ENTREP/FAM189A2 encodes a new ITCH ubiquitin ligase activator that is downregulated in breast cancer |
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| Authors: | Takumi Tsunoda Miho Riku Norika Yamada Hikaru Tsuchiya Takuya Tomita Minako Suzuki Mari Kizuki Akihito Inoko Hideaki Ito Kenta Murotani Hideki Murakami Yasushi Saeki Kenji Kasai |
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| Affiliation: | 1. Department of Pathology, Aichi Medical University School of Medicine, Nagakute Japan ; 2. Protein Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo Japan ; 3. Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya Japan ; 4. Biostatistics Center, Kurume University, Kurume Japan |
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| 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). |
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| Keywords: | breast cancer CXCR4 ENTREP FAM189A2 ITCH |
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