ERMタンパク質

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川口 高徳、浅野 真司 明海大学歯学部 病態診断治療学講座薬理学分野、立命館大学薬学部 分子生理学研究室

ERMタンパク質は、Ezrin, Radixin, MoesinおよびMerlinで構成される分子量70～75 kDaのアクチン細胞骨格関連タンパク質群である。N末端領域に約300アミノ酸残基から構成されるFERMドメインを、C末端領域にアクチン細胞骨格との結合ドメインをもつ。主に細胞の頂端領域に局在し、細胞膜のタンパク質とアクチン細胞骨格との間でのクロスリンカーとして、また、細胞骨格ダイナミクスを制御するRho-GTPaseの調節因子として、さらにシグナル伝達タンパク質の足場タンパク質としての機能を担う。さまざまながん細胞種の浸潤や転移にも関与する。どのERMタンパク質が発現するかは細胞、組織によって異なるが、神経組織では、ニューロンの神経突起の成長円錐の形成や、アストロサイトのシナプス近傍の微細な突起であるperisynaptic astrocyte process (PAP) 構造の形成、ミクログリアの細胞遊走や貪食、シュワン細胞の髄鞘の形成など、広く神経組織の構造形成や機能に関わる。

  ERMタンパク質とは 　ERMタンパク質は、Ezrin, Radixin, MoesinおよびMerlinからなる細胞骨格関連タンパク質群である。細胞膜のタンパク質とアクチン細胞骨格との間でクロスリンカーとして細胞の頂端膜の構造を維持し、膜タンパク質の機能発現に関与するタンパク質として見出された。Ezrinはニワトリの腸管上皮の刷子縁に存在する微絨毛中のタンパク質として[1] [1] 、Moesinはウシの子宮のミクロソームからヘパリンと結合するタンパク質として[2] [2]、Radixinはラットの肝細胞の接着結合から単離された[3] [3]。また、Merlinは神経線維腫症II型の原因遺伝子産物（NF2）として見出された[4][5] [4][5]。


構造 ERMタンパク質はN末端およびC末端領域で高いアミノ酸配列相同性を示す。N末端には約300アミノ酸残基から構成されるFERMドメインをもち、3つのサブドメイン (F1, F2, F3) からなる[6][7] [6][7]。FERMドメインは、膜タンパク質[8][8]や足場タンパク質[9][10][9][10]、Rho-GTPase調節に関わるタンパク質[11][12] [11][12] や、膜リン脂質に含まれるホスファチジルイノシトール4,5-二リン酸 (PIP2) [13][14][13][14] などと結合する。一方、Ezrin, Radixin, Moesin のC末端領域では、特に34アミノ酸残基がファミリー間で高度に保存されており、アクチン細胞骨格と結合する。Merlin ではこの部分での相同性が低い[15][15]。これらN末端とC末端のドメインはαヘリックス構造によって接続されている[16] [16] (図1)。

ERMタンパク質はおもにC末端ドメインのリン酸化によって活性が制御される。脱リン酸化状態では、N末端のFERMドメインとC末端ドメインとが相互作用し、C末端ドメインに存在するアクチン結合部位がマスクされ、アクチン線維と結合できない「閉じた」不活性型となる[8]。FERMドメインにPIP2が結合し[14] [14]、続いてC末端ドメインに存在するトレオニン (セリン) 残基 (マウスEzrinのThr567, RadixinのThr564, MoesinのThr558、MerlinのSer518) がLymphocyte-Oriented Kinase (LOK) やPKC、STE20様プロテインキナーゼ (SLK)、Rhoキナーゼによってリン酸化されることでFERMドメインとC末端ドメインの間の結合が解離し、「開かれた」活性型構造となる[8][17][18] [19][8][17][18][19] (図2)。後述するように、ERMタンパク質には、これ以外にも多数のリン酸化部位が存在し、リン酸化を受けてシグナル伝達などにかかわる。

発現分布 　Ezrinは、胃の壁細胞の管腔側膜や、小腸、大腸の刷子縁膜で高発現しており、腎臓の近位尿細管の刷子縁膜や糸球体、肺や気管支などの呼吸上皮にも発現する[1][20][21][22][23][24] [1][20][21][22][23][24]。Radixinは、肝臓の管腔側膜で高発現しており、腎臓の糸球体にも発現が見られる[3][25] [3][25]。Moesinは、血管内皮細胞、リンパ球、T細胞、B細胞やマスト細胞などで高発現するほか、肺や脾臓、腎臓のヘンレループの太い上行脚および糸球体内皮細胞にも発現が見られる[26][27][28][29][26][27][28][29]。ERMタンパク質は微絨毛や糸状仮足における皮質アクチン線維と結合することで、これらの構造を維持し、細胞内において極性をもって分布する。特に、上皮細胞の頂端部に局在することで、後述する膜タンパク質の局在制御やRho-GTPaseの活性調節を行うほか、シグナル伝達関連タンパク質の制御をはじめとする生理機能を実現する。

