Novel functions and regulatory mechanisms of tumor suppressor Mig-6

• Project/Area Number: 22300329
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: KITAGAWA Masatoshi 浜松医科大学, 医学部, 教授 (50294971)
• Co-Investigator(Kenkyū-buntansha): MATSUMOTO Masaki 九州大学, 生体防御医学研究所, 准教授 (60380531)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2012: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2011: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2010: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: リン酸化 / シグナル伝達 / 細胞増殖 / EGF / Mig-6 / 癌 / 癌抑制遺伝子 / リン酸

Research Abstract

Mig-6 acts as an inhibitor of EGF signaling via binding with the EGF receptor (EGFR). Downregulated expression of the Mig-6 gene is observed in breast carcinomas, in which it correlates with reduced overall survival. Mig-6-deficient mice show hyperactivation of endogenous EGFR and develop spontaneous tumors in various organs. Therefore, Mig-6 is an important tumor suppressor. However, its post-translational modifications and regulatory mechanisms have not been elucidated. Here, we investigated the phosphorylation of human Mig-6 and found that Chk1 phosphorylated Mig-6 in vivo as well as in vitro. Moreover, EGF stimulation promoted phosphorylation of Mig-6 without DNA damage and the phosphorylation was inhibited by depletion of Chk1. EGF also increased Ser280-phosphorylated Chk1, a cytoplasmic-tethering form, via PI3K pathway. Mass spectrometric analyses suggested that Ser 251 of Mig-6 was a major phosphorylation site by Chk1 in vitro and in vivo. Substitution of Ser 251 to alanine increased inhibitory activity of Mig-6 against EGFR activation. Moreover, EGF-dependent activation of EGFR and cell growth were inhibited by Chk1-depletion, and were rescued by co-depletion of Mig-6. Our results suggest that Chk1 phosphorylates Mig-6 on Ser 251, resulting in the inhibition of Mig-6, and that Chk1 acts a positive regulator of EGF signaling. This is a novel function of Chk1.

Research Products

• [Journal Article] ユビキチンシステムによる細胞周期制御と疾患 腎疾患におけるユビキチンシステムの機能 (2013)
  • Author(s): 北川雅敏
  • Journal Title: 実験医学増刊号 Volume: 31 Pages: 33-38
• [Journal Article] Decreased tonic inhibition in cerebellar granule cells causes motor dysfunction in a mouse model of Angelman syndrome (2012)
  • Author(s): Egawa, K., Kitagawa, K., Inoue K., Takayama,M.,Takayama, C., Saitoh, S., Kishino, T.,Kitagawa, M., Fukuda, A
  • Journal Title: Sci Transl Med Volume: 4 Pages: 1-10
• [Journal Article] Chk1 phosphorylates the tumor suppressor Mig-6, regulating the activation of EGF signaling (2012)
  • Author(s): Liu, N., Matsumoto M., Kitagawa K., Kotake Y., Suzuki S., Shirasawa S., Nakayama KI., Nakanishi M., Niida H., Kitagawa M
  • Journal Title: EMBO J Volume: 31 Pages: 2365-2377
• [Journal Article] Long noncoding RNA involved in cancer development and cell fate determination (2012)
  • Author(s): Kitagawa, M., Kotake, Y. and Ohhata, T
  • Journal Title: Curr. Drug Targets Volume: 13 Pages: 1616-1621
• [Journal Article] The SCF ubiquitin ligases involved in hematopoietic linage (2012)
  • Author(s): Kitagawa, K. and Kitagawa, M
  • Journal Title: Curr. Drug Targets Volume: 13 Pages: 1641-1648
• [Journal Article] Regulation of DNA replication licensing. (2012)
  • Author(s): Niida, H. and Kitagawa, M
  • Journal Title: Curr. Drug Target Volume: 13 Pages: 1588-1592
• [Journal Article] The amelioration of renal damage in Skp2-deficient mice is canceled by p27 Kip1deficiency in Skp2-/- p27-/- mice (2012)
  • Author(s): Suzuki, S., Fukasawa, H., Misaki, T., Togawa A., Ohashi, N., Kitagawa, K., Kotake, Y., Niida, H., Liu, N., Nakayama. K., Nakayama, K.I., Yamamoto, T. and Kitagawa, M
  • Journal Title: PLoS ONE Volume: 7
• [Journal Article] Protein Degradation by the Ubiquitin-Proteasome Pathway and Organ Fibrosis (2012)
  • Author(s): Fukasawa, H., Fujigaki Y., Yamamato, T., Hishida, A. and Kitagawa, M.
  • Journal Title: CurrentMedicinal Chemistry (review article) Volume: 19 Pages: 893-900
• [Journal Article] Decreased tonic inhibition in cerebellar granule cells causes motor dysfunction in a mouse model of Angelman syndrome. (2012)
  • Author(s): Egawa, K., et al.
