Thrombopoietin receptor down-modulation by JAK2 V617F: restoration of receptor levels by inhibitors of pathologic JAK2 signaling and of proteasomes
Copyright policy )Thrombopoietin receptor down-modulation by JAK2 V617F: restoration of receptor levels by inhibitors of pathologic JAK2 signaling and of proteasomes
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.
- Institut Gustave Roussy France
- University of Paris France
- de Duve Institute Belgium
- Paris-East Créteil University France
- Cliniques Universitaires Saint-Luc Belgium
Phenylalanine, Cell Membrane, Drug Evaluation, Preclinical, Mutation, Missense, Down-Regulation, Mice, Transgenic, Valine, Receptor Cross-Talk, Janus Kinase 2, Mice, Inbred C57BL, Mice, HEK293 Cells, Amino Acid Substitution, Animals, Humans, Proteasome Inhibitors, Protein Kinase Inhibitors, Receptors, Thrombopoietin, Cells, Cultured, Signal Transduction
Phenylalanine, Cell Membrane, Drug Evaluation, Preclinical, Mutation, Missense, Down-Regulation, Mice, Transgenic, Valine, Receptor Cross-Talk, Janus Kinase 2, Mice, Inbred C57BL, Mice, HEK293 Cells, Amino Acid Substitution, Animals, Humans, Proteasome Inhibitors, Protein Kinase Inhibitors, Receptors, Thrombopoietin, Cells, Cultured, Signal Transduction
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