JAK2-V617F-induced MAPK activity is regulated by PI3K and acts synergistically with PI3K on the proliferation of JAK2-V617F-positive cells.
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.
Department of Systems Biology; Institute of Biology; Otto-von-Guericke-University Magdeburg; Magdeburg, Germany ; Department of Biochemistry and Molecular Biology; RWTH-Aachen University; Aachen, Germany.
Alexandra
A
Wolf
René
R
Eulenfeld
Karoline
K
Gäbler
Catherine
C
Rolvering
Serge
S
Haan
Iris
I
Behrmann
Bernd
B
Denecke
Claude
C
Haan
Fred
F
Schaper
Gab1; JAK; JAK2-V617F; MAPK; PI3K; STAT; essential thrombocythemia; myeloid disorders; polycythemia vera; signal transduction