Transforming JAK1 mutations exhibit differential signalling, FERM domain requirements and growth responses to interferon-γ

被引:20
作者
Gordon, Geoff M. [1 ,2 ]
Lambert, Que T. [1 ]
Daniel, Kenyon G.
Reuther, Gary W. [1 ]
机构
[1] H Lee Moffitt Canc Ctr & Res Inst, Dept Mol Oncol, Tampa, FL 33612 USA
[2] Univ S Florida, Canc Biol PhD Program, Tampa, FL 33612 USA
关键词
acute leukaemia; 4.1/ezrin/radixin/moesin (FERM) domain; interferon-gamma; Janus kinase 1 (JAK1); transformation; tyrosine kinase; ACUTE LYMPHOBLASTIC-LEUKEMIA; TYROSINE KINASE JAK2; JANUS KINASES; POLYCYTHEMIA-VERA; CYTOKINE RECEPTOR; MYELOPROLIFERATIVE DISORDERS; CONSTITUTIVE ACTIVATION; PSEUDOKINASE DOMAIN; IDENTIFICATION; SPECIFICITY;
D O I
10.1042/BJ20100774
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Recent work has highlighted roles for JAK (Janus kinase) family members in haemopoietic diseases. Although sequencing efforts have uncovered transforming JAK1 mutations in acute leukaemia, they have also identified non-transforming JAM mutations. Thus with limited knowledge of the mechanisms of JAK1 activation by mutation, sequencing may not readily identify transforming mutations. Therefore we sought to further understand the repertoire of transforming mutations of JAK1. We identified seven randomly generated transforming JAK mutations, including V658L and a deletion of amino acids 629-630 in the pseudokinase domain, as well as L9 10P, F938S, P960S, K1026E and Y1035C within the kinase domain. These mutations led to differential signalling activation, but exhibited similar transforming abilities, in BaF3 cells. Interestingly, these properties did not always correlate with JAK1 activation-loop phosphorylation. We also identified a JAK1 mutant that did not require a functional FERM (4.1/ezrin/radixin/moesin) domain for transformation. Although we isolated a mutation of JAK1 at residue Val(658), which is found mutated in acute leukaemia patients, most of the mutations we identified are within the kinase domain and have yet to be identified in patients. Interestingly, compared with cells expressing JAK1-V658F, cells expressing these mutants had higher STAT1 (signal transducer and activator of transcription 1) phosphorylation and were more sensitive to interferon-gamma-mediated growth inhibition. The differential STAT1 activation and interferon-sensitivity of JAK1 mutants may contribute to the determination of which specific JAK1 mutations ultimately contribute to disease and thus are identified in patients. Our characterization of these novel mutations contributes to a better understanding of mutational activation of JAK1.
引用
收藏
页码:255 / 265
页数:11
相关论文
共 39 条
[1]   JAK1 mutations are not frequent events in adult T-ALL: a GRAALL study [J].
Asnafi, Vahid ;
Le Noir, Sandrine ;
Lhermitte, Ludovic ;
Gardin, Claude ;
Legrand, Faezeh ;
Vallantin, Xavier ;
Malfuson, Jean-Valere ;
Ifrah, Norbert ;
Dombret, Herve ;
Macintyre, Elizabeth .
BRITISH JOURNAL OF HAEMATOLOGY, 2010, 148 (01) :179-179
[2]   Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders [J].
Baxter, EJ ;
Scott, LM ;
Campbell, PJ ;
East, C ;
Fourouclas, N ;
Swanton, S ;
Vassiliou, GS ;
Bench, AJ ;
Boyd, EM ;
Curtin, N ;
Scott, MA ;
Erber, WN ;
Green, AR .
LANCET, 2005, 365 (9464) :1054-1061
[3]   Crystal structure of the Jak3 kinase domain in complex with a staurosporine analog [J].
Boggon, TJ ;
Li, YQ ;
Manley, PW ;
Eck, MJ .
BLOOD, 2005, 106 (03) :996-1002
[4]   Substitution of pseudokinase domain residue Val-617 by large non-polar amino acids causes activation of JAK2 [J].
Dusa, Alexandra ;
Staerk, Judith ;
Elliott, Joanne ;
Pecquet, Christian ;
Poirel, Helene A. ;
Johnston, James A. ;
Constantinescu, Stefan N. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (19) :12941-12948
[5]   Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia [J].
Flex, Elisabetta ;
Petrangeli, Valentina ;
Stella, Lorenzo ;
Chiaretti, Sabina ;
Hornakova, Tekla ;
Knoops, Laurent ;
Ariola, Cristina ;
Fodale, Valentina ;
Clappier, Emmanuelle ;
Paoloni, Francesca ;
Martinelli, Simone ;
Fragale, Alessandra ;
Sanchez, Massimo ;
Tavolaro, Simona ;
Messina, Monica ;
Cazzaniga, Giovanni ;
Camera, Andrea ;
Pizzolo, Giovanni ;
Tornesello, Assunta ;
Vignetti, Marco ;
Battistini, Angela ;
Cave, Helene ;
Gelb, Bruce D. ;
Renauld, Jean-Christophe ;
Biondi, Andrea ;
Constantinescu, Stefan N. ;
Foa, Robin ;
Tartaglia, Marco .
JOURNAL OF EXPERIMENTAL MEDICINE, 2008, 205 (04) :751-758
[6]   Mapping of a region within the N terminus of Jak1 involved in cytokine receptor interaction [J].
Haan, C ;
Is'harc, H ;
Hermanns, HM ;
Schmitz-Van de Leur, H ;
Kerr, IM ;
Heinrich, PC ;
Grotzinger, J ;
Behrmann, I .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (40) :37451-37458
[7]   Jaks and cytokine receptors - An intimate relationship [J].
Haan, Claude ;
Kreis, Stephanie ;
Margue, Christiane ;
Behrmann, Iris .
BIOCHEMICAL PHARMACOLOGY, 2006, 72 (11) :1538-1546
[8]   Perspectives for the use of structural information and chemical genetics to develop inhibitors of Janus kinases [J].
Haan, Claude ;
Behrmann, Iris ;
Haan, Serge .
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, 2010, 14 (03) :504-527
[9]   Dual role of the Jak1 FERM and kinase domains in cytokine receptor binding and in stimulation-dependent Jak activation [J].
Haan, Serge ;
Margue, Christiane ;
Engrand, Arnaud ;
Rolvering, Catherine ;
de Leur, Hildegard Schmitz-Van ;
Heinrich, Peter C. ;
Behrmann, Iris ;
Haan, Claude .
JOURNAL OF IMMUNOLOGY, 2008, 180 (02) :998-1007
[10]   The mutation in the ATP-binding region of JAK1, identified in human uterine leiomyosarcomas, results in defective interferon-γ inducibility of TAP1 and LMP2 [J].
Hayashi, T. ;
Kobayashi, Y. ;
Kohsaka, S. ;
Sano, K. .
ONCOGENE, 2006, 25 (29) :4016-4026