JAK1 and Tyk2 Activation by the Homologous Polycythemia Vera JAK2 V617F Mutation

Abstract

The majority of polycythemia vera (PV) patients harbor a unique somatic mutation (V617F) in the pseudokinase domain of JAK2, which leads to constitutive signaling. Here we show that the homologous mutations in JAK1 (V658F) and in Tyk2 (V678F) lead to constitutive activation of these kinases. Their expression induces autonomous growth of cytokine-dependent cells and constitutive activation of STAT5, STAT3, mitogen-activated protein kinase, and Akt signaling in Ba/F3 cells. The mutant JAKs exhibit constitutive signaling also when expressed in fibrosarcoma cells deficient in JAK proteins. Expression of the JAK2 V617F mutant renders Ba/F3 cells hypersensitive to insulin-like growth factor 1 (IGF1), which is a hallmark of PV erythroid progenitors. Upon selection of Ba/F3 cells for autonomous growth induced by the JAK2 V617F mutant, cells respond to IGF1 by activating STAT5, STAT3, Erk1/2, and Akt on top of the constitutive activation characteristic of autonomous cells. The synergic effect on proliferation and STAT activation appears specific to the JAK2 V617F mutant. Our results show that the homologous V617F mutation induces activation of JAK1 and Tyk2, suggesting a common mechanism of activation for the JAK1, JAK2, and Tyk2 mutants. JAK3 is not activated by the homologous mutation M592F, despite the presence of the conserved GVC preceding sequence. We suggest that mutations in the JAK1 and Tyk2 genes may be identified as initial molecular defects in human cancers and autoimmune diseases. The majority of polycythemia vera (PV) patients harbor a unique somatic mutation (V617F) in the pseudokinase domain of JAK2, which leads to constitutive signaling. Here we show that the homologous mutations in JAK1 (V658F) and in Tyk2 (V678F) lead to constitutive activation of these kinases. Their expression induces autonomous growth of cytokine-dependent cells and constitutive activation of STAT5, STAT3, mitogen-activated protein kinase, and Akt signaling in Ba/F3 cells. The mutant JAKs exhibit constitutive signaling also when expressed in fibrosarcoma cells deficient in JAK proteins. Expression of the JAK2 V617F mutant renders Ba/F3 cells hypersensitive to insulin-like growth factor 1 (IGF1), which is a hallmark of PV erythroid progenitors. Upon selection of Ba/F3 cells for autonomous growth induced by the JAK2 V617F mutant, cells respond to IGF1 by activating STAT5, STAT3, Erk1/2, and Akt on top of the constitutive activation characteristic of autonomous cells. The synergic effect on proliferation and STAT activation appears specific to the JAK2 V617F mutant. Our results show that the homologous V617F mutation induces activation of JAK1 and Tyk2, suggesting a common mechanism of activation for the JAK1, JAK2, and Tyk2 mutants. JAK3 is not activated by the homologous mutation M592F, despite the presence of the conserved GVC preceding sequence. We suggest that mutations in the JAK1 and Tyk2 genes may be identified as initial molecular defects in human cancers and autoimmune diseases. We and others (1James C. Ugo V. Le Couedic J.P. Staerk J. Delhommeau F. Lacout C. Garcon L. Raslova H. Berger R. Bennaceur-Griscelli A. Villeval J.L. Constantinescu S.N. Casadevall N. Vainchenker W. Nature. 2005; 434: 1144-1148Crossref PubMed Scopus (2917) Google Scholar, 2Baxter E.J. Scott L.M. Campbell P.J. East C. Fourouclas N. Swanton S. Vassiliou G.S. Bench A.J. Boyd E.M. Curtin N. Scott M.A. Erber W.N. Green A.R. Lancet. 