  • Journal Title: Sci. Transl. Med. Volume: 4 Issue: 163
  • DOI: 10.1126/scitranslmed.3004655
  • Peer Reviewed
• [Journal Article] Roles of the Skp2/p27 axis in the progression of chronic nephropathy (2012)
  • Author(s): Suzuki, S., Ohashi, N. and Kitagawa, M
  • Journal Title: Cell Mol Life Sci Volume: (in press) Issue: 18 Pages: 3277-3289
  • DOI: 10.1007/s00018-012-1232-x
  • Peer Reviewed
• [Journal Article] Chkl phosphorylates the tumor suppressor Mig-6, regulating the activation of EGF signaling. (2012)
  • Author(s): Liu, N., et al.
  • Journal Title: EMBO J. Volume: 31 Issue: 10 Pages: 2365-2377
  • DOI: 10.1038/emboj.2012.88
  • Peer Reviewed
• [Journal Article] Long noncoding RNA involved in cancer development and cell fate determination. (2012)
  • Author(s): Kitagawa, M., et al.
  • Journal Title: Curr. Drug Targets Volume: 13 Issue: 13 Pages: 1616-1621
  • DOI: 10.2174/138945012803530026
  • Peer Reviewed
• [Journal Article] The SCF ubiquitin ligases involved in hematopoietic linage. (2012)
  • Author(s): Kitagawa, K., Kitagawa, M.
  • Journal Title: Curr. Drug Targets Volume: 13 Issue: 13 Pages: 1641-1648
  • DOI: 10.2174/138945012803529974
  • Peer Reviewed
• [Journal Article] Regulation of DNA replication licensing. (2012)
  • Author(s): Niida, H., Kitagawa, M.
  • Journal Title: Curr. Drug Targets Volume: 13 Issue: 13 Pages: 1588-1592
  • DOI: 10.2174/138945012803529965
  • Peer Reviewed
• [Journal Article] Protein Degradation by the Ubiquitin-Proteasome Pathway and Organ Fibrosis (2012)
  • Author(s): Fukasawa, H., et al
  • Journal Title: Current Medicinal Chemistry Volume: 19 Pages: 893-900
  • Peer Reviewed
• [Journal Article] Up-regulation of Cks1 and Skp2 with TNFa/NFkB signaling in chronic progressive nephropathy (2011)
  • Author(s): Suzuki, S., Fukasawa, H., Misaki, T., Togawa A., Ohashi, N., Kitagawa, K., Kotake, Y., Niida, H., Hishida, A., Yamamoto, T. and Kitagawa M
  • Journal Title: Genes Cells Volume: 16 Pages: 1110-1120
• [Journal Article] (*co-corresponding authors): Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15INK4B tumor suppressor gene (2011)
  • Author(s): Kotake, Y., Nakagawa, T., Kitagawa, K., Suzuki, S., Liu, N., Kitagawa, M. and Xiong, Y
  • Journal Title: Oncogene Volume: 30 Pages: 1956-1962
• [Journal Article] Coordinated regulation of differentiation and proliferation of embryonic cardiomyocytes by a Jumonnji (Jarid2)-cyclin D1 pathway (2011)
  • Author(s): Nakajima, K., Inagawa, M., Uchida, C., Okada, K., Kojima, M., Kubota, K., Noda, M., Ogawa S., Shirato, H., Sato M., Suzuki-Migishima, R., Hino, T., Kitagawa, M. and Takeuchi, T
  • Journal Title: Development Volume: 138 Pages: 1771-1782
• [Journal Article] SCFβTrCP mediates stress-activated MAP kinase-induced Cdc25B degradation. (2011)
  • Author(s): Uchida, S., Watanabe, N., Kudo, Y., Yoshioka, K., Matsunaga, T., Ishizaka, Y., Nakagama, H., Poon, R.Y.C., and *Yamashita, K
  • Journal Title: J. Cell Sci Volume: 124 Pages: 2816-2825
• [Journal Article] Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of P15INK4B tumor suppressor gene. (2011)
  • Author(s): Kotake, Y., et al.
  • Journal Title: Oncogene Volume: 30 Issue: 16 Pages: 1110-1120
  • DOI: 10.1038/onc.2010.568
  • Peer Reviewed
• [Journal Article] Up-regulation of Cksl and Skp2 with TNFcx/NFkB signaling in chronic progressive nephropathy. (2011)
  • Author(s): Suzuki, S., et al.