脳神経系における発現分布 ERMタンパク質は脳、神経系組織にも発現するが、どのERMタンパク質が発現するかは細胞種や発生段階によって異なる。このような、部位や発生過程における発現の違いが、各ERMタンパク質の生体内での役割の違いに繋がると考えられる。 成体脳ではEzrinはおもにアストロサイトや上衣細胞に発現が見られ、アストロサイトでは主にPAP構造に集積する[30] [30]。Radixinは、脳全体でOlig2陽性細胞に発現する[31] [31]。アストロサイトのPAP構造にも見られる[30] [30]。また、脳卒中の梗塞周辺組織に見られる活性化ミクログリアにはRadixinが高発現する[31] [31]。Moesinはおもにミクログリアや血管内皮細胞に発現が見られる引用エラー: <ref> タグに対応する </ref> タグが不足しています[33]、アストロサイトやオリゴデンドロサイトで発現が見られる[32][34]。 　海馬体の歯状回の顆粒細胞層下帯と側脳室周囲の脳室下帯 (SVZ) は、成体における神経新生部位である。このうちSVZで産生された前駆細胞は神経芽細胞に分化して、rostral migration stream (RMS)と呼ばれる移動経路を嗅球まで移動して神経回路に編入される。ここではRadixinは、RMSの神経芽細胞とオリゴデンドロサイト前駆細胞に発現する[33] [35]。Radixinを特異的に阻害すると、細胞骨格との相互作用が失われて神経芽細胞の移動は傷害される[31][34] [31][36]。一方、Ezrinは神経芽細胞には見られず、RMSを取り囲むアストロサイトに発現する[35][37]。 成体脳とは異なり、培養海馬錐体ニューロンには、Ezrin、Radixin、Moesinが発現する。後述するようにRadixinおよびMoesinは、成長円錐の形成や伸長に関わる[36] [38]。


機能 

 ERMタンパク質は、さまざまな細胞膜タンパク質とアクチン細胞骨格間のクロスリンカーとして、Rho-GTPaseの調節因子として、またPI3キナーゼ (PI3K)-Akt経路などのシグナル伝達に関連するタンパク質の足場タンパク質として働く。これらの機能はがんの浸潤・転移にも密接に関わる。神経系での生理機能については、培養ニューロンや、アストロサイトおよびミクログリア、末梢神経系のシュワン細胞において特徴的な機能が報告されているため、後述する。


細胞膜タンパク質とアクチン細胞骨格間のクロスリンカーとしてのはたらき

細胞接着タンパク質との結合 　ERMタンパク質は、単一の膜貫通領域をもつ細胞接着タンパク質とFERMドメインで直接に結合し、アクチン細胞骨格へのクロスリンカータンパク質として働く。すべてのERMタンパク質が、細胞表面でヒアルロン酸の受容体として機能するCD44の細胞質ドメインと結合し、アクチン細胞骨格との間でクロスリンカーとして働き、がん細胞の遊走や浸潤に関連する[37][38][39][40]。また、Ezrinは細胞間接着分子ICAM-1およびICAM-2の細胞質ドメインに結合する[39] [41]。MoesinはCD44のほか細胞接着タンパク質であるCD43 、細胞間接着分子ICAM-2とも直接に結合する[38] [40] (図2)。

膜輸送体や受容体との結合 ERMタンパク質は、膜輸送体とも直接に結合し、アクチン細胞骨格との相互作用を介して、頂端膜で安定に発現させる。たとえば、Ezrinは、FERM ドメインでNa+/H+交換輸送体1 (NHE1) のC 末端の細胞質領域と結合する[40] [42]。また、がんにおける多剤耐性機構に重要な因子となる P糖タンパク質 (P-gp) とも同様に結合し、P-gpの細胞膜発現と基質輸送能を高める[41] [43]。Radixinは、multi-drug resistance protein 2 (MRP2)のC末端の細胞質ドメインに直接結合し、胆管への抱合型ビリルビンの分泌に関与する[42][44]。 Moesinは、FERMドメインで、Na+/K+/2Cl-共輸送体2 (NKCC2) のC末端領域と結合することで、NKCC2を頂端膜で安定に発現させる[43][45]。 　また、Ezrinは、足場タンパク質を介して膜輸送体や受容体と間接的に複合体を形成する。足場タンパク質である Na+/H+交換輸送体制御因子 (NHERF) 1および2は、2つのPDZ (PSD-95、Discs-large、ZO-1) ドメインをもつ一方、C末端でERMタンパク質のFERMドメインに結合する[9][10] [9][10]。NHERF1のPDZドメインは、クロライドチャネルである嚢胞性線維症膜コンダクタンス制御因子 (CFTR)、Na+/H+交換輸送体3 (NHE3) 、Na+/リン酸共輸送体2a (Npt2a)、グルタミン酸輸送体GLASTなどの膜輸送体のほか、β2アドレナリン受容体（β2AR）のC末端に存在する PDZ 結合モチーフと結合する。その結果、膜輸送体や受容体がアクチン細胞骨格に結合して細胞膜で安定に発現する[23][43][44][45][46][23][46][47][48][49] (図2)。

Rho-GTPaseの調節因子としてのはたらき 　Ezrinは、細胞骨格のダイナミクスを制御するRho-GTPaseの上流および下流のエフェクターとして機能する[47][50]。Rho-GTPaseは皮質アクチンの再構築を誘導し、フィロポディア、ラメリポディアといった細胞の形態変化や、遊走などの細胞運動を引き起こす。EzrinはRho関連タンパク質などに結合してRho-GTPase活性を制御する一方、Rhoキナーゼによるリン酸化によって活性化される。 　Ezrinは胃壁細胞の管腔側膜に発現する。胃壁細胞をヒスタミン処理すると、cAMP依存性プロテインキナーゼ (PKA) によってEzrinのN末端側のSer66がリン酸化を受ける。この際にEzrinはARF6 GTPaseおよびARF GTPase活性化タンパク質であるACAP4と結合し、胃酸分泌細胞内のプロトンポンプを含む細管小胞と管腔側膜との融合を促して酸分泌を開始する[48] [51]。実際にEzrinをノックダウンしたマウスでは、細管小胞と管腔側膜との融合はおこらず、胃酸の分泌が傷害される[49] [52]。 

