine receptor and to effect STAT dimerization. For some STATs, phosphorylation of a C-terminal serine residue (shown in parentheses) may also important for transcriptional activation. The extreme C terminus is divergent and influences transcriptional activation. The N terminus of the STATs, which is also conserved, is important for protein-protein interactions. Functions ascribed to this region include association with other STATs and receptor binding. The chromosomal localization of the STAT molecules is also shown. The localization of the some STATs (asterisks) is based on mapping of the mouse genes. See Ihle et al., 1995.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 1Summary of the Cytokines That Activate the Jaks and STATs and the Phenotypes Associated with Their DeficienciesMoleculeActivated byPhenotype of DeficiencyJAK1IFNsND*γc cytokines Many othersJAK2Many cytokinesNDJAK3γc cytokinesCombined immunodeficiency#TYK2IFNα/β, IL-10, IL-12, othersNDSTAT1IFNs, other cytokines and growth factorsViral susceptibility impaired IFN signalingSTAT2IFNα/βNDSTAT3Many cytokines and other stimuliEmbryonically lethalSTAT4IL-12, IFNα/β (human)Impaired IL-12 signaling and Th1 developmentSTAT5AMany hormones, interleukins, CSFs, otherImpaired lactation and mammary developmentSTAT5BMany hormones, interleukins, CSFs, otherNDSTAT6IL-4Impaired IL-4 signaling and Th2 differentiationThe Jak and STAT knockout mice that have been produced are described in the text.a A mammalian Jak1 knockout has not been reported, but in zebrafish, maternally derived Jak1 appears to be essential for embryogenesis (19Conway G Margoliath A Wong-Madden S Roberts R.J Gilbert W Jak1 kinase is required for cell migrations and anterior specification in zebrafish embryos.Proc. Natl. Acad. Sci. USA. 1997; 94: 3082-3087Crossref PubMed Scopus (39) Google Scholar).b Cases of Jak3 deficiency in humans have been identified, but no human cases have been identified that lack other Jaks or STATs.ND, no data. Open table in a new tab Cytokine binding to receptor subunits induces homo- or heterodimerization resulting in the apposition of Jaks that are bound to the receptor chains. The N terminus of the Jaks is probably important for receptor association. Bringing the Jaks into proximity allows the Jaks to become activated, likely through transphosphorylation. Like other tyrosine kinases, phosphorylation of tyrosine residues within the activation loop of the kinase domain is probably an essential part of this activation. The activated Jaks phosphorylate the cytokine receptor subunits providing docking sites for proteins with SH2 domains. The STAT family of transcription factors is one important class. STATs bound to cytokine receptors are themselves phosphorylated on a C-terminal tyrosine residue. This site in turn is recognized by the SH2 domain of another STAT molecule allowing dimerization to occur. Homo- and hetero-dimerized STATs translocate to the nucleus and bind DNA, thereby regulating gene expression. Other mechanisms may be involved in STAT–receptor interactions and alternative means for STAT activation may exist. Aside from their role as transcription factors, STATs may also function as adapter molecules for coupling receptors to other signaling pathways. That is, STAT3 has been reported to bind phosphatidylinositol 3-kinase. The signal transducer and activator of transcription (STAT) family of transcription factors are notable structurally by the presence of a central DNA binding domain, an SH3-like domain, and an SH2 domain. C-terminal to the SH2 domain there is a conserved tyrosine residue that is phosphorylated upon cytokine stimulation and that is essential for STAT dimerization. The STAT SH2 domain serves both to bind to the phosphorylated cytokine receptor and to effect STAT dimerization. For some STATs, phosphorylation of a C-terminal serine residue (shown in parentheses) may also important for transcriptional activation. The extreme