Key points are not available for this paper at this time.
Janus (Jak) tyrosine kinases contain a tyrosine kinase (JH1) domain adjacent to a catalytically inactive pseudokinase domain (JH2). The JH2 domain has been implicated in regulation of Jak activity, but its function remains poorly understood. Here, we found that the JH2 domain negatively regulates the activity of Jak2 and Jak3. Deletion of JH2 resulted in increased tyrosine phosphorylation of the Jak2- and Jak3-JH2 deletion mutants as well as of coexpressed STAT5. In cytokine receptor signaling, the deletion of the Jak2- and Jak3-JH2 domains resulted in interferon-γ and interleukin-2-independent STAT activation, respectively. However, cytokine stimulations did not further induce the JH2 deletion mutant-mediated STAT activation. The deletion of the Jak2 JH2 domain also abolished interferon-γ-inducible kinase activation, although it did not affect the reciprocal Jak1-Jak2 interaction in 293T cells. Chimeric constructs, where the JH2 domains were swapped between Jak2 and Jak3, retained low basal activity and cytokine inducible signaling, indicating functional conservation between the two JH2 domains. However, the basal activity of Jak2 was significantly lower than that of Jak3, suggesting differences in the regulation of Jak2 and Jak3 activity. In conclusion, we found that the JH2 domain has a conserved function in Jak2 and Jak3. The JH2 domain is required for two distinct functions in cytokine signaling: (i) inhibition of the basal activity of Jak2 and Jak3, and (ii) cytokine-inducible activation of signaling. The Jak-JH2 deletion mutants are catalytically active, activate STAT5, and interact with another Jak kinase, but the JH2 domain is required to connect these signaling events to receptor activation. Thus, we propose that the JH2 domain contributes to both the uninduced and ligand-induced Jak-receptor complex, where it acts as a cytokine-inducible switch to regulate signal transduction. Janus (Jak) tyrosine kinases contain a tyrosine kinase (JH1) domain adjacent to a catalytically inactive pseudokinase domain (JH2). The JH2 domain has been implicated in regulation of Jak activity, but its function remains poorly understood. Here, we found that the JH2 domain negatively regulates the activity of Jak2 and Jak3. Deletion of JH2 resulted in increased tyrosine phosphorylation of the Jak2- and Jak3-JH2 deletion mutants as well as of coexpressed STAT5. In cytokine receptor signaling, the deletion of the Jak2- and Jak3-JH2 domains resulted in interferon-γ and interleukin-2-independent STAT activation, respectively. However, cytokine stimulations did not further induce the JH2 deletion mutant-mediated STAT activation. The deletion of the Jak2 JH2 domain also abolished interferon-γ-inducible kinase activation, although it did not affect the reciprocal Jak1-Jak2 interaction in 293T cells. Chimeric constructs, where the JH2 domains were swapped between Jak2 and Jak3, retained low basal activity and cytokine inducible signaling, indicating functional conservation between the two JH2 domains. However, the basal activity of Jak2 was significantly lower than that of Jak3, suggesting differences in the regulation of Jak2 and Jak3 activity. In conclusion, we found that the JH2 domain has a conserved function in Jak2 and Jak3. The JH2 domain is required for two distinct functions in cytokine signaling: (i) inhibition of the basal activity of Jak2 and Jak3, and (ii) cytokine-inducible activation of signaling. The Jak-JH2 deletion mutants are catalytically active, activate STAT5, and interact with another Jak kinase, but the JH2 domain is required to connect these signaling events to receptor activation. Thus, we propose that the JH2 domain contributes to both the uninduced and ligand-induced Jak-receptor complex, where it acts as a cytokine-inducible switch to regulate signal transduction. Janus (Jak) 1The abbreviations used are: Jak, Janus; IFN, interferon; IL, interleukin; JH, Jak homology region; PH, pleckstrin homology; HA, hemagglutinin; SCID, severe combined immunodeficiency; SH, Src homology; STAT, signal transducer and activator of transcription; KN, kinase negative tyrosine kinases are essential mediators of cytokine-induced signal transduction (1Ihle J.N. Witthuhn B.A. Quelle F.W. Yamamoto K. Silvennoinen O. Annu. Rev. Immunol. 