 Radixinについても、前立腺がん細胞PC3や乳がん細胞MDA-MB-231においてRho-GTPaseの一種であるRac1を介して細胞形態の変化や細胞遊走、細胞接着を制御する[50][53]。Radixinをノックダウンすると細胞面積の増加を引き起こすが、Rac1を発現抑制すると、この細胞面積増加は抑制される。一方、恒常的に活性化したRac1は、細胞の拡散と細胞間接触におけるN-カドヘリンの発現増加を引き起こす[50] [53]。

Rhoグアニンヌクレオチド交換因子 (Rho-GEF) との相互作用 　Ezrinは、FERMドメインを介して、Rho-GTPaseを活性化する酵素であるRhoグアニンヌクレオチド交換因子 (Rho-GEF) の1つであるPleckstrin Homology Domain-Containing Family G Member 6 (PLEKHG6)と結合する。腎尿細管由来のLLC-PK1細胞とA431細胞において、EzrinはPLEKHG6と結合して頂端膜へと誘導し、PLEKFG6によるRhoGの活性化を介して微絨毛とラッフル膜の形成とマクロピノサイトーシスを引き起こす[51][54]。また、EzrinはRac1のGEFであるDOCK1と、engulfment and cell motility (ELMO) タンパク質、およびRac1からなる複合体と反応する。ゼブラフィッシュの胚では、線毛の形成過程で基底小体の細胞内移動や細胞膜とのドッキングにはたらく[52][55]。

Rho GDP解離阻害因子 (Rho-GDI) との相互作用 すべてのRhoファミリーメンバーの阻害性調節因子であるRho-GDIは、不活性型であるGDP結合Rho GTPaseと結合し、Rho-GDP/GDI複合体を安定化することでRho GTPaseの活性化を妨げる。EzrinはFERMドメインでRho-GDIと結合し、Rho-GDP/GDI複合体の形成を妨げることでRho GTPaseの活性化を補助する[11] [11] (図3)。

Rho関連コイルドコイル含有キナーゼ (ROCK) との相互作用 ROCKは、Rho GTPaseの1つであるRhoAの下流エフェクターである[53][54][56][57]。Myosin軽鎖を直接リン酸化、Myosinホスファターゼを阻害することで、ストレスファイバーの集合を誘導する[55][58]。その一方、ROCKはEzrinのC末端ドメインのThr567をリン酸化して活性化する。一方、ROCK阻害剤であるY27632はEzrinのリン酸化とアクチン細胞骨格への結合を阻害する[56][59]。


シグナル伝達タンパク質の足場タンパク質 Ezrinはリン酸化を受けて、肝細胞増殖因子 (HGF)、上皮成長因子 (EGF)、PI3キナーゼ(PI3K)-Akt経路などのシグナル伝達において、関連タンパク質の足場タンパク質として機能する。いくつかのシグナル伝達経路はクロストークして、細胞増殖やがんの浸潤や転移に関わる。

HGF/c-Metシグナル伝達 Ezrinは、HGF/c-Metシグナル伝達誘導性の細胞の形態変化や、がん細胞の浸潤・転移を引き起こす。HGFは受容体型チロシンキナーゼc-Metと結合してリン酸化を引き起こす。この活性化c-Metは非受容体型チロシンキナーゼc-Srcを誘導し、EzrinのTyr477をリン酸化する (Tyr477はEzrinに見られるがERMタンパク質の中では保存されていない)。リン酸化Ezrinは、細胞の形態変化にかかわる非受容体型チロシンキナーゼであるFesと結合する。活性化されたFesはEzrinによってシート状の細胞間の接着部にリクルートされ、細胞の形態変化をともなう拡散・散乱をおこす[57][60]。

EGF/EGFRシグナル伝達 ヒトの皮膚がん由来のA431細胞をEGFで処理すると、Ezrinのリン酸化と共に、ミクロビリ様構造やラッフル膜が形成されるなど細胞表面構造の変化が観察される[58][61]。EzrinはEGFRと複合体を形成する。EGF処理によってEzrinのFERMドメインのTyr145と、中央αヘリックス構造のTyr353がリン酸化を受け、EGFRとの結合が増強される[59][62]。Ezrinを欠損または阻害すると、EGFRのリン酸化やシグナル下流のErkやSTAT3の活性化、細胞増殖が阻害を受ける[60][63]。Tyr353のリン酸化は細胞増殖や上皮間葉転換、アポトーシス阻害にも関わる[61][64]。

PI3K-Akt経路 EzrinはEGFのような外部シグナルを受けてTyr353がリン酸化されると、PI3Kの調節サブユニットであるp85のC末端SH2ドメインと結合することでPI3Kを活性化する。PI3Kによって産生されるホスファチジルイノシトール3,4,5-三リン酸は、プロテインキナーゼであるAktを活性化し、細胞増殖を促すとともに細胞をアポトーシスから保護する[62][65]。また、上皮間葉転換を促進する。 一方、Merlinは脳特異的GTPaseであるPI3Kエンハンサー(PIKE) Lに結合し、PI3K活性を阻害して細胞増殖を抑制する[63][66]。


