Regulation of regeneration, disease and carcinogenesis throughthe ON-OFF conversion of the cMet/HGF receptor.

• Project/Area Number: 23790327
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General medical chemistry
• Research Institution: Kanazawa University
• Principal Investigator: NAKAMURA Takahiro 金沢大学, がん進展制御研究所, 助教 (70414018)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: HGF / Met / 組織再生 / シグナル伝達 / 肝細胞増殖因子

Research Abstract

Regulation mechanisms of the ON-OFF conversion of the HGF-cMetsignal had remained to be clarified. We found that phosphorylation of the cMet-Ser985was involved in suppression of the HGF-dependent cMet bioactivity through internalization of the cMet intracellularly from the cell surface. Moreover, we found that cMet exerts its biological activities only when they were dimer, and never exerts when monomer, even if strongly phosphorylated.

Research Products

• [Journal Article] α-Lipoic Acid-Induced Inhibition of Proliferation and Met Phosphorylation in Human Non-Small Cell Lung Cancer Cells (2013)
  • Author(s): Michikoshi H, Nakamura T (contributed equally), Sakai K, Suzuki Y, Adachi E, Matsugo S, and Matsumoto K
  • Journal Title: α-Lipoic Acid-Induced Inhibition of Proliferation and Met Phosphorylation in Human Non-Small Cell Lung Cancer Cells Volume: (in press)
  • NAID: 120005254051
  • URL: http://www.sciencedirect.com/science/article/pii/S030438351300236X
  • Peer Reviewed
• [Journal Article] Met/HGF receptor activation is regulated by juxtamembrane Ser985 phosphorylation in hepatocytes (2013)
  • Author(s): Nakayama M, Sakai K, Yamashita A, Nakamura T, Suzuki Y, and Matsumoto K
  • Journal Title: Cytokine Volume: (in press)
  • URL: http://www.sciencedirect.com/science/article/pii/S1043466613001543
  • Peer Reviewed
• [Journal Article] The novel phosphoinositide 3-kinase-mammalian target of rapamycin inhibitor, BEZ235, circumvents erlotinib resistance of epidermal growth factor receptor mutant lung cancer cells triggered by hepatocyte growth factor. (2013)
  • Author(s): Sano T, Yano S, et al.
  • Journal Title: IntJ Cancer Volume: 133 Pages: 505-13
  • DOI: 10.1002/ijc.28034
  • Peer Reviewed
• [Journal Article] HGF regulates VEGF expression via the c-Met receptor downstream pathways, PI3K/Akt, MAPK and STAT3, in CT26 murine cells (2013)
  • Author(s): Matsumura A, Kubota T, Taiyoh H, Fujiwara H, Okamoto K, Ichikawa D, Shiozaki A, Komatsu S, Nakanishi M, Kuriu Y, Murayama Y, Ikoma H, Ochiai T, Kokuba Y, Nakamura T, Matsumoto K, and Otsuji E
  • Journal Title: Int J Oncol. Volume: Vol. 42: no.2 Pages: 535-542
  • DOI: 10.3892/ijo.2012.1728
  • Peer Reviewed
• [Journal Article] Combined therapy with mutantselective EGFR inhibitor and Met kinase inhibitor for overcoming erlotinib resistance in EGFR-mutant lung cancer (2012)
  • Author(s): Nakagawa T, Takeuchi S, Yamada T, Nanjo S, Ishikawa D, Sano T, Kita K, Nakamura T, Matsumoto K, Suda K, Mitsudomi T, Sekido Y, Uenaka T, and Yano S
  • Journal Title: Mol Cancer Ther Volume: Vol. 11: no.10 Pages: 2149-2157
  • Peer Reviewed
