JAK2, the JAK2 V617F mutant and cytokine receptors
| Autor: | Jean-Baptiste Demoulin, Stefan N. Constantinescu, Carmen-Cristina Diaconu, William Vainchenker, Anders Kallin, Judith Staerk, Alexandra Dusa, Yohan Royer |
|---|---|
| Rok vydání: | 2007 |
| Předmět: |
Mutant
Mutation Missense Biology src Homology Domains Mice hemic and lymphatic diseases Receptors Erythropoietin Animals Humans Point Mutation Insulin-Like Growth Factor I Receptors Cytokine Receptor Cells Cultured Erythroid Precursor Cells TYK2 Kinase Genetics Myeloproliferative Disorders Janus kinase 2 Janus kinase 1 Wild type food and beverages Janus Kinase 1 General Medicine Janus Kinase 2 Hematopoietic Stem Cells Cell biology Erythropoietin receptor Protein Transport Amino Acid Substitution Tyrosine kinase 2 biology.protein Signal transduction Receptors Thrombopoietin Signal Transduction |
| Zdroj: | Pathologie Biologie. 55:88-91 |
| ISSN: | 0369-8114 |
| DOI: | 10.1016/j.patbio.2006.06.003 |
| Popis: | Recently, a unique recurrent somatic mutation was identified as a major molecular event in polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis. Expression of this mutant in cytokine-dependent hematopoietic cell lines induces autonomous growth. This effect is enhanced by overexpression of cytokine receptors, and can be inhibited by co-expression at higher levels of the wild type JAK2, which may compete for a limited pool of receptors. In JAK2-deficient cells, we showed that JAK2 V617F can transmit signals from ligand-activated TpoR or EpoR. Furthermore, the mutant JAK2 can be demonstrated to stimulate traffic of the EpoR. Thus, JAK2 V617F mutant must be able to interact via its intact FERM-SH2 domains with the cytosolic domains of cytokine receptors. A synergy between JAK2 V617F and insulin-like growth factor 1 receptor (IGF1R) can be detected in cytokine-dependent cell proliferation. Once cells are rendered autonomous by expression of JAK2 V617F, IGF1 acquires the ability to activate the JAK-STAT pathway. Thus, expression of JAK2 V617F may explain the described hypersensitivity of PV erythroid progenitors to IGF1. The V617 is conserved in two other mammalian JAKs, JAK1 and Tyk2. The homologous mutants JAK1 V658F and Tyk2 V678F are also active in proliferation and transcriptional assays. Such mutants may be found in human cancers or autoimmune diseases. In contrast, the JAK3 M592F does not lead to activation of JAK3. Current hypotheses on how JAK2 V617F contributes to three myeloproliferative diseases, and which other events may favor one disease versus another, are discussed. |
| Databáze: | OpenAIRE |
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