ID: 79. Issue 1 (November 2015)

• Record Type: Journal Article
• Authors: Bongartz, Hannes; Hessenkemper, Wiebke; Wolf, Alexandra; Eulenfeld, René; Simister, Philip C.; Behrmann, Iris; Tavernier, Jan; Feller, Stephan M.; Haan, Claude; Schaper, Fred
• Is Part Of: Cytokine. Volume 76:Issue 1(2015)
• Page Start: 80
• Publication Date: 2015-11
• Subjects: Cytokines -- Periodicals; 571.844
• DOI: 10.1016/j.cyto.2015.08.109
• Languages: English
• ISSNs: 1043-4666

Abstract

<abstract xml:lang="en" abstract-type="author" id="ab005"> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <p id="sp005">The activating JAK2-V617F mutation is found in many patients suffering from Myeloproliferative neoplasms such as Polycythemia Vera and Essential Thrombocythemia. JAK2-V617F mutation confers cytokine hypersensitivity, constitutive activation of the JAK-STAT pathway, and cytokine-independent growth. We demonstrate uncontrolled membrane binding of the multi-site docking protein Gab1 in JAK2-V617F expressing cells. We elaborated the molecular mechanism and regulation of Gab1-membrane recruitment. In line with the regulatory function of Gab1 on STAT-independent signalling we show that PI3K signalling regulates MAPK activation in JAK2-V617F-positive 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. In summary, our study demands to consider cross-talk mechanisms as potential new targets. This may increase the specificity for intervention approaches compared to the interference in very upstream signalling elements such as receptor kinases or receptor-associated kinases.</p> </sec> </abstract>