• [Journal Article] Dual inhibition of met kinase and angiogenesis to overcome HGF-induced EGFR-TKI resistance in EGFR mutant lung cancer (2012)
  • Author(s): Takeuchi S, Wang W, Li Q, Yamada T, Kita K, Donev IS, Nakamura T, Matsumoto K, Shimizu E, Nishioka Y, Sone S, Nakagawa T, Uenaka T, Yano
  • Journal Title: The American Journal of Pathology Volume: 181 Pages: 1034-1043
  • DOI: 10.1016/j.ajpath.2012.05.023
  • Peer Reviewed
• [Journal Article] Paracrine receptor activation by microenvironment triggers bypass survival signals and ALK inhibitor resistance in EML4-ALK lung cancer cells (2012)
  • Author(s): Yamada, T.
  • Journal Title: Clin Cancer Res. Volume: 18 Pages: 3592-35602
  • DOI: 10.1158/1078-0432.ccr-11-2972
  • Peer Reviewed
• [Journal Article] Hsp90 Inhibition Overcomes HGF Triggering Resistance to EGFR-TKIs in EGFR-Mutant Lung Cancer by Decreasing Client Protein Expression and Angiogenesis (2012)
  • Author(s): Koizumi H, Yamada T, Takeuchi S, Nakagawa T, Kita K, Nakamura T, Matsumoto K, Suda K, Mitsudomi T, and Yano S
  • Journal Title: J Thoracic Oncol Volume: Vol. 7: no.7 Pages: 1078-1085
  • DOI: 10.1097/jto.0b013e3182519a2c
  • NAID: 40019570662
  • Peer Reviewed
• [Journal Article] E7050, a Met kinase inhibitor, reverses three different mechanisms of hepatocyte growth factor-induced resistance to tyrosine kinase inhibitors in EGFR mutant lung cancer cells (2012)
  • Author(s): Wang W, Li Q, Takeuchi S, Yamada T, Koizumi H, Nakamura T, Matsumoto K, Mukaida N, Nishioka Y, Sone S, Uenaka T, Yano S
  • Journal Title: Clin Cancer Res. Volume: 18 Pages: 1663-1671
  • DOI: 10.1158/1078-0432.ccr-11-1171
  • Peer Reviewed
• [Journal Article] Suppression of acute hepatic injury by a synthetic prostacyclin agonist through hepatocyte growth factor expression (2012)
  • Author(s): Qing Xu
  • Journal Title: Am J Physiol Gastrointest Liver Physiol Volume: 302 Pages: 420-429
  • DOI: 10.1152/ajpgi.00216.2011
  • Peer Reviewed
• [Journal Article] Hepatocyte growth factor induces resistance to anti-epidermal growth factor receptor antibody in lung cancer (2012)
  • Author(s): Yamada T, Takeuchi S, Kita K, Bando H, Nakamura T, Matsumoto K, Yano S
  • Journal Title: J Thoracic Oncol Volume: 7 Pages: 272-280
  • DOI: 10.1097/jto.0b013e3182398e69
  • Peer Reviewed
• [Journal Article] Combined therapy with mutant-selective EGFR inhibitor and Met kinase inhibitor for overcoming erlotinib resistance in EGFR-mutant lung cancer (2012)
  • Author(s): Nakagawa T
  • Journal Title: Molecular Cancer Therapeutics Volume: 11 Pages: 2149-2157
  • DOI: 10.1158/1535-7163.mct-12-0195
  • Peer Reviewed
• [Journal Article] Hepatocyte Growth Factor Induces Resistance to Anti-Epidermal Growth Factor Receptor Antibody in Lung Cancer (2012)
  • Author(s): Yamada, T
  • Journal Title: J Thorac Oncol. Volume: 7 Pages: 272-280
  • Peer Reviewed
• [Journal Article] Suppression of acute hepatic injury by a synthetic prostacyclin agonist through hepatocyte growth factor expression (2012)
  • Author(s): Xu, Q
  • Journal Title: Am J Physiol Gastrointest Liver Physiol Volume: 302
  • Peer Reviewed