2005; 365: 1054-1061Abstract Full Text Full Text PDF PubMed Scopus (2300) Google Scholar, 3Levine R.L. Wadleigh M. Cools J. Ebert B.L. Wernig G. Huntly B.J. Boggon T.J. Wlodarska I. Clark J.J. Moore S. Adelsperger J. Koo S. Lee J.C. Gabriel S. Mercher T. D'Andrea A. Frohling S. Dohner K. Marynen P. Vandenberghe P. Mesa R.A. Tefferi A. Griffin J.D. Eck M.J. Sellers W.R. Meyerson M. Golub T.R. Lee S.J. Gilliland D.G. Cancer Cell. 2005; 7: 387-397Abstract Full Text Full Text PDF PubMed Scopus (2462) Google Scholar, 4Kralovics R. Passamonti F. Buser A.S. Teo S.S. Tiedt R. Passweg J.R. Tichelli A. Cazzola M. Skoda R.C. N. Engl. J. Med. 2005; 352: 1779-1790Crossref PubMed Scopus (2972) Google Scholar, 5Zhao R. Xing S. Li Z. Fu X. Li Q. Krantz S.B. Zhao Z.J. J. Biol. Chem. 2005; 280: 22788-22792Abstract Full Text Full Text PDF PubMed Scopus (554) Google Scholar) have recently reported that the majority of polycythemia vera (PV) 6The abbreviations used are: PVpolycythemia veraETessential thrombocythemiaIMFidiopathic myelofibrosisJAKJanus kinaseJHJAK homologywtwild typeGFPgreen fluorescent proteinSTATsignal transducers and activators of transcriptionILinterleukinTBSTris-buffered saline. patients harbor a unique somatic mutation in the pseudokinase domain of JAK2 (V617F), which constitutively activates signaling. Approximately 25–30% of patients with essential thrombocythemia (ET) and 50% of patients with idiopathic myelofibrosis (IMF) had this mutation also, while healthy people or patients with secondary erythrocytosis did not. The mutation is somatic and may become a key molecular marker for hematological diseases (6Vainchenker W. Constantinescu S.N. Hematology (Am. Soc. Hematol. Educ. Program). 2005; (in press)PubMed Google Scholar). Overall, the prevalence of the JAK2 V617F mutation as found by six different studies was between 66 and 85% in PV, 25% in ET, and 50% in IMF (7Zhao Z.J. Krantz S.B. Vainchenker W. Casadevall N. Constantinescu S.N. Semin. Hematol. 2005; 42: 221-229Crossref PubMed Scopus (23) Google Scholar). polycythemia vera essential thrombocythemia idiopathic myelofibrosis Janus kinase JAK homology wild type green fluorescent protein signal transducers and activators of transcription interleukin Tris-buffered saline. There are four Janus kinases (JAKs) in mammals, JAK1, JAK2, JAK3, and Tyk2 that transduce signals for over 25 cytokines, which regulate blood formation and the immune response (8Yamaoka K. Saharinen P. Pesu M. Holt 3rd, V.E. Silvennoinen O. O'Shea J.J. Genome Biol. 2004; 5: 253Crossref PubMed Scopus (449) Google Scholar). JAKs share an architecture that contains a kinase (JAK homology 1, JH1) domain at the carboxyl terminus, preceded by a pseudokinase, JAK homology 2 (JH2) domain, and an amino terminus comprising a FERM domain (protein 4.1, ezrin, moezin, radixin homologous) and an SH2 domain (8Yamaoka K. Saharinen P. Pesu M. Holt 3rd, V.E. Silvennoinen O. O'Shea J.J. Genome Biol. 2004; 5: 253Crossref PubMed Scopus (449) Google Scholar). Exactly how JH2 regulates the activity of JAKs is not clear, although JAKs require intact JH2 domains for activation via ligand-activated cytokine receptors. Work on Drosophila JAK identified a point mutant E695K in the JH2 pseudokinase domain, which constitutively activates the enzyme and leads to lympho-hemato-proliferation (9Luo H. Rose P. Barber D. Hanratty W.P. Lee S. Roberts T.M. D'Andrea A.D. Dearolf C.R. Mol. Cell. Biol. 1997; 17: 1562-1571Crossref PubMed Scopus (212) Google Scholar). The homologous E665K mutation in JAK2 also leads to constitutive activation of the enzyme (9Luo H. Rose P. Barber D. Hanratty W.P. Lee S. Roberts T.M. D'Andrea A.D. Dearolf C.R. Mol. Cell. Biol. 1997; 17: 1562-1571Crossref PubMed Scopus (212) Google Scholar), while it had no effect in JAK3 (10Chen M. Cheng A. Candotti F. Zhou Y.J. Hymel A. Fasth A. Notarangelo L.D. O'Shea J.J. Mol. Cell. Biol. 2000; 