| Project/Area Number |
17K08286
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Keio University |
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Principal Investigator |
TAGO MEGUMI 慶應義塾大学, 薬学部(芝共立), 准教授 (30445192)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
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| Keywords | 慢性骨髄増殖性腫瘍 (MPN) / JAK2V617F変異体 / エリスロポエチン受容体 (EpoR) / STAT5 / ＣＩＳ / チロシンリン酸化 / JAK2変異体 (V617F) / リン酸化 / CIS / 慢性骨髄増殖性腫瘍 / エリスロポエチン受容体 / トロンボポエチン受容体 / STAT3 / ERK / Akt / EpoR / EpoR結合分子 / シグナル伝達 |
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| Outline of Final Research Achievements |
A point mutant of tyrosine kinase JAK2 (V617F) was identified as a responsible gene for myeloproliferative neoplasm (MPN). However, the molecular mechanism by which JAK2 V617F mutant causes the onset of MPN has not yet been elucidated. In this study, we found that the co-expression of erythropoietin receptor (EpoR) was required for JAK2 V617F mutant-induced cellular transformation. We also clarified that the phosphorylation of three tyrosine residues in EpoR (Y343, Y460, Y464) was essential for JAK2 V617F mutant-induced tumorigenesis through STAT5 activation. Furthermore, we found that CIS which is a negative regulator of the JAK-STAT pathway interacted with phosphorylated EpoR at Y401 and prevented activation of STAT5 in the transformed cells.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究において、チロシンキナーゼJAK2の変異体が誘導するエリスロポエチン受容体 (EpoR) を介した発がんシグナルを解析することにより、慢性骨髄増殖性腫瘍 (MPN)の発症機序の解明へと繋がった。EpoRのY343、Y460、Y464のリン酸化は、STAT5を介した発がん誘導機構に必須であるのに対して、EpoRのY401のリン酸化は、CISとの結合を介して、発現シグナルに抑制的に機能することを見出した。本研究成果は、MPNの治療標的分子の同定へと繋がることが期待される。
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