C terminus is divergent and influences transcriptional activation. The N terminus of the STATs, which is also conserved, is important for protein-protein interactions. Functions ascribed to this region include association with other STATs and receptor binding. The chromosomal localization of the STAT molecules is also shown. The localization of the some STATs (asterisks) is based on mapping of the mouse genes. See Ihle et al., 1995. The Jak and STAT knockout mice that have been produced are described in the text. a A mammalian Jak1 knockout has not been reported, but in zebrafish, maternally derived Jak1 appears to be essential for embryogenesis (19Conway G Margoliath A Wong-Madden S Roberts R.J Gilbert W Jak1 kinase is required for cell migrations and anterior specification in zebrafish embryos.Proc. Natl. Acad. Sci. USA. 1997; 94: 3082-3087Crossref PubMed Scopus (39) Google Scholar). b Cases of Jak3 deficiency in humans have been identified, but no human cases have been identified that lack other Jaks or STATs. ND, no data. The term "cytokine" encompasses an array of diverse soluble factors. One subset of cytokines includes more than 30 factors and comprises the α-helical cytokines. These cytokines bind to a class of receptors known as type I cytokine receptors and include interleukins, colony-stimulating factors, and hormones (7Bazan J.F Haemopoietic receptors and helical cytokines.Immunol. Today. 1990; 11: 350-354Abstract Full Text PDF PubMed Google Scholar). Closely related are the receptors for the interferons (type II cytokine receptors). This superfamily can be further divided into subgroups based on the use of shared subunits (108Taga T Kishimoto T Signaling mechanisms through cytokine receptors that share signal transducing receptor components.Curr. Opin. Immunol. 1995; 7: 17-23Crossref PubMed Scopus (71) Google Scholar, 63Leonard W.J The molecular basis of X-linked severe combined immunodeficiency defective cytokine receptor signaling.Annu. Rev. Med. 1996; 47: 229-239Crossref PubMed Scopus (120) Google Scholar). For instance, the common γ chain (γc) is a subunit of the interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15 receptors. This feature of cytokine receptors provides one molecular explanation for the redundant nature of cytokines. The importance of cytokines in immunoregulation is now well documented. IL-12 and interferon-γ (IFNγ) are important in promoting cell-mediated responses, and IL-12 knockout mice have impaired T helper cell 1 (Th1) responses (71Magram J Connaughton S.E Warrier R.R Carvajal D.M Wu C.Y Ferrante J Stewart C Sarmiento U Faherty D.A Gately M.K IL-12-deficient mice are defective in IFN gamma production and type 1 cytokine responses.Immunity. 1996; 4: 471-481Abstract Full Text Full Text PDF PubMed Scopus (810) Google Scholar). Conversely, IL-4 and IL-5 are key mediators of allergic responses, and IL-4 knockout mice have impaired Th2 responses (59Kuhn R Rajewsky K Muller W Generation and analysis of interleukin-4 deficient mice.Science. 1991; 254: 707-710Crossref PubMed Google Scholar, 58Kopf M Le Gros G Bachmann M Lamers M.C Bluethmann H Kohler G Disruption of the murine IL-4 gene blocks Th2 cytokine responses.Nature. 1993; 362: 245-248Crossref PubMed Scopus (813) Google Scholar). IL-7 is important for the development and/or survival of T cells and B cells; mice lacking this cytokine or its receptor are profoundly lymphopenic (117von Freeden-Jeffry U Vieira P Lucian L.A McNeil T Burdach S.E Murray R Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine.J. Exp. Med. 1995; 181: 1519-1526Crossref PubMed Scopus (981) Google Scholar, 85Peschon J.J Morrissey P.J Grabstein K.H Ramsdell F.J Maraskovsky E Gliniak B.C Park L.S Ziegler S.F Williams D.E Ware C.B et al.Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice.J. Exp. Med. 1994; 180: 1955-1960Crossref PubMed Scopus (989) Google Scholar). IL-2, however, has both positive and negative effects on the immune response. A major abnormality seen in IL-2–, IL-2 receptor α chain (IL-2Rα)–, and IL-2Rβ–deficient mice is the development of autoimmune disease and lymphoid expansion (61Kundig T.M Schorle H Bachmann M.F Hengartner H Zinkernagel R.M Horak I Immune responses in interleukin-2-deficient mice.Science. 1993; 262: 1059-1061Crossref PubMed Google Scholar, 90Sadlack B Merz H Schorle H Schimpl A Feller A.C Horak I Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene.Cell. 1993; 75: 253-261Abstract Full Text PDF PubMed Scopus (1121) Google Scholar, 122Willerford D.M Chen J Ferry J.A Davidson L Ma A Alt F.W Interleukin-2 receptor α chain regulates the size and content of the peripheral lymphoid compartment.Immunity. 1995; 3: 521-530Abstract Full Text PDF PubMed Google Scholar, 106Suzuki H Kundig T.M Furlonger C Wakeham A Timms E Matsuyama T Schmits R Simard J.J Ohashi P.S Griesser H et al.Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta.Science. 1995; 268: 1472-1476Crossref PubMed Google Scholar). IL-10 is another cytokine that appears to hold the immune response in check; IL-10 knockout mice also have severe immunologic disease (60Kuhn R Lohler J Rennick D Rajewsky K Muller W Interleukin-10-deficient mice develop chronic enterocolitis [see comments].Cell. 1993; 75: 263-274Abstract Full Text PDF PubMed Scopus (2346) Google Scholar). Thus, it is clear that cytokines play a central role in immunoregulation. But how does this occur? What does this mean on a molecular level? How do specific cytokines regulate the expression of specific genes? Unlike growth factor receptors and the transforming growth factor β/activin family of receptors, which have intrinsic enzymatic activity (as tyrosine and serine/threonine kinases, respectively), cytokine receptors lack intrinsic catalytic activity. Rather, they are associated with a structurally unique class of kinases, the Jaks: Jak1, Jak2, Jak3, and Tyk2 (Figure 1 and Figure 2) (reviewed by45Ihle J.N Witthuhn B.A Quelle F.W Yamamoto K Silvennoinen O Signaling through the hematopoietic cytokine receptors.Annu. Rev. Immunol. 1995; 13: 369-398Crossref PubMed Google Scholar, 49Johnston J.A Bacon C.M Riedy M.C O'Shea J.J Signaling by IL-2 and related cytokines Jaks, STATs, and relationship to immunodeficiency.J. Leukocyte Biol. 1996; 60: 441-452Crossref PubMed Scopus (94) Google Scholar). The function of Jaks was uncovered by the generation of cell lines resistant to the effects of interferons, whose defects could be complemented by expression of different Jaks (115Velazquez L Fellous M Stark G.R Pellegrini S A protein tyrosine kinase in the interferon α/β signaling pathway.Cell. 1992; 70: 313-322Abstract Full Text PDF PubMed Scopus (399) Google Scholar, 77Muller M Briscoe J Laxton C Guschin D Ziemieck A Silvennoinen O Harpun A.G Barbieri G Witthuhn B.A Schindler C et al.The protein tyrosine kinase JAK1 complements defects in interferon-alpha/beta and -gamma signal transduction.Nature. 1993; 366: 129-135Crossref PubMed Google Scholar, 102Silvennoinen O Ihle J.N Schlessinger J Levy D.E Interferon-induced nuclear signalling by Jak protein tyrosine kinases.Nature. 1993; 366: 583-585Crossref PubMed Scopus (171) Google Scholar, 119Watling D Guschin D Muller M Silvennoinen O Witthuhn B.A Quelle F.W Rogers N.C Schindler C Stark G.R Ihle J.N et al.Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-gamma signal transduction pathway [see comments].Nature. 1993; 366: 166-170Crossref PubMed Google Scholar). Subsequently, it was found that various Jaks are activated by all the α-helical cytokines (summarized by44Ihle J.N Cytokine receptor signalling.Nature. 