ENTREP/FAM189A2 encodes a new ITCH ubiquitin ligase activator that is downregulated in breast cancer. (20th December 2021)

• Record Type: Journal Article
• Authors: Tsunoda, Takumi; Riku, Miho; Yamada, Norika; Tsuchiya, Hikaru; Tomita, Takuya; Suzuki, Minako; Kizuki, Mari; Inoko, Akihito; Ito, Hideaki; Murotani, Kenta; Murakami, Hideki; Saeki, Yasushi; Kasai, Kenji
• Is Part Of: EMBO reports. Volume 23:Number 2(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-12-20
• Subjects: breast cancer -- CXCR4 -- ENTREP -- FAM189A2 -- ITCH; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.202051182
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: The HECT‐type ubiquitin E3 ligases including ITCH regulate many aspects of cellular function through ubiquitinating various substrates. These ligases are known to be allosterically autoinhibited and to require an activator protein to fully achieve the ubiquitination of their substrates. Here we demonstrate that FAM189A2, a downregulated gene in breast cancer, encodes a new type of ITCH activator. FAM189A2 is a transmembrane protein harboring PPxY motifs, and the motifs mediate its association with and ubiquitination by ITCH. FAM189A2 also associates with Epsin and accumulates in early and late endosomes along with ITCH. Intriguingly, FAM189A2 facilitates the association of a chemokine receptor CXCR4 with ITCH and enhances ITCH‐mediated ubiquitination of CXCR4. FAM189A2‐knockout prohibits CXCL12‐induced endocytosis of CXCR4, thereby enhancing the effects of CXCL12 on the chemotaxis and mammosphere formation of breast cancer cells. In comparison to other activators or adaptors known in the previous studies, FAM189A2 is a unique activator for ITCH to desensitize CXCR4 activity, and we here propose that FAM189A2 be renamed as ENdosomal TRansmembrane binding with EPsin (ENTREP). Synopsis: ENTREP is an activator for HECT‐type ubiquitin E3 ligase ITCH, which mediates ubiquitination and endocytosis of a chemokine receptor CXCR4. ENTREP downregulation attenuates CXCR4 desensitization, thereby promoting breast cancer stemness. ENTREP associates with ITCH and clathrin‐associated sorting protein Epsin. ENTREP forms a ternary complex with ITCH and CXCR4 to enhance ITCH‐mediated ubiquitination of CXCR4. Downregulation of ENTREP disturbs ligand‐induced endocytosis of CXCR4, thereby enhancing CXCR4‐mediated migration and stemness of cancer cells. Abstract : ENTREP is an activator for HECT‐type ubiquitin E3 ligase ITCH, which mediates ubiquitination and endocytosis of a chemokine receptor CXCR4. ENTREP downregulation attenuates CXCR4 desensitization, thereby promoting breast cancer stemness.