神経系の各細胞における生理機能

Radixin は成長円錐の形成にはたらく Radixinはニューロンの成長円錐の形成において重要な役割を担う。たとえばニワトリの神経培養細胞の培地からNGFを除くと、成長円錐の急速な崩壊と同時にRadixinの発現は大幅に低下する。一方、NGFを再添加すると成長円錐が再形成されると同時にRadixinの成長円錐での再局在化が引き起こされる[64][67]。また、海馬ニューロンの初代培養におけるアンチセンスオリゴヌクレオチドを用いたERMファミリーの発現抑制実験では、RadixinとMoesinを二重発現抑制すると、成長円錐の劇的な減少や放射状条線の消失、糸状仮足数の減少および長さの増加など、成長円錐の形成異常が認められる。他方、EzrinとRadixin、EzrinとMoesinを二重発現抑制しても、成長円錐の形態や大きさや糸状仮足の数、細胞骨格に変化は見られない[36][38]。タイムラプスVEC-DIC顕微鏡で成長円錐の拡大を解析すると、RadixinとMoesinを二重発現抑制すると、軸索伸長速度の劇的な遅延が見られ、成長円錐の拡大が傷害される[36] [38]。 また、神経軸索の誘因/反発因子として働く分泌性タンパク質Netrin-1は、受容体であるdeleted in colorectal cancer (DCC) に結合して、PKA依存的にニューロン発達に関与する。PKAの足場となるAKAP機能を欠損したRadixin、EzrinとMoesinの変異体を導入すると、成長円錐において特徴的なラメラ構造やラメリポディアが消失する。これにRadixinを発現させると成長円錐の形態を回復させる[65][68] (図4)。

Ezrin は軸索や神経突起の形成にはたらく Ezrin はNetrin-1依存的にDCCと結合し、自らがRhoキナーゼによってリン酸化を受けて、軸索の伸長を活性化する (図4)。初代培養ニューロンにおいてEzrinの機能を欠損させると、突起伸長は阻害を受ける[66][69]。 また、Ezrinの発現が野生型マウスの5%以下まで抑制されたノックダウンマウス (Vil2kd/kd マウス) 胚由来の初代培養ニューロンでは、野生型マウスと比較して神経突起の形成障害が見られる。Vil2kd/kd マウスニューロンでは、RhoA活性の上昇およびMLC2のリン酸化が認められ、Myosin IIやROCKを阻害するとニューロンの神経突起形成が回復する[67][70]。

EzrinはアストロサイトのPAP構造を維持するほかグルタミン酸輸送に関わる 　アストロサイトにはPAPと呼ばれるシナプス近傍の微細な突起が見られ、全細胞表面の70-80%を占め、グリアとニューロンの相互作用に重要な膜タンパク質が局在する[30][68][30][71]。PAPにはEzrinおよびRadixinが高発現しており、特に活性型であるC末端リン酸化型Ezrinが集積する[68][69] [71][72]。Ezrinは足場タンパク質であるNHERF1を介して、アストロサイトの細胞骨格タンパク質であるGFAPや、グルタミン酸−アスパラギン酸トランスポーターであるGLASTと結合し、PAPを含むアストロサイト突起で共局在する[45][48]。Ezrinは、NHERF1-GLAST複合体とアクチン細胞骨格の間のリンカータンパク質として機能し、GLASTのPAPでの発現を安定化し、グルタミン酸輸送能を向上させることによってグルタミン酸による脳障害に対する保護に働く[70][73]。

Moesinは自閉症スペクトラム (ASD) に関わる Moesinは自閉症スペクトラム (ASD) に関わる因子の一つであることが知られている。ASDにかかわるlong noncoding RNA (lncRNA) の一つとして見出されたmoesin pseudogene 1 antisense (MSNP1AS) は、ASD患者の大脳皮質ではコントロール患者と比較して12倍も発現が増加する。MSNP1ASはモエシンのRNAと二本鎖を形成し、Moesinの発現を阻害する[71][74]。ヒト培養海馬ニューロンにMSNP1ASを過剰発現させるとRhoAの活性化とPI3K/Aktの活性化阻害が見られ、神経突起の数と長さの減少が観察される。さらに、自閉症のモデルであるBTBRマウスの海馬にレンチウイルスを用いてモエシンのcDNAを注入して行動観察を行ったところ、社会的な相互作用が改善され、反復行動、不安行動の減少が見られた[72][75]。オープンフィールドテストの結果、Moesinノックアウトマウスは野生型マウスと比較して不安様行動が見られることが報告されている[73][76]。

Moesinはミクログリアの活性化に関わる 　Moesinはミクログリアに発現する。マウスの初代培養ミクログリアをMoesinのリン酸化を阻害するNSC305787で処理すると、リン酸化レベルの低下に対応してUDP誘導性の食作用やADP誘導性の遊走、LPS誘導性のTNF-α分泌が阻害される[74][77]。また、Moesinノックアウトマウス由来の初代培養ミクログリアではADP誘導性の遊走活性の低下やUDP感受性の貪食能の低下が観察されることから、Moesinはミクログリアの遊走や貪食に重要な役割を担うと考えられる[75][78]。

EzrinおよびMerlinはシュワン細胞における髄鞘形成に関わる 

 Ezrinはシュワン細胞の微絨毛構造に発現する。Ezrinを高発現する突起部分ではミエリンが欠如しており、この部位がランヴィエ絞輪の形成に関与するものと見られる[76][79]。

Merlinもまたシュワン細胞の膜ドメインに高発現する[77][80]。末梢神経系では損傷後に軸索再生と再髄鞘形成が起きるが、シュワン細胞特異的Merlin欠損マウスではこれらが傷害される。Merlinは、細胞増殖とアポトーシスを通じて器官のサイズを制御するHippo経路の転写因子であるYes-associated protein (YAP) と結合することで髄鞘形成に関与し、機能的な神経修復において重要な働きを担う[78][81]。