1995; 13: 369-398Google Scholar). The Jak kinases bind to the cytoplasmic tails of receptors belonging to the hematopoietic receptor superfamily. Ligand-induced receptor aggregation results in tyrosine phosphorylation of Jak kinases and their substrate proteins, such as transcription factors called signal transducers and activators of transcription, STATs (2Darnell Jr., J.E. Kerr I.M. Stark G.R. Science. 1994; 264: 1415-1421Google Scholar, 3Horvath C.M. Darnell J.E. Curr. Opin. Cell Biol. 1997; 9: 233-239Google Scholar). Each Jak kinase specifically binds to only a subset of cytokine receptors. Jak2 associates with single chain receptors for erythropoietin, growth hormone and prolactin, type two cytokine receptors (IFNγRII, IL-10R), and the β chain of receptors for IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor (1Ihle J.N. Witthuhn B.A. Quelle F.W. Yamamoto K. Silvennoinen O. Annu. Rev. Immunol. 1995; 13: 369-398Google Scholar). Lack of Jak2 causes embryonic lethality in mice because of absence of definitive erythropoiesis, and these cells also fail to respond to interferon-γ (IFN-γ), IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor (4Neubauer H. Cumano A. Muller M. Wu H. Huffstadt U. Pfeffer K. Cell. 1998; 93: 397-409Google Scholar, 5Parganas E. Wang D. Stravopodis D. Topham D.J. Marine J.C. Teglund S. Vanin E.F. Bodner S. Colamonici O.R. van Deursen J.M. Grosveld G. Ihle J.N. Cell. 1998; 93: 385-395Google Scholar). On the other hand, Jak3 has been found as the only signaling molecule so far to associate with the common γ chain of IL-2, IL-4, IL-7, IL-9, and IL-15 receptors (6Leonard W.J. O'Shea J.J. Annu. Rev. Immunol. 1998; 16: 293-322Google Scholar). Lack of functional Jak3 results in severe combined immunodeficiency (SCID) with varying defects on T and B cells both in human and mice (7Macchi P. Villa A. Giliani S. Sacco M.G. Frattini A. Porta F. Ugazio A.G. Johnston J.A. Candotti F. O'Shea J.J. Vezzoni P. Notargangelo L.D. Nature. 1995; 377: 65-68Google Scholar, 8Russell 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. O'Shea J.J. Leonard W. Science. 1995; 270: 797-800Google Scholar, 9Nosaka 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. Science. 1995; 270: 800-802Google Scholar, 10Thomis D.C. Gurniak C.B. Tivol E. Sharpe A.H. Berg L.J. Science. 1995; 270: 794-797Google Scholar). The Jak kinases are characterized by the presence of seven regions of sequence similarity found between Jak kinases and designated as Jak homology domains A. A. A. Cell Biol. 1994; Scholar). is a catalytically tyrosine kinase domain in the of Jak kinases and to it is also called the pseudokinase The JH2 domain has conserved sequence found in but these are and the JH2 domain is catalytically the are conserved between the JH2 domains of Jak suggesting that the JH2 domain has function in Jak the of and a domain in the and regions of Jak Scholar, D. Scholar, U. S. A. Scholar, J.A. G. Scholar). The domain of Jak kinases to cytokine receptors F. D. D. Witthuhn B.A. S. Stark G.R. Ihle J.N. Kerr I.M. Cell. Biol. 1997; Scholar, G. G. M. S. Biol. 1998; Scholar, Migone T.S. F. M. Candotti F. O'Shea J.J. Johnston J.A. and the domains of and Jak2 been found to in of cytokine receptors L.J. Cell. Scholar, S. H. H. P.C. Biol. Scholar). The domain of Jak3 was also found to regulate kinase activity, such function has been to domain in Jak2 M.C. G. G. M. S. U. S. A. 