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2019 Fiscal Year Final Research Report

Fate determination of nuclear STAT3

Research Project

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Project/Area Number 17K08639
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field General medical chemistry
Research InstitutionOsaka City University

Principal Investigator

Nakajima Koichi  大阪市立大学, 大学院医学研究科, 教授 (00227787)

Co-Investigator(Kenkyū-buntansha) 趙 虹  大阪市立大学, 大学院医学研究科, 特任講師 (10596183)
國本 浩之  大阪市立大学, 大学院医学研究科, 助教 (80372853)
Project Period (FY) 2017-04-01 – 2020-03-31
KeywordsSTAT3 / pY705-SH2 構造 / pS727 / コンフォメーション変化 / 核外輸送系
Outline of Final Research Achievements

STAT3 pY705 stabilizes STAT3 dimer with reciprocal pY705-SH2 interaction and pS727 accelerates pY705 dephosphorylation. We studied how pS727 regulates STAT3 in both structural and biological perspectives. Using reconstituted STAT3 in HepG2, we showed that pS727, together with a hand-shake NTD interaction, causes rapid inactivation of STAT3 for pY705 dephosphorylation and a CRM1-independent nuclear export. Various N-terminal tags rendered the export CRM1-dependent, suggesting the importance of conformational changes in inactivation. The detailed analysis of the pY705-SH2 structure identified the C-terminal-tail (CTT) from L706 to P715 as a key regulator for the CTT-CTT intermolecular and the CTT-SH2 intramolecular interactions that support pY705-SH2 association. Importantly, Pro715 was critical for the pS727’s destabilizing activity. Thus, pS727 triggers pY705-SH2 dissociation by weakening the supportive interactions likely through CTT modulation for proper function of STAT3.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

いずれのSTATファミリーも活性化ー非活性化サイクルを行うことで正しく細胞内シグナルを受容し、遺伝子発現制御を行っている。このSTAT 活性化ー非活性化サイクルの実体を明らかにし、制御系を知ることが、生理的意味を知るだけでなく、治療法開発に重要である。申請者らのSTAT3研究で、この活性化ー非活性化サイクルがpS727リン酸化、NTD相互作用、コンフォーメーション変化、CRM1非依存的核外輸送系などにより制御されることがわかってきた。さらなる研究のもと効果的な制御方開発を進める基盤ができたきたと考えている。

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Published: 2021-02-19  

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