[en] The identification of a constitutively active JAK2 mutant, namely JAK2-V617F, was a milestone in the understanding of Philadelphia chromosome-negative myeloproliferative neoplasms. The JAK2-V617F mutation confers cytokine hypersensitivity, constitutive activation of the JAK-STAT pathway, and cytokine-independent growth. In this study we investigated the mechanism of JAK2-V617F-dependent signaling with a special focus on the activation of the MAPK pathway. We observed JAK2-V617F-dependent deregulated activation of the multi-site docking protein Gab1 as indicated by constitutive, PI3K-dependent membrane localization and tyrosine phosphorylation of Gab1. Furthermore, we demonstrate that PI3K signaling regulates MAPK activation in JAK2-V617F-positve cells. This cross-regulation of the MAPK pathway by PI3K affects JAK2-V617F-specific target gene induction, erythroid colony formation, and regulates proliferation of JAK2-V617F-positive patient cells in a synergistically manner.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Wolf, Alexandra
Eulenfeld, Rene
Gäbler, Karoline ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Rolvering, Catherine ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Haan, Serge ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Behrmann, Iris ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Denecke, Bernd
Haan, Claude ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Schaper, Fred
Language :
English
Title :
JAK2-V617F-induced MAPK activity is regulated by PI3K and acts synergistically with PI3K on the proliferation of JAK2-V617F-positive cells.