1997; Scholar, Curr. Biol. 1997; Scholar, P. K. Silvennoinen O. Cell. Biol. Scholar, M. W. Roberts J.L. A. Buckley R.H. Candotti F. M. O'Shea J.J. Cell. Scholar). The function of the domain in Jak kinases is In cytokine Jak activation is ligand-induced aggregation of receptor the Jak kinases in a in the receptor cytoplasmic domains of a receptor and further of signal transduction. The activity of Jak kinases is by phosphorylation of tyrosine in the kinase activation by another Jak The in Jak kinases a conserved and the functional of these between of the tyrosine in the the activity of and but has a in Jak3 Curr. Biol. 1997; Scholar, Witthuhn B.A. T. F. Kerr I.M. Ihle J.N. Cell. Biol. 1997; Scholar, K. M. O'Shea J.J. U. S. A. 1997; Scholar). of the tyrosine in the the activity of Jak3, in Jak2 Curr. Biol. 1997; Scholar, Witthuhn B.A. T. F. Kerr I.M. Ihle J.N. Cell. Biol. 1997; Scholar, K. M. O'Shea J.J. U. S. A. 1997; Scholar). The tyrosine is also a for negative regulation of of cytokine signaling and bind to the activation of Jak2 to kinase activity, and in the of interaction has been to induce of Jak2 H. H. H. M. A. T. S. T. T. Ihle J.N. A. Scholar, A. H. A. S. T. M. Johnston J.A. A. Scholar, D. P. D.J. Silvennoinen O. Cell. Biol. Scholar). the and signaling by and specifically the tyrosine of Jak2 and J.N. A. M.L. C.M. A. D. Biol. Scholar). Jak3 and on the other hand, are negatively the T A. M.L. Curr. Biol. Scholar). catalytically the JH2 domain has been found to a of Jak found that JH2 is a negative domain in and deletion of JH2 to activation of Jak2 P. K. Silvennoinen O. Cell. Biol. Scholar). in the JH2 domain Jak kinase, has been found to kinase activity and in in the also a for JH2 in negative regulation of H. P. D. S. Roberts Cell. Biol. 1997; Scholar). On the other hand, in the Jak3-JH2 domain been found to the kinase, and in of signaling to F. Johnston J.A. Giliani S. P. M. Ugazio A.G. L.D. F. P. D. Vezzoni P. O'Shea J.J. Villa A. 1997; M. A. Candotti F. A. A. L.D. O'Shea J.J. Cell. Biol. Scholar). in the JH2 domain of been to with activity, and deletion of JH2 resulted in of the kinase G. M. G. S. Biol. 1995; 270: Scholar, E. G. S. U. S. A. Scholar). Thus, the JH2 domain has been found to regulate Jak activity the of the JH2 domain in it is not the JH2 domain has a conserved function in Jak activity the of the JH2 domain is distinct in In we the regulation of Jak2 and Jak3 to the function of the JH2 domain in cytokine signaling. results that the JH2 domain is required to low basal activity of both Jak2 and Jak3. the results that JH2 specifically cytokine Jak activation and cytokine-inducible activation of signaling. Chimeric constructs, where the JH2 domains are swapped between Jak2 and Jak3, low basal activity and cytokine-inducible signaling, indicating functional conservation of the two JH2 domains. In the absence of the Jak JH2 deletion mutants are catalytically active, activate STAT5, and interact with another Jak kinase, but are to respond to cytokine on these we propose that in to basal Jak activity in the uninduced Jak-receptor complex, the JH2 domain is of the receptor by required for cytokine of cells. and D. D. Muller M. Silvennoinen O. Witthuhn B.A. Quelle F.W. Stark G.R. Ihle J.N. Kerr I.M. Nature. were in with and The cells were the to the of on the were used to of 293T and of was used for of a well of cells. The of was a single to of the by The cells were with The cells were for and for The were and and a Ihle O. Witthuhn B.A. Quelle F.W. J.L. T. Ihle J.N. U. S. A. Scholar, B.A. Silvennoinen O. O. Ihle J.N. Nature. 1994; Scholar). The by the Jak2 and Jak3 are in and the to Jak2 and Jak3 for and been and contain the in their P. K. Silvennoinen O. Cell. Biol. Scholar). The Jak3 was for a was to the of Jak3 T. A. H. Silvennoinen O. Witthuhn B.A. Ihle J.N. T. Science. 