  • Journal Title: Genes Cells Volume: 16 Issue: 11 Pages: 1110-1120
  • DOI: 10.1111/j.1365-2443.2011.01553.x
  • Peer Reviewed
• [Journal Article] 長鎖ncRNAによるクロマチン修飾因子のリクルートメント機構 (2011)
  • Author(s): 神武洋二郎、北川雅敏
  • Journal Title: 実験医学 Volume: 29 Pages: 1716-1721
• [Journal Article] 長鎖ノンコーディングRNAと細胞老化 (2011)
  • Author(s): 神武洋二郎、北川雅敏
  • Journal Title: 細胞工学 Volume: 20 Pages: 729-733
• [Journal Article] GSK3 regulates the expression of human and mouse c-Myb via different mechanisms (2010)
  • Author(s): Kitagawa, K., Kotake, Y., Hiramatsu, Y., Liu, N., Suzuki, S., Nakamura, S., Kikuchi, A. and Kitagawa, M
  • Journal Title: Cell Div Volume: 5 Pages: 27-27
  • NAID: 120005305355
• [Journal Article] Kaposi's sarcoma-associated herpesvirus- encoded LANA positively affects on ubiquitylation of p53 (2010)
  • Author(s): Suzuki, T., Isobe, T., Kitagawa, M. and Ueda, K.
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 403 Pages: 194-197
• [Journal Article] Hepatocyte Growth Factor stimulated cell scattering requires ERK and Cdc42-dependent Tight Junction Disassembly (2010)
  • Author(s): Togawa, A., Sfakianos, J., Ishibe, S., Suzuki, S., Fujigaki, Y., Kitagawa, M., Mellman, I. and Cantley, L.G
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 400 Pages: 271-277
• [Journal Article] Dual mode of regulation of Cdc25A protein by TRB3 (2010)
  • Author(s): Sakai, S., Ohoka, N., Onozaki, K., Kitagawa, M., Nakanishi, M. and Hayashi, H
  • Journal Title: Biol. Pharm. Bull Volume: 33 Pages: 1112-1116
• [Journal Article] Reduction of transforming growth factor-ss type II receptor is caused by the enhanced ubiquitin-dependent degradation in human renal cell carcinoma (2010)
  • Author(s): Fukasawa, H., Yamamoto, T., Fujigaki, Y., Misaki, T., Ohashi, N., Takayama, T., Suzuki, S., Mugiya, S., Oda, T., Uchida, C., Kitagawa, K., Hattori, T., Hayashi, H., Ozono, S., Kitagawa, M. and Hishida, A
  • Journal Title: Int. J. Cancer Volume: 127 Pages: 1517-1525
• [Journal Article] p27 modulates tropism of mesenchymal stem cells toward brain tumors.Exp (2010)
  • Author(s): Gao, Y., Gu, C., Li, S., Tokuyama, T.,Yokota, N., Nakayama, K.I., Kitagawa, M.and Namba, H
  • Journal Title: Ther. Med Volume: 1 Pages: 695-699
• [Journal Article] GSK3 regulates the expression of human and mouse c-Myb via different mechanisms. (2010)
  • Author(s): Kitagawa, K., et al.
  • Journal Title: Cell Division Volume: 5 Pages: 27-27
  • NAID: 120005305355
  • Peer Reviewed
• [Journal Article] Kaposi's sarcoma-associated herpesvirus-encoded LANA positively affects on ubiquitylation of p53. (2010)
  • Author(s): Suzuki, T., et al.
  • Journal Title: Biochem.Biophys.Res.Commun. Volume: 403 Pages: 194-197
  • Peer Reviewed
• [Journal Article] Hepatocyte Growth Factor stimulated cell scattering requires ERK and Cdc42-dependent Tight Junction Disassembly. (2010)
  • Author(s): Togawa, A., et al.
  • Journal Title: Biochem.Biophys.Res.Commun. Volume: 400 Pages: 271-277
  • Peer Reviewed
• [Journal Article] Dual mode of regulation of Cdc25A protein by TRB3. (2010)
  • Author(s): Sakai, S., et al.
  • Journal Title: Biol.Pharm.Bull. Volume: 33 Pages: 1112-1116
  • Peer Reviewed
• [Journal Article] Reduction of transforming growth factor-ss type II receptor is caused by the enhanced ubiquitin-dependent degradation in human renal cell carcinoma. (2010)
  • Author(s): Fukasawa, H., et al.
  • Journal Title: Int.J.Cancer Volume: 127 Pages: 1517-1525
  • Peer Reviewed
• [Journal Article] p27 modulates tropism of mesenchymal stem cells toward brain tumors. (2010)
  • Author(s): Gao, Y., et al.