20: 947-956Crossref PubMed Scopus (111) Google Scholar). Moreover, it has been shown that the kinase activity of JH1 is inhibited when appended to JH2 (11Saharinen P. Takaluoma K. Silvennoinen O. Mol. Cell. Biol. 2000; 20: 3387-3395Crossref PubMed Scopus (284) Google Scholar). These results strongly suggest that one role of the JH2 domain, at least in JAK2, is to keep the kinase domain inactive in the absence of cytokines. Furthermore, upon phosphorylation, Tyr570 in the JH2 domain of JAK2 negatively regulates activity (12Feener E.P. Rosario F. Z. Mol. Cell. Biol. 2004; PubMed Scopus Google Scholar, J.L. H. A. C. Mol. Cell. Biol. 2004; PubMed Scopus (111) Google Scholar). is in to as the J.L. H. A. C. Mol. Cell. Biol. 2004; PubMed Scopus (111) Google Scholar), Zhou Y.J. J.L. O'Shea J.J. C. Mol. Cell. Biol. 2004; PubMed Scopus Google Scholar) of the activation which is for activation J. T. F. Mol. Cell. Biol. 1997; 17: PubMed Scopus Google Scholar). JH2 domains shown to be for the activity of JAK3 (10Chen M. Cheng A. Candotti F. Zhou Y.J. Hymel A. Fasth A. Notarangelo L.D. O'Shea J.J. Mol. Cell. Biol. 2000; 20: 947-956Crossref PubMed Scopus (111) Google Scholar) and of Tyk2 L. G. M. G. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, G. S. S. A. 2000; PubMed Scopus Google Scholar). a role for JH2 domains in the and of JAK and cytokine the at is conserved in JAK1 and Tyk2, while in JAK3 it is by a We the of a homologous mutation in activation of JAK1 and Tyk2 and a mutation Here we show that the homologous mutations for JAK1 and for Tyk2 lead to constitutive activation of these kinases. The homologous mutation in JAK3 not lead to activation of JAK3, that JAK3 is different the We also show that the mutant JAK2 with IGF1 to proliferation of Ba/F3 cells and activation of and on top of the constitutive induced by the JAK2 mutant. to IGF1 is one characteristic of PV erythroid D. PubMed Google Scholar, PubMed Google Scholar, S. 1997; PubMed Google Scholar), we how this JAK2 may and role this in the of diseases. of the JAK for the human Tyk2 with the at the carboxyl terminus L. R. M. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) was by for the human Tyk2, human JAK3, and JAK1 the in the or X. Constantinescu S.N. D. R.A. 2000; 280: PubMed Scopus Google Scholar, N. Staerk J. V. S. Constantinescu S.N. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar) and by The human JAK2 V617F mutant was (1James C. Ugo V. Le Couedic J.P. Staerk J. Delhommeau F. Lacout C. Garcon L. Raslova H. Berger R. Bennaceur-Griscelli A. Villeval J.L. Constantinescu S.N. Casadevall N. Vainchenker W. Nature. 2005; 434: 1144-1148Crossref PubMed Scopus (2917) Google Scholar). and human fibrosarcoma cells M. J. C. D. A. Silvennoinen O. G. C. S. Nature. PubMed Scopus Google Scholar) a of Cancer and The The human fibrosarcoma cells S. J. M. Mol. Cell. Biol. PubMed Scopus Google Scholar, L. M. S. Cell. Full Text PDF PubMed Scopus Google Scholar) a of Ba/F3 cells are cells. type or mutant JAK1, JAK3, or Tyk2 the cells to as N. Staerk J. V. S. Constantinescu S.N. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). Ba/F3 cells and or cells Ba/F3 cells in with and and cells in and in the absence of for growth or in the presence of a was a of and while and IGF1 activity of signal and of transcription was by expression in cells with the a that to STAT5, STAT3, and L. D. J.C. S. A. 2000; PubMed Scopus Google a that to S. W. A. D. J. J. Google Scholar) or the which to A. S. N. J. PubMed Scopus Google Scholar), as N. Staerk J. V. S. Constantinescu S.N. