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Thrombopoietin receptor down-modulation by JAK2 V617F: restoration of receptor levels by inhibitors of pathologic JAK2 signaling and of proteasomes.
- Source :
-
Blood [Blood] 2012 May 17; Vol. 119 (20), pp. 4625-35. Date of Electronic Publication: 2012 Feb 29. - Publication Year :
- 2012
-
Abstract
- The constitutively active JAK2 V617F mutant is the major determinant of human myeloproliferative neoplasms (MPNs). We show that coexpression of murine JAK2 V617F and the murine thrombopoietin (Tpo) receptor (TpoR, c-MPL) in hematopoietic cell lines or heterozygous knock-in of JAK2 V617F in mice leads to down-modulation of TpoR levels. Enhanced TpoR ubiquitinylation, proteasomal degradation, reduced recycling, and maturation are induced by the constitutive JAK2 V617F activity. These effects can be prevented in cell lines by JAK2 and proteasome inhibitors. Restoration of TpoR levels by inhibitors could be detected in platelets from JAK2 inhibitor-treated myelofibrosis patients that express the JAK2 V617F mutant, and in platelets from JAK2 V617F knock-in mice that were treated in vivo with JAK2 or proteasome inhibitors. In addition, we show that Tpo can induce both proliferative and antiproliferative effects via TpoR at low and high JAK2 activation levels, respectively, or on expression of JAK2 V617F. The antiproliferative signaling and receptor down-modulation by JAK2 V617F were dependent on signaling via TpoR cytosolic tyrosine 626. We propose that selection against TpoR antiproliferative signaling occurs by TpoR down-modulation and that restoration of down-modulated TpoR levels could become a biomarker for the treatment of MPNs.
- Subjects :
- Amino Acid Substitution genetics
Amino Acid Substitution physiology
Animals
Cell Membrane drug effects
Cell Membrane metabolism
Cells, Cultured
Down-Regulation drug effects
Drug Evaluation, Preclinical
HEK293 Cells
Humans
Janus Kinase 2 genetics
Janus Kinase 2 metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutation, Missense physiology
Phenylalanine genetics
Receptor Cross-Talk drug effects
Receptor Cross-Talk physiology
Receptors, Thrombopoietin metabolism
Signal Transduction drug effects
Valine genetics
Janus Kinase 2 antagonists & inhibitors
Janus Kinase 2 physiology
Proteasome Inhibitors
Protein Kinase Inhibitors pharmacology
Receptors, Thrombopoietin genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 119
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 22378845
- Full Text :
- https://doi.org/10.1182/blood-2011-08-372524