title: Amino acid residue E543 in JAK2 C618R is a potential therapeutic target for myeloproliferative disorders caused by JAK2 C618R mutation.
abstract: Janus kinase 2 (JAK2) is an important mediator of cytokine receptor signaling and plays a key role in the hematopoietic and immune responses. The acquired JAK2 C618R somatic mutation is detected in a subset of myeloproliferative disorders (MPDs) patients and presumed to be a biomarker for MPDs. However, how JAK2 C618R mutation causes MPDs is still unclear. Our results indicate that the amino acid residue E543 in JAK2 C618R is indispensable for its constitutive activation. When the glutamic acid at this position was mutated to alanine (E543A) in the JAK2 C618R, its activity significantly decreased. However when the glutamic acid was mutated to the acidic amino acid, aspartic acid, JAK2 C618R activity changed little. These results suggest that there is an interaction between the amino acid residue R618 and E543, and that this interaction is crucial to sustain the constitutive activation of JAK2 C618R. More importantly, the E543 single mutation had no effects on the function of wild type JAK2 (WT JAK2). This study suggests that the amino acid residue E543 might be a potential target for specific inhibitors to treat MPDs caused by the JAK2 C618R mutation.
authors.affiliation: Department of Hematology, The Affiliated Hospital of Xuzhou Medical College, No. 99 West Huaihai Road, Xuzhou 221002, China. qywu82@163.com
authors.forename: Qing-Yun
authors.initials: QY
authors.lastname: Wu
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Hua-Yan
authors.initials: HY
authors.lastname: Guo
authors.forename: Jiang
authors.initials: J
authors.lastname: Cao
authors.forename: Chong
authors.initials: C
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Kai
authors.initials: K
authors.lastname: Zhao
authors.forename: Ling-Yu
authors.initials: LY
authors.lastname: Zeng
authors.forename: Zheng-Xiang
authors.initials: ZX
authors.lastname: Han
authors.forename: Zhen-Yu
authors.initials: ZY
authors.lastname: Li
authors.forename: Xiao-Yun
authors.initials: XY
authors.lastname: Wang
authors.forename: Kai-Lin
authors.initials: KL
authors.lastname: Xu
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018698:Glutamic Acid / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D053614:Janus Kinase 2 / Q000737:chemistry / Q000235:genetics*; D051379:Mice; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009196:Myeloproliferative Disorders / Q000235:genetics*; D017354:Point Mutation; D011487:Protein Conformation; D058849:Protein Refolding; D058767:Protein Unfolding
chemical_list: D018698:Glutamic Acid; D053614:Janus Kinase 2