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J Biol Chem. 2010 Feb 19;285(8):5296-307. doi: 10.1074/jbc.M109.040733. Epub 2009 Dec 22.

STAT5 activation is critical for the transformation mediated by myeloproliferative disorder-associated JAK2 V617F mutant.

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1
Department of Biochemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, USA. tago-mg@pha.keio.ac.jp

Abstract

It has been well established that disruption of JAK2 signaling regulation is involved in various hematopoietic disorders; however, the detailed mechanism by which abnormal activation of JAK2 exhibits transforming activity remains to be elucidated. Here, to clarify the functional role of the erythropoietin receptor (EpoR) and its downstream transcription factor STAT5 in the abnormal activation of JAK2-induced hematopoietic diseases, we generated a stable transfectant of Ba/F3 cells expressing EpoR and analyzed the molecular mechanism of how JAK2 mutation induces cell growth disorder. JAK2 V617F mutant exhibited transforming activity when EpoR was coexpressed. According to a study utilizing several truncated mutants of EpoR, the ability of EpoR to facilitate the transforming activity of JAK2 V617F mutant required the intracellular domain to interact with STAT5. Strikingly, once the truncated EpoR (EpoR-H) was mutated on Tyr-343, the phosphorylation of which is known to be important for interaction with STAT5, JAK2 V617F mutant failed to exhibit transforming activity, suggesting that STAT5 is critical for JAK2 mutant-induced hematopoietic disorder. Furthermore, the expression of the constitutively active STAT5 mutant exhibited transforming activity in Ba/F3 cells, and short hairpin RNA-mediated knockdown of STAT5 significantly inhibited the transforming activity of JAK2 V617F mutant. Taking these observations together, STAT5 plays an essential role in EpoR-JAK2 V617F mutant-induced hematopoietic disorder. Although it remains unclear why the presence of EpoR is required to activate oncogenic signaling via the JAK2 mutant and STAT5, its interacting ability is a target for the treatment of these hematopoietic diseases.

PMID:
20028972
PMCID:
PMC2820758
DOI:
10.1074/jbc.M109.040733
[Indexed for MEDLINE]
Free PMC Article
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