ID: 79: Constitutive membrane binding of the multi-site docking protein Gab1 in JAK2-V617F expressing cells

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• 作者：Hannes Bongartz¹ ; Wiebke Hessenkemper¹ ; Alexandra Wolf¹ ; René ; Eulenfeld¹ ; Philip C. Simister² ; Iris Behrmann³ ; Jan Tavernier⁴ ; Stephan M. Feller⁵ ; Claude Haan³ ; Fred Schaper¹ ;
• 刊名：Cytokine
• 出版年：2015
• 出版时间：November 2015
• 年：2015
• 卷：76
• 期：1
• 页码：80
• 全文大小：45 K

文摘

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.