がんにおけるERMタンパク質の関わり Ezrinはがん細胞の浸潤や転移に関連し、一方、Merlinは腫瘍増殖抑制に関わる。

Ezrinとがん 一般にEzrinの発現が高い程、予後が悪く生存率は低下する。その原因の一つとしてがんの転移能が上昇することがある。Ezrinが転移に関わるメカニズムの例として、CD44とアクチン細胞骨格とのクロスリンクや、EGF/EGFRを介した上皮間葉転換が挙げられる。CD44v6 (変異型エクソンv6配列を含むCD44アイソフォーム) はHGF/c-Metの共受容体としてEzrinと結合し、アクチン細胞骨格に繋留されることでがん細胞の浸潤を促進する[79][82]。上皮間葉転換には、EGF/EGFRシグナル伝達が関与する。舌扁平上皮癌 (TSCC) において、EGFがEzrinのTyr353をリン酸化し、AktおよびNF-κBの活性化を介して上皮間葉転換とがん転移を誘導する[61][64]。

Merlinの抗腫瘍作用 がん抑制遺伝子であるnf2はMerlinをコードする。nf2の不活化は、両側性に発生する前庭神経鞘腫および髄膜腫や脳室上衣腫などの脳腫瘍を特徴とする優性遺伝疾患である神経線維腫症II型を引き起こす[80][83]。神経線維腫症II型は、特有の疾患として両側性前庭神経鞘腫 (第VIII脳神経に発生する腫瘍) を、一般的には脳神経や¬後根神経節、末梢神経にも神経鞘種を引き起こす。Merlinは、PI3KやRaf/ERK、Wnt/β-Catenin、受容体型チロシンキナーゼ、mTOR、Hippo経路などさまざまなシグナル伝達経路を阻害することで腫瘍抑制効果を示す[81][84]。

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  表1. ERMタンパク質の中枢神経系における発現 発現部位 タンパク質 文献 in vivo (成体) アストロサイト Ezrin, Radixin, Merlin [28,32] ミクログリア Radixin, Moesin [29,30] オリゴデンドロサイト Merlin [32] ニューロン Merlin [31] 上衣細胞 Ezrin [28] 血管内皮細胞 Moesin [30] in vivo (分化過程) 神経芽細胞 (RMS) Radixin [33,34] オリゴデンドロサイト 前駆細胞 (RMS) Radixin [33] アストロサイト Ezrin [35] in vitro 海馬錐体初代培養 ニューロン Ezrin, Radixin, Moesin [36]

  Figure legends 図1. ERMタンパク質の構造 ERMタンパク質は、N末端に3つのサブドメイン (F1-F3) からなるFERMドメイン、C末端にアクチン結合ドメイン、中央にαヘリックス構造をもつ。アクチン結合ドメイン内に示した赤い星印は、活性化に重要なリン酸化部位であるEzrin, Radixin, MoesinのThr残基およびMerlinのSer残基を表す (表記した数字は、マウスERMタンパク質のアミノ酸番号を示す)。本文中で紹介したシグナル伝達に関わるTyr145, Tyr353, Tyr477を白い星印で示す。

図2. ERMタンパク質のリン酸化と、膜タンパク質およびアクチン細胞骨格との結合 ERMタンパク質は、N末端のFERMドメイン（赤〇）とC末端領域（青色）が相互作用し、アクチン細胞骨格と結合不能な「閉じた」不活性型構造をとる。FERMドメインのF3部位がPIP2に結合し、PKCやLOK、SLK、RhoキナーゼによってC末端ドメインのThr残基 (MerlinはSer残基) がリン酸化され (赤い星印)、「開いた」活性型構造となる。ERMタンパク質は単一の膜貫通領域をもつ細胞接着タンパク質と直接に (図左)、あるいは膜輸送体や受容体と直接または間接的に結合する (図右では足場タンパク質であるNHERFを介した間接的結合を示す)。

図3. ERMタンパク質によるRho-GTPase活性の制御 GTP結合型のRho-GTPaseは活性型であり、下流のエフェクターと相互作用する。GDP結合型のRho-GTPaseは不活性型であり、下流のエフェクターとの親和性が大幅に低下している。Rho-GEFは、結合したGDPからGTPへの交換を誘導し、Rho-GTPaseを活性化する。Rho-GDIは、不活性型のGDP結合型Rho-GTPaseと結合し、安定化させることで活性型への変換を妨げる。ERMタンパク質はRho-GEFとFERMドメインで結合し、Rho-GTPaseにおいてGDPからGTPへの交換を促進することで活性化する (図中(a))。また、Rho-GDIともFERMドメインで結合し、Rho GTPaseからのRho-GDIの解離を促進することで活性化する (図中(b))。

図4. 成長円錐におけるガイダンス因子を受容するERMタンパク質複合体 神経軸索の誘因/反発因子として働く分泌性タンパク質Netrin-1は受容体であるDCCに結合し、PKA依存的にニューロン発達を誘導する。ERMタンパク質はDCCと結合すると共にPKAとも結合し、タンパク質複合体を形成する。この複合体形成が、DCCを介したPKAの活性化に重要である。特にEzrin は、Netrin-1依存的にDCCと結合し、Rhoキナーゼによって自身がリン酸化を受けてアクチン細胞骨格の再構築を引き起こし、神経軸索伸長などを引き起こすと考えられる。