1994; Scholar). Jak2 and Jak3 were and the were by Jak3 to and and were a deletion and a respectively. was a with in the between the kinase and pseudokinase domains. of the domains was the F. P. U. S. A. 1998; Scholar). were by for and the the the of the were D. G. Biol. 1994; Scholar). the the of the was a A. 1994; 13: of the Jak2 the JH2 domain of Jak3. the Jak2 for the Jak2 kinase Jak2 where the JH2 domain has been and the JH2 domain of Jak3 are and are to the Jak2 and Jak3 The a in the for and were 293T cells and were The were in and in and Cell were in and by with 293T cells were with with for and was and of the were in by and of were in by The of the are on the of the Jak3 the JH2 domain of the Jak3 for the Jak3 kinase Jak3 where the JH2 domain has been and the JH2 domain of Jak2 are and are to the Jak3 and Jak2 The a in the Jak3, and were cells and were The were in and were in and Cell were in and by with cells were with with Jak3, and was and of the were in by and of were in by The of the are on the were in kinase with and the were used for for The has been P. N. K. P. K. Silvennoinen O. 1997; Scholar). The were to used for kinase kinase the were with kinase and with kinase The were in kinase The were used as of was to the by a and in The were in by of of were used for and of were the was and by activity was to the The activity was to the activity of the the of the domains in regulation of Jak2 and found that the pseudokinase negatively regulates the activity of Jak2 P. K. Silvennoinen O. Cell. Biol. Scholar). the JH2 domain is conserved the Jak we to the function of the JH2 domain also in other Jak In we to the JH2 domains regulate Jak kinases domain distinct functions in Jak the by the of and Jak3. and Jak3 kinases were in 293T cells and the Jak were The were to in to the tyrosine in the kinase activation of and Jak3 and the tyrosine phosphorylation in Curr. Biol. 1997; Scholar, Witthuhn B.A. T. F. Kerr I.M. Ihle J.N. Cell. Biol. 1997; K. M. O'Shea J.J. U. S. A. 1997; Scholar, F. H. M. 1994; 13: Scholar). The activity of Jak2 of the substrate was low with the of Jak3 although Jak2 was than Jak3 The of Jak3 was and to the but Jak3 the lower of tyrosine phosphorylation of Jak3 was to that of indicating that Jak3 was a than Jak2 of tyrosine phosphorylation than and Jak3 differences in phosphorylation of the substrate The was the substrate for Jak3 for the of and Jak3 kinases The results the kinase that the activity of Jak2 was lower than the activity of Jak3. two for The in kinase activity because of of the tyrosine kinase domains. but not the kinase domains by other such as the pseudokinase in Jak the of the tyrosine kinase and to the of Jak2 and Jak3, the in the kinase for the tyrosine kinase domain of Jak3, and P. K. Silvennoinen O. Cell. Biol. was in 293T cells. The domains were and to in kinase with as a substrate to with lower of both kinase activity and of tyrosine phosphorylation than indicating that the tyrosine kinase domain of Jak3 was than that of found that deletion of JH2 resulted in activation of the pseudokinase regulation of Jak2 and Jak3, we deletion a Jak3 the pseudokinase for the kinase and for the tyrosine kinase domain of Jak3 Jak3, and were in Jak3 were and the were by The in the as well as in the were found to the pseudokinase as well as increased tyrosine phosphorylation with Jak3 B However, the presence of the pseudokinase domain in resulted in phosphorylation with Jak3 that the pseudokinase domain to tyrosine phosphorylation of Jak3. the JH2 domain also signaling by Jak3, we the Jak3 deletion mutants with The of the Jak3 kinases to tyrosine phosphorylation of was by with Jak3, as well as increased tyrosine phosphorylation of The on the other hand, resulted in phosphorylation with Jak3 Thus, the JH2 domain also the of Jak3 to activate STAT5. the in tyrosine phosphorylation of the Jak3 mutants JH2 with