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Disruption of R867 and Y613 interaction plays key roles in JAK2 R867Q mutation caused acute leukemia
- Source :
- International Journal of Biological Macromolecules. 136:209-219
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
Abstract
- Janus tyrosine kinase 2 (JAK2) mediates downstream signaling of cytokine receptors in all hematological lineages, constitutively active somatic JAK2 mutations were important for the leukemogenesis of acute leukemia (AL). The JAK2 R867Q somatic mutation is detected in a subset of AL patients. However, roles of JAK2 R867Q mutation in the pathogenesis of AL remain unclear. In this study, homology modeling analysis showed that loss of interaction between R867 and Y613 disrupted the JAK2 JH1/JH2 domain's interactions was responsible for its activation. JAK2 R867Q and mutations (R867A and R867G) abolished this interaction caused JAK2 constitutive activation. While, mutations (R867K, Y613E, R867K/Y613E) repairing this interaction reduced JAK2 R867Q mutation's activity. Furthermore, our studies showed that abolished R867 and Y613 interaction disrupted JH1/JH2 domains' interactions and led to JAK2 constitutive activation. More importantly, mutations (R867Q, R867A and R867G) disrupted this interaction enhanced the activity of JAK2-STAT5 pathway and the proliferation of Ba/F3 and MV4-11 cells. Further study showed that JAK2 R867Q mutation promoted the expression of proliferation marker and inhibited the differentiation marker of Ba/F3 and MV4-11 cells. Thus our studies provide clues in understanding the pathogenesis of JAK2 R867Q mutation in AL.
- Subjects :
- Models, Molecular
Somatic cell
02 engineering and technology
medicine.disease_cause
Biochemistry
Protein Refolding
Protein Structure, Secondary
Pathogenesis
03 medical and health sciences
Germline mutation
Structural Biology
Cell Line, Tumor
hemic and lymphatic diseases
medicine
Humans
Proliferation Marker
Receptor
Molecular Biology
Cell Proliferation
030304 developmental biology
0303 health sciences
Mutation
Leukemia
Janus kinase 2
biology
food and beverages
General Medicine
Janus Kinase 2
021001 nanoscience & nanotechnology
Protein Structure, Tertiary
Cell biology
Tyrosine kinase 2
Acute Disease
biology.protein
Interleukin-3
Mutant Proteins
0210 nano-technology
hormones, hormone substitutes, and hormone antagonists
Subjects
Details
- ISSN :
- 01418130
- Volume :
- 136
- Database :
- OpenAIRE
- Journal :
- International Journal of Biological Macromolecules
- Accession number :
- edsair.doi.dedup.....ef0e2ecec5d9bd9ccb643a2d530b722f