Regulation of cell polarity formation and maintenance by Rho/Rhotekin signal and septins

2008 Fiscal Year Final Research Report

• Project/Area Number: 19590299
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Institute for Developmental Research, Aichi Human Service Center
• Principal Investigator: NAGATA Koh-ichi Institute for Developmental Research, Aichi Human Service Center, 神経制御学部, 部長 (50252143)
• Project Period (FY): 2007 – 2008
• Keywords: シグナル伝達 / 生体分子 / セプチン / 細胞骨格 / Rho

Research Abstract

低分子量G蛋白質Rhoとその標的蛋白質であるRhotekinの下流で機能する蛋白質の候補として,多機能アダプター蛋白質であるVinexinとp140Capを見出した。シナプスに局在するVinexinのMAPキナ-ゼによるリン酸化の分子機構を明らかにした。また、がん細胞においてはERK-MAPキナ-ゼによるVinexinのリン酸化は細胞の伸展、遊走、および足場非依存性の増殖に必須であることを示した。さらに、p140Capのシナプスにおける機能解析を遂行した。また、最近、遺伝性神経痛性筋萎縮症(HNA)の原因遺伝子としてセプチン分子の一種であるSept9が同定された。この知見に基づき、Rho/RhotekinとSept9との相互作用の異常がHNAの病態の基礎になり、それが神経細胞自身の機能異常に基づく可能性を示した。また、ラット脳の発達に伴うセプチンの発現変化を調べたところ、生後発達に伴ってSept8の発現が顕著に増加していた。また、蛍光抗体法により、ラット海馬神経細胞におけるSept8の局在を検討したところ、シナプスのマーカーであるシナプトフイシンとよく一致していた Sept8の生理機能を明らかにすることを目指し、Sept8と結合するタンパク質を酵母two-hybrid法により検索したところ、シナプス小胞に存在し、神経伝達物質の放出に関与するシナプトブレビンと結合することがわかった。