  • Journal Title: Exp.Ther.Med. Volume: 1 Pages: 595-699
  • Peer Reviewed
• [Journal Article] Roles of the Skp2/p27 axis in the progression of chronic nephropathy
  • Author(s): Suzuki, S., Ohashi, N. and Kitagawa, M
  • Journal Title: Cell Mol Life Sci
• [Presentation] Chk1 phosphorylates the tumor suppressor Mig-6, regulating the activation of EGF signaling. (2012)
  • Author(s): 北川雅敏、劉寧
  • Organizer: 第45回日本発生生物学会、第64回日本細胞生物学会合同年会
  • Place of Presentation: 神戸
  • Year and Date: 2012-05-31
• [Presentation] Phosphorylation-mediated regulation of the tumor suppressor Mig-6. (2011)
  • Author(s): 北川雅敏
  • Organizer: 日本癌学会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-04
• [Presentation] Phosphorylation-mediated regulation of the tumor suppressor Mig-6 (2011)
  • Author(s): 北川雅敏
  • Organizer: 日本癌学会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-04
• [Presentation] Chk1 の新機能 (2011)
  • Author(s): 北川雅敏
  • Organizer: 日本生化学会
  • Place of Presentation: 日横浜
  • Year and Date: 2011-09-22
• [Presentation] Chk1の新機能 (2011)
  • Author(s): 北川雅敏
  • Organizer: 日本生化学会
  • Place of Presentation: 横浜
  • Year and Date: 2011-09-22
• [Presentation] 長鎖ノンコーディング RNAANRIL は INK4 locus の転写抑制を介し細胞増殖に関与する (2011)
  • Author(s): 北川雅敏
  • Organizer: 日本細胞生物学会
  • Place of Presentation: 札幌
  • Year and Date: 2011-06-27
• [Presentation] 長鎖ノンコーディングRNA ANRILはINK4 locusの転写抑制を介し細胞増殖に関与する (2011)
  • Author(s): 北川雅敏
  • Organizer: 日本細胞生物学会
  • Place of Presentation: 札幌
  • Year and Date: 2011-06-27
• [Presentation] 増殖シグナルの新たな制御機構 (2010)
  • Author(s): 北川雅敏, 他
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会合同大会(BMB2010)
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-10
• [Presentation] 癌抑制遺伝子産物Mig-6のリン酸化とその責任酵素の解析 (2010)
  • Author(s): Ning Liu, 他
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会合同大会(BMB2010)
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-10
• [Presentation] 慢性進行性腎障害におけるCks1およびSkp2の発現亢進の意義 (2010)
  • Author(s): 鈴木小由里, 他
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会合同大会(BMB2010)
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-09
• [Presentation] CUL4-DDB1/MLL complex activates the p16 transcription through histone H3K4 methylation (2010)
  • Author(s): Yojiro Kotake, 他
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会合同大会(BMB2010)
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-08
• [Presentation] GSK3によるc-Mybの量的制御機構 (2010)
  • Author(s): 北川恭子, 他
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会合同大会(BMB2010)
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-07
• [Presentation] A novel target and function of Chk1 (2010)
  • Author(s): Masatoshi Kitagawa
  • Organizer: MEXT Priority Research Project "Cell Proliferation Control" International Symposium Cell Cycle and Cell Differentiation From A to Z
  • Place of Presentation: 名古屋
  • Year and Date: 2010-11-06
• [Presentation] Recent Progress of long non-coding RNA research
  • Author(s): 大畑樹也
  • Organizer: 鰢台1回日本癌学会総会
  • Place of Presentation: 札幌
  • Invited
• [Presentation] Chk1 phosphorylates the tumor suppressor Mig-6, regulating the activation of EGF signaling.
  • Author(s): 北川雅敏
  • Organizer: 第45回日本発生生物学会、第64回日本細胞生物学会合同年会
  • Place of Presentation: 神戸
• [Remarks]
  • URL: http://www.hama-med.ac.jp/uni_education_igakubu_igaku_seika1.html
• [Remarks] 浜松医科大学医学部 分子生物学講座
  • URL: http://www.hama-med.ac.jp/uni_education_igakubu_igaku_seika1.html
• [Remarks]
  • URL: http://www.hama-med.ac.jp/uni_education_igakubu_igaku_seika1.html
• [Remarks]
  • URL: http://www2.hama-med.ac.jp/w1a/bio1/index-j.html
• [Patent(Industrial Property Rights)] 癌治療用組成物 (2012)
  • Inventor(s): 北川雅敏、高芸、北川恭子
  • Industrial Property Rights Holder: 浜松医科大学
  • Acquisition Date: 2012-04-13
• [Patent(Industrial Property Rights)] 癌の転移性及び浸潤能の検査方法 (2011)
  • Inventor(s): 北川雅敏、高芸、北川恭子
  • Industrial Property Rights Holder: 浜松医科大学
  • Acquisition Date: 2011-12-22