Expression level and differential JAK2-V617F-binding of the adaptor protein Lnk regulates JAK2-mediated signals in myeloproliferative neoplasms
| Autor: | Laura Velazquez, Sylvie Chevret, E. Mazoyer, Anabell Alvarado, Marie-Caroline Le Bousse-Kerdilès, Christophe Desterke, Jean-Jacques Kiladjian, Fanny Baran-Marszak, Bruno Cassinat, Stéphane Giraudier, Hajer Magdoud, Claudine Roger, Nadine Varin-Blank, Carole Tonetti, Florence Cymbalista, Stephanie Harel, Pierre Fenaux |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Cell signaling
Immunology Immunoblotting Biology medicine.disease_cause Biochemistry Mice hemic and lymphatic diseases medicine Animals Humans Immunoprecipitation RNA Messenger Progenitor cell Thrombopoietin Cells Cultured Adaptor Proteins Signal Transducing Cell Proliferation Thrombopoietin receptor Mice Knockout Mutation Myeloproliferative Disorders Cell growth Reverse Transcriptase Polymerase Chain Reaction Intracellular Signaling Peptides and Proteins food and beverages Signal transducing adaptor protein Proteins Cell Biology Hematology Janus Kinase 2 Cancer research Signal transduction Megakaryocytes Protein Binding Signal Transduction |
| Zdroj: | Blood. 116(26) |
| ISSN: | 1528-0020 |
| Popis: | Activating mutations in signaling molecules, such as JAK2-V617F, have been associated with myeloproliferative neoplasms (MPNs). Mice lacking the inhibitory adaptor protein Lnk display deregulation of thrombopoietin/thrombopoietin receptor signaling pathways and exhibit similar myeloproliferative characteristics to those found in MPN patients, suggesting a role for Lnk in the molecular pathogenesis of these diseases. Here, we showed that LNK levels are up-regulated and correlate with an increase in the JAK2-V617F mutant allele burden in MPN patients. Using megakaryocytic cells, we demonstrated that Lnk expression is regulated by the TPO-signaling pathway, thus indicating an important negative control loop in these cells. Analysis of platelets derived from MPN patients and megakaryocytic cell lines showed that Lnk can interact with JAK2-WT and V617F through its SH2 domain, but also through an unrevealed JAK2-binding site within its N-terminal region. In addition, the presence of the V617F mutation causes a tighter association with Lnk. Finally, we found that the expression level of the Lnk protein can modulate JAK2-V617F–dependent cell proliferation and that its different domains contribute to the inhibition of multilineage and megakaryocytic progenitor cell growth in vitro. Together, our results indicate that changes in Lnk expression and JAK2-V617F–binding regulate JAK2-mediated signals in MPNs. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|