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Amino acid residue E543 in JAK2 C618R is a potential therapeutic target for myeloproliferative disorders caused by JAK2 C618R mutation.
- Source :
-
Archives of biochemistry and biophysics [Arch Biochem Biophys] 2012 Dec 01; Vol. 528 (1), pp. 57-66. Date of Electronic Publication: 2012 Aug 29. - Publication Year :
- 2012
-
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.<br /> (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Subjects :
- Amino Acid Substitution
Animals
Cell Line
Cell Line, Tumor
Cell Proliferation
Cell Transformation, Neoplastic genetics
Glutamic Acid chemistry
Humans
Janus Kinase 2 chemistry
Mice
Models, Molecular
Mutagenesis, Site-Directed
Protein Conformation
Protein Refolding
Protein Unfolding
Glutamic Acid genetics
Janus Kinase 2 genetics
Myeloproliferative Disorders genetics
Point Mutation
Subjects
Details
- Language :
- English
- ISSN :
- 1096-0384
- Volume :
- 528
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Archives of biochemistry and biophysics
- Publication Type :
- Academic Journal
- Accession number :
- 22960131
- Full Text :
- https://doi.org/10.1016/j.abb.2012.08.010