title: Activating JAK2 mutants reveal cytokine receptor coupling differences that impact outcomes in myeloproliferative neoplasm.
abstract: Janus tyrosine kinase 2 (JAK2) mediates downstream signaling of cytokine receptors in all hematological lineages, yet constitutively active JAK2 mutants are able to drive selective expansion of particular lineage(s) in myeloproliferative neoplasm (MPN). The molecular basis of lineage specificity is unclear. Here, we show that three activating JAK2 mutants with similar kinase activities in vitro elicit distinctive MPN phenotypes in mice by differentially expanding erythroid vs granulocytic precursors. Molecularly, this reflects the differential binding of JAK2 mutants to cytokine receptors EpoR and GCSFR in the erythroid vs granulocytic lineage and the creation of unique receptor/JAK2 complexes that generate qualitatively distinct downstream signals. Our results demonstrate that activating JAK2 mutants can differentially couple to selective cytokine receptors and change the signaling repertoire, revealing the molecular basis for phenotypic differences elicited by JAK2 (V617F) or mutations in exon 12. On the basis of these findings, receptor-JAK2 interactions could represent new targets of lineage-specific therapeutic approaches against MPN, which may be applicable to other cancers with aberrant JAK-STAT signaling.
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Yao
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Hong
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Monaghan
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: M-C
authors.initials: MC
authors.lastname: Hu
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Huang
mesh_terms: D000818:Animals; D002455:Cell Division; D002460:Cell Line; D019070:Cell Lineage; D004789:Enzyme Activation / Q000235:genetics; D004920:Erythropoiesis / Q000235:genetics / Q000502:physiology*; D005091:Exons / Q000235:genetics; D017930:Genes, Reporter; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D020125:Mutation, Missense; D038042:Myelopoiesis / Q000235:genetics / Q000502:physiology*; D009196:Myeloproliferative Disorders / Q000201:enzymology / Q000235:genetics*; D010641:Phenotype; D017354:Point Mutation; D025941:Protein Interaction Mapping; D011828:Radiation Chimera; D017467:Receptors, Erythropoietin / Q000378:metabolism*; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D014161:Transduction, Genetic; D014410:Tumor Stem Cell Assay
chemical_list: D017467:Receptors, Erythropoietin; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D011993:Recombinant Fusion Proteins; C507924:JAK2 protein, human; D053614:Janus Kinase 2