Structural basis for activation of the oncogenic nonreceptor tyrosine kinase Fer

• Project/Area Number: 16K07268
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Structural biochemistry
• Research Institution: Nagoya University
• Principal Investigator: Matsuura Yoshiyuki 名古屋大学, 理学研究科, 准教授 (10402413)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: シグナル伝達 / X線結晶解析 / チロシンキナーゼ / がん / 構造生物学

Outline of Final Research Achievements

Fer and Fes proteins constitute a distinct subfamily of nonreceptor tyrosine kinases characterized by a unique multidomain structure. Fer is ubiquitously expressed, and can be activated as a response to stimulation of growth factor receptors including epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR). Upregulation of Fer has been implicated in tumorigenesis and malignant progression of various human cancers. This study was undertaken to understand the activation mechanism of Fer, and a structure of one of the domains of Fer bound to a ligand molecule was determined at high resolution.

Academic Significance and Societal Importance of the Research Achievements

がんの増殖には、基質タンパク質のチロシンをリン酸化するチロシンキナーゼが深く関わっている。一般にチロシンキナーゼは、細胞の増殖・分化、細胞運動、免疫応答など、多様な生理機能を制御する複雑なシグナル伝達系の鍵を握る酵素である。本研究では、抗がん剤開発の標的タンパク質として注目されている非受容体型チロシンキナーゼFerに関する構造解析を行った。本研究はチロシンキナーゼの作用機序を解き明かすための基礎研究としての意義をもつ。