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  30. ↑ 30.0 30.1 30.2 Derouiche, A., & Frotscher, M. (2001).
    Peripheral astrocyte processes: monitoring by selective immunostaining for the actin-binding ERM proteins. Glia, 36(3), 330-41. [PubMed:11746770] [WorldCat] [DOI]
  31. ↑ 31.0 31.1 31.2 Persson, Å., Osman, A., Bolouri, H., Mallard, C., & Kuhn, H.G. (2013).
    Radixin expression in microglia after cortical stroke lesion. Glia, 61(5), 790-9. [PubMed:23440885] [WorldCat] [DOI]
  32. ↑ Toledo, A., Grieger, E., Karram, K., Morrison, H., & Baader, S.L. (2018).
    Neurofibromatosis type 2 tumor suppressor protein is expressed in oligodendrocytes and regulates cell proliferation and process formation. PloS one, 13(5), e0196726. [PubMed:29715273] [PMC] [WorldCat] [DOI]
  33. ↑ Persson, A., Lindwall, C., Curtis, M.A., & Kuhn, H.G. (2010).
    Expression of ezrin radixin moesin proteins in the adult subventricular zone and the rostral migratory stream. Neuroscience, 167(2), 312-22. [PubMed:20109539] [WorldCat] [DOI]
  34. ↑ Persson, A., Lindberg, O.R., & Kuhn, H.G. (2013).
    Radixin inhibition decreases adult neural progenitor cell migration and proliferation in vitro and in vivo. Frontiers in cellular neuroscience, 7, 161. [PubMed:24065889] [PMC] [WorldCat] [DOI]
  35. ↑ Cleary, M.A., Uboha, N., Picciotto, M.R., & Beech, R.D. (2006).
    Expression of ezrin in glial tubes in the adult subventricular zone and rostral migratory stream. Neuroscience, 143(3), 851-61. [PubMed:16996217] [PMC] [WorldCat] [DOI]
  36. ↑ 36.0 36.1 36.2 Paglini, G., Kunda, P., Quiroga, S., Kosik, K., & Cáceres, A. (1998).
    Suppression of radixin and moesin alters growth cone morphology, motility, and process formation in primary cultured neurons. The Journal of cell biology, 143(2), 443-55. [PubMed:9786954] [PMC] [WorldCat] [DOI]
  37. ↑ Tsukita, S., Oishi, K., Sato, N., Sagara, J., Kawai, A., & Tsukita, S. (1994).
    ERM family members as molecular linkers between the cell surface glycoprotein CD44 and actin-based cytoskeletons. The Journal of cell biology, 126(2), 391-401. [PubMed:7518464] [PMC] [WorldCat] [DOI]
  38. ↑ 38.0 38.1 Yonemura, S., Hirao, M., Doi, Y., Takahashi, N., Kondo, T., Tsukita, S., & Tsukita, S. (1998).
    Ezrin/radixin/moesin (ERM) proteins bind to a positively charged amino acid cluster in the juxta-membrane cytoplasmic domain of CD44, CD43, and ICAM-2. The Journal of cell biology, 140(4), 885-95. [PubMed:9472040] [PMC] [WorldCat] [DOI]
  39. ↑ Heiska, L., Alfthan, K., Grönholm, M., Vilja, P., Vaheri, A., & Carpén, O. (1998).
    Association of ezrin with intercellular adhesion molecule-1 and -2 (ICAM-1 and ICAM-2). Regulation by phosphatidylinositol 4, 5-bisphosphate. The Journal of biological chemistry, 273(34), 21893-900. [PubMed:9705328] [WorldCat] [DOI]
  40. ↑ Denker, S.P., Huang, D.C., Orlowski, J., Furthmayr, H., & Barber, D.L. (2000).
    Direct binding of the Na--H exchanger NHE1 to ERM proteins regulates the cortical cytoskeleton and cell shape independently of H(+) translocation. Molecular cell, 6(6), 1425-36. [PubMed:11163215] [WorldCat] [DOI]
  41. ↑ Luciani, F., Molinari, A., Lozupone, F., Calcabrini, A., Lugini, L., Stringaro, A., ..., & Fais, S. (2002).
    P-glycoprotein-actin association through ERM family proteins: a role in P-glycoprotein function in human cells of lymphoid origin. Blood, 99(2), 641-8. [PubMed:11781249] [WorldCat] [DOI]
  42. ↑ Kikuchi, S., Hata, M., Fukumoto, K., Yamane, Y., Matsui, T., Tamura, A., ..., & Tsukita, S. (2002).
    Radixin deficiency causes conjugated hyperbilirubinemia with loss of Mrp2 from bile canalicular membranes. Nature genetics, 31(3), 320-5. [PubMed:12068294] [WorldCat] [DOI]
  43. ↑ 43.0 43.1 Short, D.B., Trotter, K.W., Reczek, D., Kreda, S.M., Bretscher, A., Boucher, R.C., ..., & Milgram, S.L. (1998).
    An apical PDZ protein anchors the cystic fibrosis transmembrane conductance regulator to the cytoskeleton. The Journal of biological chemistry, 273(31), 19797-801. [PubMed:9677412] [WorldCat] [DOI]
  44. ↑ Lamprecht, G., Weinman, E.J., & Yun, C.H. (1998).
    The role of NHERF and E3KARP in the cAMP-mediated inhibition of NHE3. The Journal of biological chemistry, 273(45), 29972-8. [PubMed:9792717] [WorldCat] [DOI]
  45. ↑ 45.0 45.1 Lee, A., Rayfield, A., Hryciw, D.H., Ma, T.A., Wang, D., Pow, D., ..., & Poronnik, P. (2007).
    Na+-H+ exchanger regulatory factor 1 is a PDZ scaffold for the astroglial glutamate transporter GLAST. Glia, 55(2), 119-29. [PubMed:17048262] [PMC] [WorldCat] [DOI]