1995; 377: 591-594Crossref PubMed Google Scholar, 49Johnston J.A Bacon C.M Riedy M.C O'Shea J.J Signaling by IL-2 and related cytokines Jaks, STATs, and relationship to immunodeficiency.J. Leukocyte Biol. 1996; 60: 441-452Crossref PubMed Scopus (94) Google Scholar). Jak1 and Jak2 are activated by a broad range of cytokines, and Tyk2 is activated by cytokines that utilize gp130 (IL-6 and other cytokines), IL-10, IL-12, and IL-13 in addition to IFNα/β. In contrast, Jak3 specifically associates only with γc (88Russell S.M Johnston J.A Noguchi M Kawamura M Bacon C.M Friedmann M Berg M McVicar D.W Witthuhn B.A Silvennoinen O et al.Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3 implications for XSCID and XCID.Science. 1994; 266: 1042-1045Crossref PubMed Google Scholar, 76Miyazaki T Kawahara A Fujii H Nakagawa Y Minami Y Liu Z.J Oishi I Silvennoinen O Witthuhn B.A Ihle J.N et al.Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits.Science. 1994; 266: 1045-1047Crossref PubMed Google Scholar, 12Boussiotis V.A Barber D.L Nakarai T Freeman G.J Gribben J.G Bernstein G.M D'Andrea A.D Ritz J Nadler L.M Prevention of T cell anergy by signaling through the gamma c chain of the IL-2 receptor.Science. 1994; 266: 1039-1042Crossref PubMed Google Scholar) and is only activated by cytokines that bind to γc-containing receptors. The use of Jaks by different cytokine receptors is illustrated in Figure 4. Thus, Jaks fit the bill as key mediators of signaling by cytokine receptors in that they physically associate with cytokine receptor subunits and are essential for cytokine signaling. What is the significance to the organism of the absence of a given Jak? Thus far we only have information on one mammalian Jak, Jak3. Mutation of γc, which specifically associates with Jak3, is the molecular basis of X-linked severe combined immunodeficiency (X-SCID) (Table 1) (80Noguchi M Yi H Rosenblatt H.M Filipovich A.H Adelstein S Modi W.S McBride O.W Leonard W.J Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans.Cell. 1993; 73: 147-157Abstract Full Text PDF PubMed Scopus (686) Google Scholar, 63Leonard W.J The molecular basis of X-linked severe combined immunodeficiency defective cytokine receptor signaling.Annu. Rev. Med. 1996; 47: 229-239Crossref PubMed Scopus (120) Google Scholar). The function of γc as a component of many cytokine receptors helps to explain the severity of this immunodeficiency. The intimate association of Jak3 and γc suggested that mutations of Jak3 itself might also cause SCID (88Russell S.M Johnston J.A Noguchi M Kawamura M Bacon C.M Friedmann M Berg M McVicar D.W Witthuhn B.A Silvennoinen O et al.Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3 implications for XSCID and XCID.Science. 1994; 266: 1042-1045Crossref PubMed Google Scholar), and patients with autosomal recessive SCID due to Jak3 mutations were subsequently identified (70Macchi P Villa A Gillani S Sacco M.G Frattini A Porta F Ugazio A.G Johnston J.A Candotti F O'Shea J.J et al.Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID).Nature. 1995; 377: 65-68Crossref PubMed Scopus (493) Google Scholar, 89Russell S.M Tayebi N Nakajima H Riedy M.C Roberts J.L Aman M.J Migone T.S Noguchi M Markert M.L Buckley R.H et al.Mutation of Jak3 in a patient with SCID essential role of Jak3 in lymphoid development.Science. 1995; 270: 797-800Crossref PubMed Google Scholar). Jak3 knockout mice have also been generated, and they too are immunodeficient (114Thomis D.C Gurniak C.B Tivol E Sharpe A.H Berg L.J Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3.Science. 1995; 270: 794-797Crossref PubMed Google Scholar, 81Nosaka T van Deursen J.M Tripp R.A Thierfelder W.E Witthuhn B.A McMickle A.P Doherty P.C Grosveld G.C Ihle J.N Defective lymphoid development in mice lacking Jak3.Science. 1995; 270: 800-802Crossref PubMed Google Scholar, 83Park S.Y Saijo K Takahashi T Osawa M Arase H Hirayama N Miyake K Nakauchi H Shirasawa T Saito T Developmental defects of lymphoid cells in Jak3 kinase-deficient mice.Immunity. 1995; 3: 771-782Abstract Full Text PDF PubMed Scopus (335) Google Scholar). Curiously, the phenotype of Jak3-deficiency differs in humans and mice. Whereas Jak3- and γc- deficient humans lack T cells but contain B cells (albeit dysfunctional B cells), Jak3- and γc-deficient mice (13Cao X Shores E.W Hu-Li J Anver M.R Kelsall B.L Russell S.M Drago J Noguchi M Grinberg A Bloom E.T et al.Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain.Immunity. 1995; 2: 223-238Abstract Full Text PDF PubMed Google Scholar, 24DiSanto J.P Muller W Guy-Grand D Fischer A Rajewsky K Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain.Proc. Natl. Acad. Sci. USA. 1995; 92: 377-381Crossref PubMed Scopus (578) Google Scholar) have a few functionally impaired T cells but lack B cells. Precisely why Jak3- and γc-deficiency blocks normal lymphocyte development is not completely understood, but may relate to absent IL-7 signaling. But why the difference between mice and humans? Perhaps there exist alternative receptors or cytokines that rescue B cell development in a species-specific manner. T cells that are produced in γc- and Jak3-deficient mice have an abnormal phenotype. They appear activated in their expression of high levels of CD44 and low levels of CD62L (113Thomis D.C Berg L.J Peripheral expression of Jak3 is required to maintain T lymphocyte function.J. Exp. Med. 1997; 185: 197-206Crossref PubMed Scopus (71) Google Scholar, 79Nakajima Hm Shores E.W Noguchi M Leonard W.J The common cytokine receptor γ chain plays an essential role in regulating lymphoid homeostasis.J. Exp. Med. 1997; 185: 189-196Crossref PubMed Scopus (132) Google Scholar, 92Saijo K Park S.Y Ishida Y Arase H Saito T Crucial role of Jak3 in negative selection of self-reactive T cells.J. Exp. Med. 1997; 185: 351-356Crossref PubMed Scopus (55) Google Scholar). In the case of Jak3-deficient mice, impaired negative selection in the thymus has been reported (92Saijo K Park S.Y Ishida Y Arase H Saito T Crucial role of Jak3 in negative selection of self-reactive T cells.J. Exp. Med. 1997; 185: 351-356Crossref PubMed Scopus (55) Google Scholar), suggesting that their abnormal T cell phenotype may reflect activation of autoreactive clones in the periphery. The phenotype of Jak3 deficiency may also be analogous to the lymphoid expansion seen IL-2Rα nullizygous mice. In addition, the phenotype of Jak3 deficiency may be unrelated to γc mediated signaling and may reflect a requirement for Jak3 functioning in other signaling pathways. For example, Jak2 has recently been shown to be involved CD40 signaling (35Hanissian S.H Geha R.S Jak3 is associated with CD40 and is critical for CD40 induction of gene expression in B cells.Immunity. 1997; 6: 379-387Abstract Full Text Full Text PDF PubMed Google Scholar). Despite the documented essential role of Jaks in cytokine signaling, only Jak3 knockout mice have been generated. However, the zebrafish Jak1 was recently cloned and was shown to play an important role in early vertebrate development (19Conway G Margoliath A Wong-Madden S Roberts R.J Gilbert W Jak1 kinase is required for cell migrations and anterior specification in zebrafish embryos.Proc. Natl. Acad. Sci. USA. 1997; 94: 3082-3087Crossref PubMed Scopus (39) Google Scholar). It was found to be maternally encoded, stored in unfertilized eggs, and expressed throughout the midblastula stage. Thereafter it rapidly disappears but is reexpressed later. The mRNA is evenly distributed among the cells of blastula-stage embryos, and injection of RNA encoding dominant-negative Jak1 kinases inhibited cell migration; reduced expression of goosecoid, a transcription factor that is expressed in dorsal mesoderm; and interfered with anterior structure formation. Another system that vividly demonstrates the importance of the Jaks in development is the analysis of the function of the Drosophila Jak (43Hou X.S Perrimon N The Jak-STAT pathway in Drosophila.Trends Genet. 