title: Nuclear Import of JAK1 Is Mediated by a Classical NLS and Is Required for Survival of Diffuse Large B-cell Lymphoma.
abstract: JAKs are non-receptor tyrosine kinases that are generally found in association with cytokine receptors. In the canonical pathway, roles of JAKs have well been established in activating STATs in response to cytokine stimulation to modulate gene transcription. In contrast, a noncanonical role of JAK2 has recently been discovered, in which JAK2 in the nucleus imparts the epigenetic regulation of gene transcription through phosphorylation of tyrosine 41 on the histone protein H3. Recent work further demonstrated that this noncanonical mechanism is conserved with JAK1, which is activated by the autocrine cytokines IL6 and IL10 in activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL), a cancer type that is particularly difficult to treat and has poor prognosis. However, how JAK1 gains access to the nucleus to enable epigenetic regulation remains undefined. Here, we investigated this question and revealed that JAK1 has a classical nuclear localization signal toward the N-terminal region, which can be recognized by multiple importin α isoforms. Moreover, the nuclear import of JAK1 is independent of its kinase activity but is required for the optimal expansion of ABC DLBCL cellsin vitroImplications:This study demonstrates that the nuclear import of JAK1 is essential for the optimal fitness of ABC DLBCL cells, and targeting JAK1 nuclear localization is a potential therapeutic strategy for ABC DLBCL.Mol Cancer Res; 15(3); 348-57. ©2016 AACR.
authors.affiliation: Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.|Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Fen
authors.initials: F
authors.lastname: Zhu
authors.affiliation: Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.|Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Byounghoon
authors.initials: B
authors.lastname: Hwang
authors.affiliation: Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.|Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Miyamoto
authors.affiliation: Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin. lrui@medicine.wisc.edu.|Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
authors.forename: Lixin
authors.initials: L
authors.lastname: Rui
mesh_terms: D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology; D006801:Humans; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D019913:Nuclear Localization Signals / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction
chemical_list: D019913:Nuclear Localization Signals; C507904:JAK1 protein, human; D053613:Janus Kinase 1