  46. ↑ Kawaguchi, K., Nakayama, S., Saito, D., Kogiso, H., Yasuoka, K., Marunaka, Y., ..., & Asano, S. (2022).
    Ezrin knockdown reduces procaterol-stimulated ciliary beating without morphological changes in mouse airway cilia. Journal of cell science, 135(6). [PubMed:35132996] [WorldCat] [DOI]
  47. ↑ Ivetic, A., & Ridley, A.J. (2004).
    Ezrin/radixin/moesin proteins and Rho GTPase signalling in leucocytes. Immunology, 112(2), 165-76. [PubMed:15147559] [PMC] [WorldCat] [DOI]
  48. ↑ Ding, X., Deng, H., Wang, D., Zhou, J., Huang, Y., Zhao, X., ..., & Yao, X. (2010).
    Phospho-regulated ACAP4-Ezrin interaction is essential for histamine-stimulated parietal cell secretion. The Journal of biological chemistry, 285(24), 18769-80. [PubMed:20360010] [PMC] [WorldCat] [DOI]
  49. ↑ Tamura, A., Kikuchi, S., Hata, M., Katsuno, T., Matsui, T., Hayashi, H., ..., & Tsukita, S. (2005).
    Achlorhydria by ezrin knockdown: defects in the formation/expansion of apical canaliculi in gastric parietal cells. The Journal of cell biology, 169(1), 21-8. [PubMed:15809309] [PMC] [WorldCat] [DOI]
  50. ↑ 50.0 50.1 Valderrama, F., Thevapala, S., & Ridley, A.J. (2012).
    Radixin regulates cell migration and cell-cell adhesion through Rac1. Journal of cell science, 125(Pt 14), 3310-9. [PubMed:22467863] [WorldCat] [DOI]
  51. ↑ D'Angelo, R., Aresta, S., Blangy, A., Del Maestro, L., Louvard, D., & Arpin, M. (2007).
    Interaction of ezrin with the novel guanine nucleotide exchange factor PLEKHG6 promotes RhoG-dependent apical cytoskeleton rearrangements in epithelial cells. Molecular biology of the cell, 18(12), 4780-93. [PubMed:17881735] [PMC] [WorldCat] [DOI]
  52. ↑ Epting, D., Slanchev, K., Boehlke, C., Hoff, S., Loges, N.T., Yasunaga, T., ..., & Kramer-Zucker, A. (2015).
    The Rac1 regulator ELMO controls basal body migration and docking in multiciliated cells through interaction with Ezrin. Development (Cambridge, England), 142(1), 174-84. [PubMed:25516973] [WorldCat] [DOI]
  53. ↑ Leung, T., Manser, E., Tan, L., & Lim, L. (1995).
    A novel serine/threonine kinase binding the Ras-related RhoA GTPase which translocates the kinase to peripheral membranes. The Journal of biological chemistry, 270(49), 29051-4. [PubMed:7493923] [WorldCat] [DOI]
  54. ↑ Nakagawa, O., Fujisawa, K., Ishizaki, T., Saito, Y., Nakao, K., & Narumiya, S. (1996).
    ROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in mice. FEBS letters, 392(2), 189-93. [PubMed:8772201] [WorldCat] [DOI]
  55. ↑ Totsukawa, G., Yamakita, Y., Yamashiro, S., Hartshorne, D.J., Sasaki, Y., & Matsumura, F. (2000).
    Distinct roles of ROCK (Rho-kinase) and MLCK in spatial regulation of MLC phosphorylation for assembly of stress fibers and focal adhesions in 3T3 fibroblasts. The Journal of cell biology, 150(4), 797-806. [PubMed:10953004] [PMC] [WorldCat] [DOI]
  56. ↑ Tran Quang, C., Gautreau, A., Arpin, M., & Treisman, R. (2000).
    Ezrin function is required for ROCK-mediated fibroblast transformation by the Net and Dbl oncogenes. The EMBO journal, 19(17), 4565-76. [PubMed:10970850] [PMC] [WorldCat] [DOI]
  57. ↑ Naba, A., Reverdy, C., Louvard, D., & Arpin, M. (2008).
    Spatial recruitment and activation of the Fes kinase by ezrin promotes HGF-induced cell scattering. The EMBO journal, 27(1), 38-50. [PubMed:18046454] [PMC] [WorldCat] [DOI]
  58. ↑ Bretscher, A. (1989).
    Rapid phosphorylation and reorganization of ezrin and spectrin accompany morphological changes induced in A-431 cells by epidermal growth factor. The Journal of cell biology, 108(3), 921-30. [PubMed:2646308] [PMC] [WorldCat] [DOI]
  59. ↑ Krieg, J., & Hunter, T. (1992).
    Identification of the two major epidermal growth factor-induced tyrosine phosphorylation sites in the microvillar core protein ezrin. The Journal of biological chemistry, 267(27), 19258-65. [PubMed:1382070] [WorldCat]
  60. ↑ Saygideğer-Kont, Y., Minas, T.Z., Jones, H., Hour, S., Çelik, H., Temel, I., ..., & Üren, A. (2016).
    Ezrin Enhances EGFR Signaling and Modulates Erlotinib Sensitivity in Non-Small Cell Lung Cancer Cells. Neoplasia (New York, N.Y.), 18(2), 111-20. [PubMed:26936397] [PMC] [WorldCat] [DOI]
  61. ↑ 61.0 61.1 Wang, Y., Lin, Z., Sun, L., Fan, S., Huang, Z., Zhang, D., ..., & Chen, W. (2014).
    Akt/Ezrin Tyr353/NF-κB pathway regulates EGF-induced EMT and metastasis in tongue squamous cell carcinoma. British journal of cancer, 110(3), 695-705. [PubMed:24346284] [PMC] [WorldCat] [DOI]
  62. ↑ Gautreau, A., Poullet, P., Louvard, D., & Arpin, M. (1999).
