JAK2-V617F-induced MAPK Activity is Regulated by PI3K and Acts Synergistically with PI3K on the Proliferation of JAK2-V617F-positive Cells

Overview

Journal JAKSTAT

Date 2013 Sep 27

PMID 24069558

Citations 20

Authors

Alexandra Wolf

Rene Eulenfeld

Karoline Gabler

Catherine Rolvering

Serge Haan

Iris Behrmann

Bernd Denecke

Claude Haan

Fred Schaper

Affiliations

Soon will be listed here.

Abstract

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.

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