Investigation of the Roles of Dephosphorylated Parafibromin by SHP2 in Oncogenesis

2013 Fiscal Year Final Research Report

• Project/Area Number: 24700965
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: The University of Tokyo
• Principal Investigator: TAKAHASHI Atsushi 東京大学, 医学(系)研究科(研究院), 助教 (00624496)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Keywords: 分子生物学 / がん / シグナル伝達 / タンパク質リン酸化／脱リン酸化 / 遺伝子発現制御

Research Abstract

In the 1st fiscal year ended March 2013, (1) We found a cancer-derived point mutant of parafibromin functionally mimicking the tyrosine-dephosphorylated parafibromin, which promotes the Wnt signaling pathway through forming a complex with beta-catenin. (2) We identified a nuclear tyrosine kinase that can elevate the tyrosine-phosphorylation of parafibromin.
In the 2nd fiscal year ended March 2014, (3) We found that SHP2 physically interacts with transcriptional co-activators YAP and TAZ, components of the cell-density sensing Hippo signaling pathway. We revealed the YAP/TAZ-dependent regulatory mechanism of the nuclear accumulation of SHP2, which promotes the Wnt signaling pathway through tyrosine-dephosphorylation of parafibromin.

Research Products

• [Journal Article] YAP and TAZ, Hippo Signaling Targets, Act as a Rheostat for Nuclear SHP2 Function (2013)
  • Author(s): 堤良平, マサウディムハンマド, 高橋昌史, 藤井裕美子, 林剛瑠, 菊地逸平, 佐藤夢子, 平良眞規, 畠山昌則
  • Journal Title: Developmental Cell Volume: 26巻 Pages: 658-665
  • DOI: 10.1016/j.devcel.2013.08.013
  • Peer Reviewed
• [Presentation] LEOPARD症候群特異的変異型SHP2のチロシンホスファターゼ活性解析 (2014)
  • Author(s): 野田沙織, 高橋昌史, 林剛瑠, 畠山昌則
  • Organizer: 第6回日本プロテインホスファターゼ研究会学術集会
  • Place of Presentation: 三重大学
  • Year and Date: 20140220-21
• [Presentation] SHP2 tyrosine phosphatase converts parafibromin/Cdc73 from a tumor suppressor to an oncogenic driver (2014)
  • Author(s): 高橋昌史
  • Organizer: 第6回日本プロテインホスファターゼ研究会学術集会
  • Place of Presentation: 三重大学
  • Year and Date: 20140220-21
• [Presentation] YAP1-mRNAの選択的スプライシングによるSHP2/YAP1相互作用の制御 (2014)
  • Author(s): 高橋昌史, 堤良平, マサウディムハンマド, 林剛瑠, 畠山昌則
  • Organizer: がん研究分野の特性等を踏まえた支援活動公開シンポジウム
  • Place of Presentation: 一橋記念講堂(学術総合センター)
  • Year and Date: 20140130-31
• [Presentation] Regulation of SHP2-YAP Interaction by Differential Splicing of YAP mRNA (2013)
  • Author(s): M.Masoudi, R.Tsutsumi, T.Hayashi, A.Takahashi, M.Hatakeyama
  • Organizer: The 4^<th> JCA-AACR Special Joint Conference
  • Place of Presentation: Tokyo Bay Maihama Hotel Club Resort
  • Year and Date: 20131216-18
• [Presentation] Tyrosine Phosphatase Activity of SHP2 Mutants Derived from LEOPARD Syndrome (2013)
  • Author(s): S.Noda, A.Takahashi, T.Hayashi, R.Tsutsumi, M.Hatakeyama
  • Organizer: The 4^<th> JCA-AACR Special Joint Conference
  • Place of Presentation: Tokyo Bay Maihama Hotel Club Resort
  • Year and Date: 20131216-18
• [Presentation] LEOPARD症候群由来変異型SHP2ホスファターゼのin vitro酵素活性解析 (2013)
  • Author(s): 野田沙織, 高橋昌史, 林剛瑠, 堤良平, 畠山昌則
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 20131003-05
• [Presentation] 複数のチロシンキナーゼによるSHP2/parafibromin依存的Wntシグナル活性化の拮抗制御 (2012)
  • Author(s): 高橋昌史, 齊藤康弘, 畠山昌則
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌市教育文化会館・ロイトン札幌・さっぽろ芸文館
  • Year and Date: 20120919-21