    Ezrin, a plasma membrane-microfilament linker, signals cell survival through the phosphatidylinositol 3-kinase/Akt pathway. Proceedings of the National Academy of Sciences of the United States of America, 96(13), 7300-5. [PubMed:10377409] [PMC] [WorldCat] [DOI]
  63. ↑ Rong, R., Tang, X., Gutmann, D.H., & Ye, K. (2004).
    Neurofibromatosis 2 (NF2) tumor suppressor merlin inhibits phosphatidylinositol 3-kinase through binding to PIKE-L. Proceedings of the National Academy of Sciences of the United States of America, 101(52), 18200-5. [PubMed:15598747] [PMC] [WorldCat] [DOI]
  64. ↑ Gonzalez-Agosti, C., & Solomon, F. (1996).
    Response of radixin to perturbations of growth cone morphology and motility in chick sympathetic neurons in vitro. Cell motility and the cytoskeleton, 34(2), 122-36. [PubMed:8769724] [WorldCat] [DOI]
  65. ↑ Deming, P.B., Campbell, S.L., Stone, J.B., Rivard, R.L., Mercier, A.L., & Howe, A.K. (2015).
    Anchoring of protein kinase A by ERM (ezrin-radixin-moesin) proteins is required for proper netrin signaling through DCC (deleted in colorectal cancer). The Journal of biological chemistry, 290(9), 5783-96. [PubMed:25575591] [PMC] [WorldCat] [DOI]
  66. ↑ Antoine-Bertrand, J., Ghogha, A., Luangrath, V., Bedford, F.K., & Lamarche-Vane, N. (2011).
    The activation of ezrin-radixin-moesin proteins is regulated by netrin-1 through Src kinase and RhoA/Rho kinase activities and mediates netrin-1-induced axon outgrowth. Molecular biology of the cell, 22(19), 3734-46. [PubMed:21849478] [PMC] [WorldCat] [DOI]
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    Ezrin mediates neuritogenesis via down-regulation of RhoA activity in cultured cortical neurons. PloS one, 9(8), e105435. [PubMed:25144196] [PMC] [WorldCat] [DOI]
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    Perspectives for Ezrin and Radixin in Astrocytes: Kinases, Functions and Pathology. International journal of molecular sciences, 20(15). [PubMed:31382374] [PMC] [WorldCat] [DOI]
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    Structural plasticity of perisynaptic astrocyte processes involves ezrin and metabotropic glutamate receptors. Proceedings of the National Academy of Sciences of the United States of America, 108(31), 12915-9. [PubMed:21753079] [PMC] [WorldCat] [DOI]
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    Cytoskeletal anchoring of GLAST determines susceptibility to brain damage: an identified role for GFAP. The Journal of biological chemistry, 282(40), 29414-23. [PubMed:17684014] [WorldCat] [DOI]
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    The Autism-Related lncRNA MSNP1AS Regulates Moesin Protein to Influence the RhoA, Rac1, and PI3K/Akt Pathways and Regulate the Structure and Survival of Neurons. Autism research : official journal of the International Society for Autism Research, 13(12), 2073-2082. [PubMed:33215882] [WorldCat] [DOI]
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    Memory Decline and Aberration of Synaptic Proteins in X-Linked Moesin Knockout Male Mice. Psychiatry investigation, 22(1), 10-25. [PubMed:39885788] [PMC] [WorldCat] [DOI]
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    Moesin is involved in microglial activation accompanying morphological changes and reorganization of the actin cytoskeleton. The journal of physiological sciences : JPS, 70(1), 52. [PubMed:33129281] [PMC] [WorldCat] [DOI]
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    Nodes of Ranvier form in association with ezrin-radixin-moesin (ERM)-positive Schwann cell processes. Proceedings of the National Academy of Sciences of the United States of America, 98(3), 1235-40. [PubMed:11158623] [PMC] [WorldCat] [DOI]
  77. ↑ Scherer, S.S., & Gutmann, D.H. (1996).
    Expression of the neurofibromatosis 2 tumor suppressor gene product, merlin, in Schwann cells. Journal of neuroscience research, 46(5), 595-605. [PubMed:8951671] [WorldCat] [DOI]
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    Merlin controls the repair capacity of Schwann cells after injury by regulating Hippo/YAP activity. The Journal of cell biology, 216(2), 495-510. [PubMed:28137778] [PMC] [WorldCat] [DOI]
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    CD44 is required for two consecutive steps in HGF/c-Met signaling. Genes & development, 16(23), 3074-86. [PubMed:12464636] [PMC] [WorldCat] [DOI]
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    The molecular biology of NF2/Merlin on tumorigenesis and development. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 38(13), e23809. [PubMed:38967126] [WorldCat] [DOI]
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