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). activity induced by upon JAK1 activation was in cells that with the with for JAK to be and of the activity induced by upon Tyk2 activation was in cells that with the for with the the for the JAK to be and for the as (1James C. Ugo V. Le Couedic J.P. Staerk J. Delhommeau F. Lacout C. Garcon L. Raslova H. Berger R. Bennaceur-Griscelli A. Villeval J.L. Constantinescu S.N. Casadevall N. Vainchenker W. Nature. 2005; 434: 1144-1148Crossref PubMed Scopus (2917) Google Scholar). activity of and in Ba/F3 cells mutant JAK was by the STAT cells in to and and for in in The cells and to cells of for JAK the Ba/F3 Ba/F3 cells for wild type JAK or mutant JAK expression and cells for growth to the expression of the mutant in of 1 and with IGF1 or for or or the cells and the in of a by on by the of cells and to the in was by in the with in the by the of in the with secondary in of was and on of signaling was by and with the JAK2, JAK1, Tyk2, STAT5, STAT3, Erk1/2, and to protein of STAT5, STAT3, and also the of an was protein of JAK2 and Tyk2, we used the and the for JAK1 we used the and for JAK3 we used of JAK2 and are four JAK1, JAK2, Tyk2, and JAK3 (8Yamaoka K. Saharinen P. Pesu M. Holt 3rd, V.E. Silvennoinen O. O'Shea J.J. Genome Biol. 2004; 5: 253Crossref PubMed Scopus (449) Google Scholar). We the protein for the Janus kinases and that the JAK2 is conserved in JAK1 and Tyk2 and is by in JAK3 The preceding is conserved in four Janus kinases. on the of the growth factor kinase domain M. J. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar), these are to be of a while is to be of a M. J. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, K. T. PubMed Scopus Google Scholar). we (1James C. Ugo V. Le Couedic J.P. Staerk J. Delhommeau F. Lacout C. Garcon L. Raslova H. Berger R. Bennaceur-Griscelli A. Villeval J.L. Constantinescu S.N. Casadevall N. Vainchenker W. Nature. 2005; 434: 1144-1148Crossref PubMed Scopus (2917) Google Scholar, W. Constantinescu S.N. Hematology (Am. Soc. Hematol. Educ. Program). 2005; (in press)PubMed Google Scholar), the V617F mutation may the activity of the pseudokinase JH2 domain on the kinase JH1 domain, by an activated of the activation of JAK1 and Tyk2 in Ba/F3 the of a at the homologous of JAK2 the activity of we JAK1 Tyk2 and JAK3 and in as N. Staerk J. V. S. Constantinescu S.N. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). that the mutant JAK1 is constitutively as shown by to Ba/F3 cells autonomous for the the of growth by Ba/F3 cells the JAK2 V617F or the Tyk2 is is that mutant JAKs are constitutively is to the is in by different for type of JAK of wild type and mutant as shown by with to JAK protein and Ba/F3 cells for expression of wild type and JAK1 and Tyk2 are constitutively and proliferation in Ba/F3 between the and the JAK1 mutant. Ba/F3 cells for the expression of the wild type JAK1 or JAK1 mutant at in the absence of or with or as are of with activation of of JAK1, STAT5, STAT3, Erk1/2, and Akt in Ba/F3 in cells for expression of the wild type JAK1 or of the mutant JAK1 and in cells for autonomous growth induced by the JAK1 mutant. of signaling was by with the while protein the signaling and between the and the Tyk2 mutant. Ba/F3 cells for expression of of wild type Tyk2 or the Tyk2 mutant in the absence of or with are of with activation of of Tyk2, STAT5, STAT3, Erk1/2, and Akt in Ba/F3 in cells for expression of the wild type Tyk2 or of the mutant Tyk2 and in cells for autonomous growth induced by the Tyk2 mutant. of signaling was by with the while protein the the signaling and to the Tyk2 the Tyk2 in Ba/F3 also that the JAK3 mutant is not constitutively although this mutant is expressed and signaling the wild type JAK3 not JAK1 and Tyk2 are activated by the homologous V617F while JAK3 is not. results reported for JH2 mutation in Drosophila JAK and E665K in which had no effect in JAK3 (9Luo H. Rose P. Barber D. Hanratty W.P. Lee S. Roberts T.M. D'Andrea A.D. Dearolf C.R. Mol. Cell. Biol. 1997; 17: 1562-1571Crossref PubMed Scopus (212) Google Scholar). and of STAT by the JAK1 and we the activity induced by the mutant JAKs via the JAK1 mutant we used cells M. J. C. D. A. Silvennoinen O. G. C. S. Nature. