The Jak2V617F oncogene associated with myeloproliferative diseases requires a functional FERM domain for transformation and for expression of the Myc and Pim proto-oncogenes. Blood

Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Blood (Impact Factor: 10.43). 05/2008; 111(7):3751-9. DOI: 10.1182/blood-2007-07-102186
Source: PubMed

ABSTRACT The V617F activating point mutation in Jak2 is associated with a proportion of myeloproliferative disorders. In normal hematopoietic cells, Jak2 signals only when associated with a growth factor receptor, such as the erythropoietin receptor (EpoR). We sought to identify the molecular requirements for activation of Jak2V617F by introducing a point mutation in the FERM domain (Y114A), required for receptor binding. Whereas BaF3.EpoR cells are readily transformed by Jak2V617F to Epo independence, we found that the addition of the FERM domain mutation blocked transformation and the induction of reactive oxygen species. Further, while cells expressing Jak2V617F had constitutive activation of STAT5, cells expressing Jak2V617F/Y114A did not, suggesting that signaling is defective at a very proximal level. In addition, expression of the Myc and Pim proto-oncogenes by Jak2V617F was found to be FERM domain dependent. An inducible constitutively active STAT5 mutant expressed in BaF3 cells was sufficient to induce Myc and Pim. Finally, the FERM domain in Jak2V617F was also required for abnormal hematopoiesis in transduced primary murine fetal liver cells. Overall, our results suggest that constitutive activation of Jak2 requires an intact FERM domain for a transforming phenotype, and is necessary for activation of the major target of Jak2, STAT5.

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Available from: James D Griffin, Aug 22, 2015
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    • "EpoR homodimers are pre‐formed prior to their interaction with the ligands [Livnah et al., 1999; Constantinescu et al., 2001]; the latter trigger activation via inducing a conformational change leading to JAK2 activation [Remy et al., 1999]. This dimerization is required even for enhanced signaling mediated by a constitutively active JAK2 V617F oncogene found in patients with diverse myeloproliferative diseases and present in almost all patients with polycythemia vera [Lu et al., 2008]; accordingly, the integrity of the FERM domain in this mutant is essential for its high intrinsic activity [Wernig et al., 2008]. It would be expected that the latter activity should promote receptor elimination. "
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    Journal of Cellular Biochemistry 01/2014; 115(1). DOI:10.1002/jcb.24647 · 3.37 Impact Factor
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    • "Hyperproliferation induced by JAK2V617F involves activation of STAT5 and its downstream targets (Walz et al., 2006; Wernig et al., 2008). It has been reported that transcriptional downregulation of cyclin D 2 and upregulation of p27 Kip1 is a central mechanism of growth arrest upon JAK2V617F inhibition (Walz et al., 2006). "
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    • "Murine JAK2 knockout embryos die of severe anemia on days 11–13 in utero, demonstrating the importance of JAK2 in hematopoietic cytokine signaling (Neubauer et al., 1998; Parganas et al., 1998). It has been reported by several groups that the transforming effects of JAK2V617F require an intact FERM domain, which binds to homodimeric type I cytokine receptors (Lu et al., 2005; Wernig et al., 2008a). This suggests that interactions between JAK2 and cytokine receptors remain capable of regulating the biological function of JAK2V617F. "
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