• [Journal Article] 3-D collagen-dependent cell surface expression of MT1-MMP and MMP-2 activation regardless of integrin β1 function and matrix stiffness (2011)
  • Author(s): Sakai K, Nakamura T, Suzuki Y, ImizuT, and Matsumoto K
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 412 Pages: 98-103
  • DOI: 10.1016/j.bbrc.2011.07.050
  • NAID: 120003308573
  • Peer Reviewed
• [Journal Article] NK4 Gene Expression Enhances 5-Fluorouracil -induced Apoptosis of Murine Colon Cancer Cells (2011)
  • Author(s): Taiyoh H, Kubota T, Fujiwara H, Matsumura A, Murayama Y, Okamoto K, Ichikawa D, Ochiai T, Nakamura T, Matsumoto K, Nnakamura T, and Otsuji E
  • Journal Title: ANTICANCER RESEARCH Volume: Vol. 31 Pages: 2217-2224
  • URL: http://ar.iiarjournals.org/content/31/6/2217.long
  • Peer Reviewed
• [Journal Article] NK4 Gene Expression Enhances 5-Fluorouracil-induced Apoptosis of Murine Colon Cancer Cells (2011)
  • Author(s): Taiyo, H
  • Journal Title: Anticancer Res Volume: 31 Pages: 2217-2224
  • Peer Reviewed
• [Presentation] 肺がん細胞を用いたWnt/betacateninシグナル抑制におけるKremen1の機能解析 (2012)
  • Author(s): 中村隆弘
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌(北海道)
  • Year and Date: 2012-09-19
• [Presentation] Dual inhibition of Met kinase and angiogenesis to overcome HGF-induced EGFR-TKI resistance in EGFR mutantlung cancer (2011)
  • Author(s): 竹内伸司
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 第70回日本癌学会学術総会
  • Year and Date: 2011-10-03
• [Presentation] Functional Analyses of the Kremen in Lung Cancer Cells through Wnt/β-catenin Signaling Pathway (2011)
  • Author(s): 中村隆弘
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都国際会議場(京都府)
  • Year and Date: 2011-09-22
• [Presentation] Suppression of acute hepatic injury by prostacyclin agonist through enhancing hepatocyte growth factor expression in mice (2011)
  • Author(s): 徐慶
  • Organizer: 日本分子生物学会北陸支部第11回シンホシウム
  • Place of Presentation: 石川県立音楽堂(石川県)
  • Year and Date: 2011-05-25
• [Presentation] Functional Analyses of the Kremen in Lung Cancer Cells through Wnt/β-catenin Signaling Pathway (2011)
  • Author(s): 中村隆弘
  • Organizer: 日本分子生物学会北陸支部第11回シンホシウム
  • Place of Presentation: 石川県立音楽堂(石川県)
  • Year and Date: 2011-05-25
• [Presentation] ヒト肺がん細胞に対するリポ酸の増殖抑制作用とそのメカニズム (2011)
  • Author(s): 道越洸充
  • Organizer: 第63回日本生物工学会大会
  • Place of Presentation: 東京農工大学(東京都)
• [Presentation] Functional Analyses of the Kremen in Lung Cancer Cells through Wnt/β-catenin Signaling Pathway (2011)
  • Author(s): 中村隆弘
  • Organizer: 日本生化学会第84回大会
  • Place of Presentation: 京都国際会議場（京都府）
• [Presentation] 肺がん細胞を用いたWnt/beta-cateninシグナル抑制におけるKremen1の機能解析
  • Author(s): 中村隆弘
  • Organizer: 日本癌学会学術総会
  • Place of Presentation: ロイトン札幌（札幌）
• [Book] Advances in Cancer Therapy (2011)
  • Author(s): Sakai K, Nakamura T, Suzuki Y, and Matsumoto K
  • Publisher: Significance, Mechanisms, and Progress of Anticancer Drugs Targeting HGF-Met
• [Remarks]
  • URL: http://www.kanazawa-u.ac.jp/~ganken/shuyoudoutaiseigyo/index.html
• [Remarks] 金沢大学がん進展制御研究所腫瘍動態制御研究分野
  • URL: http://www.kanazawa-u.ac.jp/~ganken/shuyoudoutaiseigyo/index.html