their in activity. Jak3 and the Jak3 deletion constructs, and were in and the Jak3 were in in kinase as a substrate a the tyrosine of Jak3 with of the Jak3 kinases in and with Jak3 phosphorylation of the substrate in kinase activity was with the with Jak3 the activity of was increased with Jak3. However, the activity of was than of the activity of indicating that the presence of JH2 the activity of The lower activity of with Jak3 is in with the results that the domain regulates Jak3 M. W. Roberts J.L. A. Buckley R.H. Candotti F. M. O'Shea J.J. Cell. Scholar). In the results that Jak3 is negatively by its pseudokinase The pseudokinase negative regulation of Jak3 to results with However, deletion of JH2 increased the kinase activity of Jak3 only we found a in kinase activity of Jak2 deletion of the JH2 Thus, we the that the JH2 domain of Jak3 was not as in Jak activity as and to the pseudokinase domains of Jak2 and Jak3 are where the JH2 domain of Jak2 was by that of Jak3 and where the JH2 domain of Jak3 was by that of Jak2 the and constructs, respectively. the tyrosine kinase domains and the adjacent regions between the kinase and pseudokinase domains. the pseudokinase domain of Jak3 was to the pseudokinase domain of the was a we both Jak2 and a Jak2 kinase the pseudokinase domain P. K. Silvennoinen O. Cell. Biol. Scholar). The Jak2 were and by significantly increased tyrosine phosphorylation with tyrosine phosphorylation of was to Jak2 also the signaling of the by it with STAT5. and Jak2 significantly increased tyrosine phosphorylation of Thus, the pseudokinase domain of Jak3 was to type function in suggesting that it was to the pseudokinase domain of the function of the in the of Jak3 was by the a we type Jak3 phosphorylation of was found to to Jak3, significantly increased tyrosine phosphorylation The of to induce signaling was by it with STAT5. The results that and Jak3 increased phosphorylation Thus, the pseudokinase domain of Jak2 was to Jak3 function in the to the function of the pseudokinase domain of Jak3 in cytokine receptor signaling, where activation of Jak3 is on cytokine-induced receptor to the where Jak3 is essential kinase for signaling. receptor in Jak3, by β and γ of the receptor with and the Jak3 kinase of was by in did not induce signaling in the absence of Jak3, that also in the signaling the receptor was on Jak3. of cells with resulted in a in activity In of resulted in increased activation in the absence of IL-2, and activity did not was to induce activation although not to the of type Jak3. Thus, the results the receptor also a for JH2 in inhibition of the basal activity of Jak3. the JH2 domain was essential for inducible activation of STAT5. function was in the Jak3 the JH2 domain of although not to the of Jak3. the function of the Jak3 pseudokinase domain in Jak2 in signaling, we with a in a Jak2 negative found that of in cells results in activation of P. K. Silvennoinen O. Cell. Biol. Scholar). of Jak2 on activation, but of the cells with resulted in activation significantly activation of in the absence of and activity was not further increased by The as type Jak2 low basal activity and activation in to Thus, the JH2 domain of Jak3 was to type regulation of Jak2 in signaling, functional similarity between the JH2 domains of Jak2 and Jak3. In results that a functional pseudokinase domain is required for of the basal activity of Jak2 and Jak3 the pseudokinase domain is required to to respond to cytokine with of STAT activation. the of JH2 on cytokine-induced Jak activation. Jak2 and were in and activation of the Jak2 kinases was by phosphorylation of Jak2 was was to the tyrosine phosphorylation of Jak2 and were to the in tyrosine phosphorylation of was found to than that of Thus, the JH2 domain was required for inhibition of basal Jak2 activity and for activation of the of of Jak2 activity, we