Research Products

• [Journal Article] Interaction of a multidomain adaptor protein, vinexin, with a Rho-effector, Rhotekin (2009)
  • Author(s): Nagata K, Ito H, Iwamoto I, Morishita R, Asano T
  • Journal Title: Med. Mol. Morphol. 42 Pages: 9-15
• [Journal Article] Biochemical characterization of membrane- associated septin from rat brain (2008)
  • Author(s): Maimaitiyiming M, Kumanogoh H, Nakamura S, Nagata K, Suzaki T, Maekawa S
  • Journal Title: J. Neurochem. 106 Pages: 1175-1183
• [Journal Article] A phase advance of the light-dark cycle stimulates production of BDNF, but not of other neurotrophins, in the adult rat cerebral cortex : association with the activation of CREB (2008)
  • Author(s): Katoh-Semba R, Tsuzuki M, Miyazaki N, Matsuda M, Nakagawa C, Ichisaka S, Sudo K, Kitajima S, Hamatake M, Hata Y, Nagata K
  • Journal Title: J. Neurochem. 106 Pages: 2131-2142
• [Journal Article] Characterization of a multi-domain adaptor protein, p140Cap, as part of a presynaptic complex (2008)
  • Author(s): Ito H, Atsuzawa K, Sudo K, Di Stefano P, Iwamoto I, Morishita R, Takei S, Semba R, Defilippi P, Asano T, Usuda N, Nagata K
  • Journal Title: J. Neurochem. 107 Pages: 61-72
• [Journal Article] Sept8 controls the binding of vesicle-associated membrane protein 2 to synaptophysin (2008)
  • Author(s): Ito H, Atsuzawa K, Morishita R, Usuda N, Sudo K, Iwamoto I, Mizutani K, Katoh-Semba R, Nozawa Y, Asano T, Nagata K
  • Journal Title: J. Neurochem. 108 Pages: 867-880
• [Journal Article] Phosphorylation by extracellular signal-regulated kinase of a multidomain adaptor protein, vinexm, at synapses (2007)
  • Author(s): Ito H, Usuda N, Atsuzawa K, Iwamoto I, Sudo K, Katoh-Semba R, Mizutani K, Morishita R, Deguchi T, Nozawa Y, Asano T, Nagata K
  • Journal Title: J. Neurochem. 100 Pages: 545-554
• [Journal Article] Expression of smooth muscle cell-specific proteins in neural progenitor cells-induced by agonists of G protein-coupled receptors and transforming growth Factor-β (2007)
  • Author(s): Morishita R, Nagata K, Ito H, Ueda H, Asano M, Shinohara H, Kato K, Asano T
  • Journal Title: J. Neurochem. 101 Pages: 1031-1040
• [Journal Article] SEPT9 sequence alterations causing hereditary neuralgic amyotrophy are associated with altered interactions with SEPT4/11 and resistance to Rho/Rhotekin-signaling (2007)
  • Author(s): Sudo K, Ito H, Iwamoto I, Morishita R, Asano T, Nagata K
  • Journal Title: Hum. Hut. 28 Pages: 1005-1013
• [Journal Article] Essential roles of ERK-mediated phosphorylation of vinexin in cell spreading, migration and anchorage-independent growth (2007)
  • Author(s): Mizutani K, Ito H, Iwamoto I, Morishita R, Deguchi T, Nozawa Y, Asano T, Nagata K
  • Journal Title: Oncogene 26 Pages: 7122-7131
• [Journal Article] Involvement of Gq/11 in both integrin signal-dependent and -independent pathways regulating endothelin-induced neural progenitor proliferation (2007)
  • Author(s): Morishita R, Ueda H, Ito H, Takasaki J, Nagata K, Asano T
  • Journal Title: Neurosci. Res. 59 Pages: 205-214
• [Journal Article] Localization of septin 8 in murine retina, and spatiotemporal expression of septin 8 in a murine model of photoreceptor cell degeneration (2007)
  • Author(s): ara A, Taguchi A, Niwa M, Aoki H, Yamada Y, Ito H, Nagata K, Kunisada T, Mori H
  • Journal Title: Neurosci. Lett. 423 Pages: 205-210
• [Journal Article] Possible roles of vinexinβ in growth and paclitaxel sensitivity in human prostate cancer PC-3 cells
  • Author(s): Mizutani K, Nagata K, Ito H, Ehara H, Nozawa Y, Deguchi T
• [Presentation] Possible role of in neurotransmitter release and signaling of a multi-domain adaptor protein, p140Cap, in the presynapse(ポスター) (2008)
  • Author(s): Nagata K, Ito H, Atsuzawa K, Sudo K, DiStefano P, Iwamoto I, Morishita R,Takei S, SembaR, Defilippi P, Asano T, Usuda N
  • Organizer: 48th American Society of Cell Biology Annual Meeting
  • Place of Presentation: San Francisco
  • Year and Date: 2008-12-16
• [Presentation] Biochemical and histological analyses of dysbindin-1 in rat brain(ポスター) (2008)
  • Author(s): Ito H, Morishita R, Sudo K, Iwamoto I, Shinoda T, Okamoto K, Nagata K
  • Organizer: 48th American Society of Cell Biology Annual Meeting
  • Place of Presentation: San Francisco
  • Year and Date: 2008-12-16
• [Presentation] Septins are present in GABAergic synapses(ポスター) (2007)
  • Author(s): Li X, Serwanski DR, Miralles CP, Nagata K, De Bias AL
  • Organizer: Society for Neuroscience Annual Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 2007-11-05
• [Presentation] Epigenetic regulation of expression of Septin9 isoforms in cancer cells(ポスター) (2007)
  • Author(s): Nguyen S, Connolly D, Suzuki M, Nagata K, Roohi J, Hatchwell E, Glass JL, Greally JM, Horwitz SB, Verdier-Pinard P, Montagna C
  • Organizer: 57^<th> Annual Meeting of American Society for Human Genetics
  • Place of Presentation: San Diego, USA
  • Year and Date: 2007-10-26
• [Presentation] EMBO Workshop : The Molecular Biology Biochemistry of Septins and Septin Function(ワークショップ) (2007)
  • Author(s): Nagata K, Ito H, Iwamoto I, Sudo K, Morishita R, Asano T
  • Organizer: Biochemical and cell biological analyses of a developmentally regulated septin, Sept8, enriched inpresynaptic nerve terminals
  • Place of Presentation: Ascona, Switzerland
  • Year and Date: 2007-05-09
• [Presentation] Septin9 isoform expression in cancer cells is regulated by methylation changes at specific CG di-nucleotides at 17q25.3(ワークショップ) (2007)
  • Author(s): Nguyen S, Connolly D, Suzuki M, Nagata K, Rohodi J, Hatchwel E, Glass J, Greally J, Horwitz SB, Verdier-Pinard P, Montagna C
  • Organizer: EMBO Workshop : The Molecular Biology & Biochemistry of Septins and Septin Function
  • Place of Presentation: Ascona, Switzerland
  • Year and Date: 2007-05-08
• [Presentation] SEPT9 sequence alterations causing hereditary neuralgic amyotrophy are associated with altered interactions with SEPT4/11 and resistance to Rho/Rhotekin-signaling(ポスター) (2007)
  • Author(s): Sudo K, Ito H, Iwamoto I, Morishita R, Asano T, Nagata K
  • Organizer: EMBO Workshop : The Molecular Biology & Biochemistry of Septins and Septin Functio
  • Place of Presentation: Ascona, Switzerland
  • Year and Date: 2007-05-07
• [Presentation] Septin9 isoform expression in cancer cells is regulated by methylation changes at specific CG di-nucleotides at 17q25.3(ポスター) (2007)
  • Author(s): Nguyen S, Connolly D, Suzuki M, Nagata K, Rohodi J, Hatchwel E, Glass J,Greally J, Horwitz SB, Verdier-Pinard P, Montagna C
  • Organizer: American Association for Cancer Research Annual Meeting
  • Place of Presentation: Los Angels
  • Year and Date: 2007-04-15
• [Book] Research Advances in Biochemistry 1(A. Gayathri Ed.) Possible Interaction of Rho-signaling with the Cytoskeleton- related Protein Septins (2007)
  • Author(s): Nagata K
  • Total Pages: 1-7
  • Publisher: Global Research Network, Kerala
• [Book] Transworld Research Network, Kerala (2007)
  • Author(s): Nagata K, Ito H, Sudo K, Iwamoto I, Morishita R, Asano T
  • Total Pages: 23-32
  • Publisher: Recent Research Developments in Cell Biology (S.G. Pandalai Ed.) Interaction of a Small GTPase Rho Effector, Rhotekin, with Cell Polarity-related Proteins, PIST and Lin-7, in Neuronal Cells