Malacrida_2018_RAB40C.pdf (1.5 MB)
RAB40C regulates RACK1 stability via theubiquitin–proteasome system
journal contribution
posted on 2018-10-03, 11:50 authored by John P. Day, Ellanor Whiteley, Michael Freeley, Aideen Long, Beatrice Malacrida, Patrick A. Kiely, George S. BaillieAim: RACK1 is a multifunctional scaffolding protein that is expressed in many cellular compartments, orchestrating a number of signaling processes. RACK1 acts as a signaling hub to localize active enzymes to discrete locations; therefore tight control of RACK1 is vital to cellular homeostasis. Our aim was to identify the mechanisms responsible for RACK1 turnover and show that degradation is directed by the ubiquitin proteasome system. Results: Using siRNA screening, we identified RAB40C as the ubiquitin E3 ligase responsible for ubiquitination of RACK1, and that the action of RAB40C in controlling RACK1 levels is crucial to both cancer cell growth and migration of T cells. Conclusion: Our data suggest that manipulation of RACK1 levels in this way may provide a novel strategy to explore RACK1 function. Lay abstract: When cells in the body grow and divide there is a coordination underpinned by intra- and inter-cell communication. This process depends on anchoring proteins that bring cell communication proteins together in the correct amounts, in the correct place, and at the right time. RACK1 is a scaffolding
protein that is known to fulfill this function and as a result a balance of cellular synthesis versus controlled breakdown tightly controls its concentration in cells. This study, for the first time, demonstrates that RACK1 concentration and function is controlled by another protein called RAB40C, which ‘tags’ it for destruction by the 26S proteasome. This may have therapeutic implications for certain kinds of cancerous cell growth.
Funding
Earthquake Vulnerability of Water Supply and Natural Gas Systems
Directorate for Engineering
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Future Science OA;(2018) 4(7), FSO317Publisher
Future ScienceNote
peer-reviewedOther Funding information
Medical Research CouncilLanguage
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