the JH2 domain was required for the reciprocal interaction and activation of and Jak2 coexpressed kinase inactive of Jak2 and with type The kinase inactive Jak2 were and their tyrosine phosphorylation was was found to the and The tyrosine phosphorylation of the Jak2 was with Jak2 because of inhibition of activity by Jak2 Thus, both kinase negative Jak2 proteins, and the Jak1-Jak2 interaction not the JH2 However, in Jak receptor inducible Jak activation is in the absence of suggesting that the JH2 domain contributes to signaling in the The Jak kinases a distinct of cytoplasmic tyrosine kinases characterized by the kinase domain the of the Jak kinases the function of the inactive kinase domain has been a of that the JH2 domain is in regulation of the Jak the the JH2 domains regulate Jak kinases the JH2 domains distinct functions in Jak kinases P. K. Silvennoinen O. Cell. Biol. Scholar, M. A. Candotti F. A. A. L.D. O'Shea J.J. Cell. Biol. Scholar, E. G. S. U. S. A. Scholar). the of the regulation In we found that the function of the JH2 domain to a conserved between Jak2 and Jak3. In we that the JH2 domain has a in cytokine of cells and propose a function for the JH2 domain in Jak-receptor Deletion of JH2 was found to tyrosine phosphorylation of Jak3 and in activation of STAT5, a negative for the JH2 domain in Jak3. are in with results regulation of Jak2 P. K. Silvennoinen O. Cell. Biol. and regulation of Jak2 and Jak3 by their JH2 domains. a Jak2 kinase the JH2 domain of Jak3 as type indicating that the Jak3-JH2 domain was in function to the JH2 domain of increased basal activity, the Jak2- and Jak3-JH2 deletion mutants were to cytokine and to further STAT activation respectively. results that the JH2 domain is in a to regulate Jak activity in to cytokine both by basal activity of in the absence of cytokine and by increased activity cytokine has been for the regulation of the tyrosine Deletion of the pleckstrin homology domain resulted in increased activation of indicating that the domain kinase activity K. Biol. Scholar). of to the domain increased activity, suggesting that However, the domain was to signal B receptor K. Biol. Scholar). results that although JH2 was essential for cytokine-inducible activation of signaling, JH2 was not required for kinase activity of Jak3 Jak2 as because Jak kinases JH2 retained activity. deletion in the JH2 domains of Jak3 and been found to cytokine signaling, because of of kinase activity of these kinases M. A. Candotti F. A. A. L.D. O'Shea J.J. Cell. Biol. Scholar, G. M. G. S. Biol. 1995; 270: Scholar, E. G. S. U. S. A. Scholar). results in to the function of the JH2 domain in Jak is that the JH2 domain is to the function of the tyrosine kinase Thus, and differences in the JH2 regions to Jak mutants with and in the JH2 domain not the Here, Jak2 and Jak3 we been to activity of these Thus, results a function for the JH2 by the of kinase activity of the deletion JH2 the basal activity of Jak2 was lower than that of Jak3, indicating that the two kinases are results that the domains is in with the of in results also the that the deletion of JH2 distinct in because of activation of the domains. the JH2 domain has been to the kinase domain interaction by of and to the in the absence of cytokine P. K. Silvennoinen O. Cell. Biol. Scholar, M. A. Candotti F. A. A. L.D. O'Shea J.J. Cell. Biol. Scholar). to of and results that in cytokine receptor signaling the activation of as well as STATs the JH2 results that (i) the Jak JH2 deletion mutants were catalytically active, (ii) were to activate and interact with other and the results other that JH2 is not required for to cytokine that are to interact with of the signaling in the absence of but the JH2 domain is required to connect cytokine receptor activation to Jak activation and of signaling. Thus, the functions of JH2 are in the of the