Злитий білок BCR/ABL, утворений транслокацією філадельфійської хромосоми, викликає хронічний мієлолейкоз (ХМЛ) та інші мієлопроліферативні захворювання. Ізоформа p210 включає домен гомології плекстрину (PH) відсутній в ізоформі p190, яка в свою чергу пов’язана з гострим лімфобластним лейкозом (ALL). Ця структурна відмінність може лежати в основі відмінної субклітинної локалізації та сигнальних профілів двох ізоформ. В цій роботі ми досліджуємо роль домену PH білка BCR у взаємодії з кортактином і FBP17, білками, що беруть участь у ремоделюванні цитоскелета та динаміці мембран. Використовуючи GST-пулдаун і вестерн-блот, ми продемонстрували пряму взаємодію домена PH білка BCR як з кортактином, так і з FBP17. Дослідження колокалізації, підтверджені конфокальною та STED-мікроскопією, показали, що кортактин спільно локалізується з PH-доменом BCR у центросомальних та перимембранних областях клітин. Примітно, що окремий домен SH3 кортактину не був необхідним для цієї взаємодії, що свідчить про те, що інші домени опосередковують зв’язування. Ці висновки підкреслюють роль домену PH у спрямуванні BCR/ABL до центросоми, де він взаємодіє з кортактином, потенційно впливаючи на динаміку актину та везикулярний транспорт. Ця центросомальна локалізація може просторово обмежувати активність конститутивної тирозинкінази ABL, сприяючи менш агресивному фенотипу p210-асоційованої ХМЛ порівняно з p190-керованим ГЛЛ. Розуміння ролі домену PH як ключової структурної відмінності між p210 і p190 має вирішальне значення для з’ясування молекулярної основи BCR/ABL-опосередкованого лейкемогенезу. У майбутніх дослідженнях буде досліджено фосфорилювання кортактину та FBP17 ABL-кіназою та домени, відповідальні за ці взаємодії.
Ключові слова: BCR/ABL, кортактин, FBP17, PH домен, ХМЛ, GST-пулдаун, білок-білкові взаємодії
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