RACK1/TRAF2 regulation of modulator of apoptosis-1 (MOAP-1) |
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Authors: | Jennifer Law Isabel Kwek Orysya Svystun Jonathan Lim Chong Teik Tan Le Luong Victor C Yu Shairaz Baksh |
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Institution: | 1. Department of Pediatrics, Faculty of Science, National University of Singapore, Singapore 117543, Singapore;2. Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore 117543, Singapore;3. Oncology, Faculty of Medicine and Dentistry, 3055, Katz Group Centre for Pharmacy and Health Research, 113 Street 87 Avenue, University of Alberta, Edmonton, AB T6G 2E1, Canada;4. Biochemistry, Faculty of Medicine and Dentistry, 3055 Katz Group Centre for Pharmacy and Health Research, 113 Street 87 Avenue, University of Alberta, Edmonton, AB T6G 2E1, Canada;5. Cancer Research Institute of Northern Alberta, 4-120 Katz Group Centre for Pharmacy and Health Research, Edmonton, AB, T6G 2J7, Canada;6. Women and Children''s Health Research Institute, University of Alberta, 5-083 Edmonton Clinic Health Academy (ECHA) 11405 87 Avenue NW, Edmonton, AB, T6G 1C9, Canada |
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Abstract: | MOAP-1 is a pro-apoptotic tumor suppressor molecule with a growing set of known interacting partners. We have demonstrated that during death receptor-dependent apoptosis, MOAP-1 is recruited to TNF-R1 or TRAIL-R1, followed by RASSF1A and Bax association. MOAP-1/Bax association promotes Bax conformational change resulting in the translocation of Bax into the mitochondrial membrane, mitochondrial membrane insertion and dysregulation resulting in several hallmark events that execute apoptosis. Although a role in apoptosis is established, it is currently unknown how MOAP-1 is regulated and how it links to Bax to promote apoptosis. In this study, we demonstrate robust association with RACK1, a versatile scaffolding protein that responds to activation of protein kinase C. Furthermore, we can demonstrate that RACK1 functions to bring the E3 ligase, TRAF2, to MOAP-1 in order to undergo a K63-dependent ubiquitination. Furthermore, RACK1 associates with MOAP-1 via electrostatic associations similar to those observed between MOAP-1/RASSF1A and MOAP-1/TNF-R1. These events illustrate the complex nature of MOAP-1 regulation and characterizes the important role of the scaffolding protein, RACK1, in influencing MOAP-1 biology. |
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Keywords: | MOAP-1 Ubiquitination Apoptosis TRAF2 RACK1 RASSF1A PKC |
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