Jak-receptor of negative regulation by the JH2 deletion for of proteins, is for the of cytokine However, the low activity of in the receptor is to in of further signaling by the JH2 domain required for the domain to its However, the Jak2 domain is with for the JH2 for cytokine-inducible signaling that the JH2 domain has in Jak-receptor signaling by to the of the of the receptor cytokine In the JH2 interaction with but ligand-induced in the receptor between JH2 and other domains in the receptor been found to essential of cytokine receptors. been found to interact with the receptor in interaction required for of cytokine receptors and for of a Jak kinase to its and the other required for Jak activation L.J. Cell. Scholar, S. H. H. P.C. Biol. Scholar). receptor required for activation of were that are not in the of to the receptor L.J. Cell. Scholar, L.J. H. Cell. Scholar, P.C. Scholar). that the cytoplasmic domain of the receptor a to Jak activation L.J. H. Cell. Scholar, P.C. Biol. Scholar). activation of Jak2 by a in the is to interact with the of Jak2 L.J. Cell. Scholar, L.J. H. Cell. Scholar). and on the of JH2 in of Jak activity cytokine that cytokine-induced in the of the receptor are required for of signal transduction. the JH2 domains functions in Jak2 and Jak3, the JH2 domains in signaling the and receptors. Deletion of JH2 resulted in STAT activation, but activation was lower in signaling than in signaling. the Jak2 and Jak3 inducible STAT activation by and IL-2, but the as type Jak2 in signaling, the was not as in STAT activation by as type Jak3. On the other hand, in a the Jak3 as type Jak3. results that the JH2 domain was for signaling the receptor than the and that the JH2 domain of Jak3 a in the by the JH2 domain of In with in JH2 resulted in tyrosine phosphorylation of Jak3, but of Jak3 to signaling the receptor F. Johnston J.A. Giliani S. P. M. Ugazio A.G. L.D. F. P. D. Vezzoni P. O'Shea J.J. Villa A. 1997; M. A. Candotti F. A. A. L.D. O'Shea J.J. Cell. Biol. Scholar). The JH2 domains were found to of the domain than the type JH2 the of signaling by the not contain the of inducible signaling in is not because of increased inhibition by Thus, results on the of the JH2 domain in basal as well as Jak3 activation for the of JH2 in Jak3, to in the by the of the JH2 The Jak3 mutants were of signaling, although a with type Jak3 F. Johnston J.A. Giliani S. P. M. Ugazio A.G. L.D. F. P. D. Vezzoni P. O'Shea J.J. Villa A. 1997; Scholar). the of Jak3 JH2 is in the receptor and in signaling, where STAT activation also in the absence of Jak3 Candotti F. Johnston J.A. J.J. N. L.D. W.E. O'Shea J.J. Scholar). results that JH2 with other domains in receptor to regulate cytokine and it is that these are the distinct functions of JH2 domains in cytokine receptors. The that Jak3 for Jak the was a substrate for a for signaling, where Jak3 STAT5. However, Jak3 functional JH2 is to in activation of signaling, the of JH2 in signaling. In with has been found to a substrate for than for Jak3 Curr. Biol. 1997; Scholar). deletion of JH2 abolished Jak2 activation, indicating that the reciprocal activation of was JH2 In signaling, Jak2 the kinase, for activation of and activation by activation of Jak2 JH2 is by results indicating that by in the absence of type Jak2 in signaling. and O. In conclusion, results that the JH2 domain has a conserved function in Jak2 and Jak3 by both basal as well as inducible Jak activity in Jak-receptor The JH2 domain as inducible switch in Jak kinases of signal transduction in to cytokine regulation interaction of the JH2 domain with other in Jak-receptor to but the domain in cytokine receptors is interaction L.J. H. Cell. Scholar). of the interaction essential for cytokine signaling for of a for cytokine-induced Jak signaling. and N. Ihle for the and for on the
Saharinen et al. (Thu,) studied this question.