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar), the S. W. A. D. J. J. Google Scholar) was with with the for wild type or mutant JAK1 or with the for the of the the the common and JAK3, which are to signaling in these cells. that expression of JAK1 leads to constitutive the of the of the activity of in cells with the wild type JAK1, while no was for the mutant JAK1, the was by the We also the activation of and activity by the Tyk2 mutant. We used Ba/F3 cells for expression of the mutant Tyk2 or cells that for autonomous shown in activation of STAT signaling be in the and the cells when the a that to STAT5, STAT3, and L. D. J.C. S. A. 2000; PubMed Scopus Google Scholar) was results when the was which to A. S. N. J. PubMed Scopus Google Scholar) not We also signaling by the mutant Tyk2 in cells deficient in Tyk2, the fibrosarcoma cells S. J. M. Mol. Cell. Biol. PubMed Scopus Google Scholar, L. M. S. Cell. Full Text PDF PubMed Scopus Google Scholar). signaling the activated JAK2, Tyk2 also transduce the signal in the absence of cells is not JAK2 activity to signaling not activation of was the which to S. W. A. D. J. J. Google Scholar), we that the Tyk2 mutant is constitutively in cells and that of this activity that the mutant Tyk2 the wild type Tyk2 and be appended to the domain, as the cells are deficient for with have a of PV to IGF1 D. PubMed Google Scholar, PubMed Google Scholar, S. 1997; PubMed Google Scholar). to growth one of the of PV, with the or hypersensitive erythroid formation and of the in and A.R. J.L. N. Engl. J. Med. PubMed Scopus Google Scholar, A.R. J.L. PubMed Google Scholar). Our is that the JAK2 V617F mutant is for of PV (6Vainchenker W. Constantinescu S.N. Hematology (Am. Soc. Hematol. Educ. Program). 2005; (in press)PubMed Google Scholar, Z.J. Krantz S.B. Vainchenker W. Casadevall N. Constantinescu S.N. Semin. Hematol. 2005; 42: 221-229Crossref PubMed Scopus (23) Google Scholar). We the response of Ba/F3 cells and of Ba/F3 cells for expression of JAK2 and the mutant JAK2 shown in these Ba/F3 cells expressed of JAK2 that the These cells in and not to selection for which of in the absence of we show that when cells with the JAK2 V617F cells with a in wild type JAK2 a response at of and Ba/F3 cells a response at The response of Ba/F3 JAK2 V617F cells to IGF1 was and did not require a or selection for autonomous results when cells in in the absence of and in the presence of human not These show that Ba/F3 cells that the mutant JAK2 V617F the to in the presence of growth was that the JAK2 V617F cells respond to while cells the wild type JAK2 for a we signaling of IGF1 and on Ba/F3 cells for JAK2 V617F mutant or the wild type JAK2, and on cells autonomous by the JAK2 V617F mutant. The was at the activation to in cells. as we of the JAK2 mutant. of activation was by of IGF1 as by (1James C. Ugo V. Le Couedic J.P. Staerk J. Delhommeau F. Lacout C. Garcon L. Raslova H. Berger R. Bennaceur-Griscelli A. Villeval J.L. Constantinescu S.N. Casadevall N. Vainchenker W. Nature. 