1997; 13: 105-110Abstract Full Text PDF PubMed Scopus (49) Google Scholar). Termed Hopscotch (HOP), it is structurally remarkably similar to the mammalian Jaks. It is about 26% identical and 50% similar to Jak2; identity within the catalytic (JH1) domain is even greater. Mutation of the hop gene results in marked developmental abnormalities through both maternal and zygotic effects. Absence of maternal and zygotic hop results in severe segmentation defects, whereas embryos that have one copy of a paternally derived wild-type allele have less severe defects. Progeny from females homozygous for the weak hop allele, hopmsv1, have subtle segmentation defects. In embryos with mutation of hop, stripe-specific defects in the expression patterns of pair-rule genes (even-skipped, runt, and fushi tarazu) and segment-polarity genes (engrailed and wingless) occur (10Binari R Perrimon N Stripe-specific regulation of pair-rule genes by hopscotch, a putative Jak family tyrosine kinase in Drosophila.Genes Dev. 1994; 8: 300-312Crossref PubMed Google Scholar). These findings raise a number of important questions. For instance, how many Jaks do Drosophila have, or do they have just one? Are there separate Jak1, Jak2 and Tyk2 orthologs? If so, are they regulated by cytokines? Indeed, if flies have cytokines and Jaks, what about other organisms, such as Caenorhabditis elegans? Interestingly, a C. elegans Jak has been identified in the sequencing of the C. elegans genome. Clearly this is a very old pathway for cellular differentiation. In several circumstances, mutations of Jaks provide clear evidence that Jaks are essential for normal growth and development. But what about transformation? Can dysregulation of Jaks lead to cancer? Of great interest in this regard is that activating mutations of hop also have striking consequences. These mutations, known as Tum-l (tumorous lethal) mutations, result in leukemia in flies (36Hanratty W.P Dearolf C.R The Drosophila Tumorous-lethal hematopoietic oncogene is a dominant mutation in the hopscotch locus.Mol. Gen. 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This was first demonstrated in human T cell leukemia virus I–transformed T cells (75Migone T.S Lin J.X Cereseto A Mulloy J.C O'Shea J.J Franchini G Leonard W.J Constitutively activated Jak-STAT pathway in T cells transformed with HTLV-I.Science. 1995; 269: 79-81Crossref PubMed Google Scholar). Constitutive Jak activation has also been found in other settings, including Sezary's syndrome (131Zhang Q Nowack I Vonderheid E.C Rook A.H Kadin M.E Nowell P.C Shaw L.M Wasik M.A 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.Proc. Natl. Acad. Sci. 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Two examples are mutations of the thrombopoietin receptors (v-mpl) (103Souyri M Vigon I Penciolelli J.F Heard J.M Tambourin P Wendling F A putative truncated cytokine receptor gene transduced by the myeloproliferative leukemia virus immortalizes hematopoietic progenitors.Cell. 1990; 63: 1137-1147Abstract Full Text PDF PubMed Google Scholar) and erythropoietin receptors (67Longmore G.D Lodish H.F An activating mutation in the murine erythropoietin receptor induces erythroleukemia in mice a cytokine receptor superfamily oncogene.Cell. 1991; 67: 1089-1102Abstract Full Text PDF PubMed Google Scholar), both of which lead to constitutive dimerization of the receptors and, hence, constitutive Jak activation. A number important points regarding the Jaks remain incompletely understood. For instance, how does Jak structure related to its functions and how is Jak catalytic activity regulated? Phosphorylation of tyrosine residues that reside in the activation loop of tyrosine kinases typically positively regulate catalytic activity. For Tyk2 and Jak2, mutation of these tyrosines are known to inhibit Jak activity (30Gauzzi M.C Velazquez L McKendry R Mogensen K.E Fellous M Pellegrini S Interferon-alpha-dependent activation of Tyk2 requires phosphorylation of positive regulatory tyrosines by another kinase.J. Biol. Chem. 1996; 271: 20494-20500Crossref PubMed Scopus (104) Google Scholar, 26Feng 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; 17: 2497-2501Crossref PubMed Google Scholar).