Revealing β-TrCP activity dynamics in live cells with a genetically encoded biosensor

Debasish Paul, Stephen C. Kales, James A. Cornwell, Marwa M. Afifi, Ganesha Rai, Alexey Zakharov, Anton Simeonov and Steven D. Cappell ()
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Debasish Paul: National Cancer Institute
Stephen C. Kales: National Institutes of Health
James A. Cornwell: National Cancer Institute
Marwa M. Afifi: National Cancer Institute
Ganesha Rai: National Institutes of Health
Alexey Zakharov: National Institutes of Health
Anton Simeonov: National Institutes of Health
Steven D. Cappell: National Cancer Institute

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract The F-box protein beta-transducin repeat containing protein (β-TrCP) acts as a substrate adapter for the SCF E3 ubiquitin ligase complex, plays a crucial role in cell physiology, and is often deregulated in many types of cancers. Here, we develop a fluorescent biosensor to quantitatively measure β-TrCP activity in live, single cells in real-time. We find β-TrCP remains constitutively active throughout the cell cycle and functions to maintain discreet steady-state levels of its substrates. We find no correlation between expression levels of β-TrCP and β-TrCP activity, indicating post-transcriptional regulation. A high throughput screen of small-molecules using our reporter identifies receptor-tyrosine kinase signaling as a key axis for regulating β-TrCP activity by inhibiting binding between β-TrCP and the core SCF complex. Our study introduces a method to monitor β-TrCP activity in live cells and identifies a key signaling network that regulates β-TrCP activity throughout the cell cycle.

Date: 2022
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DOI: 10.1038/s41467-022-33762-3

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