2005; 434: 1144-1148Crossref PubMed Scopus (2917) Google Scholar). selection lead to a of the protein of the JAK2 V617F mutant over the in by selection for expression as the in these cells also in cells. key in IGF1 signaling induced by the expression of the JAK2 V617F and selection for autonomous IGF1 the to of JAK2, STAT5, and on top of the constitutive induced by the JAK2 mutant (1James C. Ugo V. Le Couedic J.P. Staerk J. Delhommeau F. Lacout C. Garcon L. Raslova H. Berger R. Bennaceur-Griscelli A. Villeval J.L. Constantinescu S.N. Casadevall N. Vainchenker W. Nature. 2005; 434: 1144-1148Crossref PubMed Scopus (2917) Google Scholar). IGF1 induced of activation of and as shown by with The in activation of between and cells is not to protein of or as by with We not these of IGF1 on JAK2, STAT5, and on cells that for expression of JAK2 V617F mutant, to of shown in is to cells selection with IGF1 was in the absence of and cells to the selection IGF1 induces proliferation in cells the JAK2 V617F mutant and this with activation of STAT signaling. We JAK1 and Tyk2 activated with to proliferation and signaling. and we show that these not to with the JAK1 and Tyk2 to be in proliferation when with the JAK2 mutant. for the of Tyk2, the and mutant Tyk2 to with IGF1 at it is that the constitutive of activation of these may a synergic effect of IGF1 with the Tyk2 or JAK1 mutants. these as as in the of be at the signaling between the JAK and and show that in cells the mutant JAK1 or Tyk2, IGF1 not the to or or JAKs of STAT activation is different that of cells autonomous by the JAK2 V617F mutant we an effect of on JAK1 in cells the or mutant JAK1 it has been reported that JAK1 PubMed Google Scholar). we show that in cells for expression of the Tyk2 mutant as as in cells autonomous for growth by the Tyk2 mutant, of is The Tyk2 in be as the Tyk2 in it contains a at the carboxyl cells by constitutively JAKs a response to IGF1 with to the of and Akt and of between and cells in the of JAK2 and JAK1 selection for autonomous growth of Tyk2 cells lead to a in protein not We suggest that between and JAKs to activation of and Akt may not be to which appears to with activation of STAT signaling. Our is that JAK1 and Tyk2 are activated by the homologous mutation of the JAK2 V617F mutant, which we in polycythemia vera (1James C. Ugo V. Le Couedic J.P. Staerk J. Delhommeau F. Lacout C. Garcon L. Raslova H. Berger R. Bennaceur-Griscelli A. Villeval J.L. Constantinescu S.N. Casadevall N. Vainchenker W. Nature. 2005; 434: 1144-1148Crossref PubMed Scopus (2917) Google Scholar). The preceding in JAK2 is conserved in four JAK3, is a at the homologous and the mutation not the a is that the V617F mutation the of the JH1 kinase domain by the JH2 pseudokinase domain and may a activating of the JH1 activation Janus kinases to require an intact JH2 domain for as shown by of the Tyk2 JH2 domain and of that activity G. S. S. A. 2000; PubMed Scopus Google Scholar). of the pseudokinase domain Drosophila JAK (9Luo H. Rose P. Barber D. Hanratty W.P. Lee S. Roberts T.M. D'Andrea A.D. Dearolf C.R. Mol. Cell. Biol. 1997; 17: 1562-1571Crossref PubMed Scopus (212) Google Scholar) and human Tyk2 L. G. M. G. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), while of JH2 in JAK2 activates the kinase activity S.J. W. Zhao Gilliland G. J. I. A.S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). it appears that JAKs require a JH2 domain and with JH1 for between the JH1 and JH2 domains has been reported for JAK1 Biol. PubMed Scopus Google Scholar), for JAK3 (10Chen M. Cheng A. Candotti F. Zhou Y.J. Hymel A. Fasth A. Notarangelo L.D. O'Shea J.J. Mol. Cell. Biol. 2000; 20: 947-956Crossref PubMed Scopus (111) Google Scholar) and JAK2 (11Saharinen P. Takaluoma K. Silvennoinen O. Mol. Cell. Biol. 2000; 20: 3387-3395Crossref PubMed Scopus (284) Google Scholar). K. T. PubMed Scopus Google Scholar) JAK2 JH2 and on the of the kinase which found as that M. J. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). The was that JH2 may JH1 via and that the which contains may the inactive of the activation of JH1 K. T. PubMed Scopus Google Scholar). these with the results on JAK2 V617F activation and with the reported in this on JAK1 and a role in with the activating of or amino also the is not the by K. T. PubMed Scopus Google Scholar), no was on or the mutations as may not lead to a in studies in at the effect of mutations at the of JAK2 and at the conserved GVC that this the of the JAK2 V617F mutant and of the activated wild type JAK2 the of the V617F mutant the activated of the wild type JAKs or a different these to be different for JAK3, the JAK3 mutant is not constitutively Our results the that mutations in the JAK1 or Tyk2 pseudokinase domains may be found in human diseases. for JAK1, the mutation be by one this mutation may lead to autoimmune or cancers of different on the type this mutant may of with cells with the mutant JAK1 or Tyk2 the these in the the JAK1 or Tyk2 genes in the of wild type JAK1 and Tyk2 be for the JAK2 to the in of these on suggest that of the JAK JH2 may be in human are four Janus kinases that transduce signals 25 or cytokine receptors. may be found for the V617F and of may be common and specific for the mutant and not the wild type appears that the mutant JAKs to JAK2 V617F in that JAK2, or for Tyk2 in that Tyk2, of with (1James C. Ugo V. Le Couedic J.P. Staerk J. Delhommeau F. Lacout C. Garcon L. Raslova H. Berger R. Bennaceur-Griscelli A. Villeval J.L. Constantinescu S.N. Casadevall N. Vainchenker W. Nature. 2005; 434: 1144-1148Crossref PubMed Scopus (2917) Google Scholar) or with leads to signaling via the mutant JAKs the activated JAK transduce it is that signaling for the JAKs that induced by the activated as the mutant JAKs are and in one is to that of JAK signaling may not be in the hallmark of polycythemia vera is by of erythroid to growth as the IGF1 D. PubMed Google Scholar, PubMed Google Scholar). Our results show JAK2 V617F leads to with to proliferation and activation of JAK2, STAT5, and may be by expression of that the to the mutant JAKs or by a between and the in and in cells it has been reported that IGF1 JAK1, JAK2, and J. C. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) and that the with JAK1 P. V. V. PubMed Scopus Google Scholar). in Ba/F3 the JAK2 V617F mutant be shown to be in an in we not to between mutant JAKs and we suggest that JAK2 V617F signaling induces the expression of that may and JAK2 with with to proliferation and activation of STAT signaling appears to be specific to the JAK2 mutant and not to JAK1 or Tyk2 shown in and JAKs activation of and which in may not be to lead to Furthermore, it was that the of a that erythrocytosis in A. S. A. PubMed Scopus Google Scholar) signals the IGF1 in J. D. S. G. PubMed Google Scholar). studies are for the of the the STAT and the mitogen-activated protein kinase is that the JAK2 V617F mutant appears to PV, ET, and is that different of with the JAK2 V617F mutant and with of A.R. J.L. N. Engl. J. Med. PubMed Scopus Google Scholar), to these different results show that mutation of the conserved to JH2 and in JAK2, JAK1, and Tyk2, results in constitutive kinase a common mechanism of activation for these mutant The JAK3, not share the mechanism of as the homologous mutation not lead to constitutive The mutant JAK2 with the to proliferation and activation of and We suggest that mutations at the homologous JAK2 in JAK1 and Tyk2 may be found in human diseases and that the of polycythemia vera erythroid to IGF1 is to with the JAK2 V617F mutant. We for the Tyk2 and for the fibrosarcoma and for the fibrosarcoma and for human interleukin for and and for and