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Oral Sessions
Day 4, June 25（Wed.） 11:40-11:55
Room C (Top of Yaima)
- 4C-O1-1140
Mass spectrometry-based assay to screen for PTP dysregulation and activation: a case study in metabolic disease management and reversal.
(1A*STAR-SIgN, 2NUS)
Elisavet Kalaitsidou1,2, Ziliang Ma1, oWei Wu1,2
The human genome encodes for 37 cysteine-catalytic Protein Tyrosine Phosphatases (PTPs) that restrict growth, signaling and control metabolism in a spatial and temporally regulated manner. Pinpointing increased abundance and activity of specific PTPs in disease contexts is clinically useful, as a number of inhibitors and RNAi modalities are currently available against PTPs. Here, we set up a targeted mass spectrometry assay, coupled to catalytic site peptide affinity purification, to identify clinically relevant PTP dysregulation. The assay is not selective for starting material, and can read out (i) composition of the PTP repertoire, (ii) the abundance of each PTP, and finally (iii) reveal the activation associated with each phosphatase. Using this assay, we identify consistent and significant PTPRK elevation in livers with fat accumulation and associated inflammation. High fat, high fructose and high cholesterol (HFHFHC) diet induced PTPRK expression in mice, and PTPRK knockout mice do not gain weight or develop insulin resistance despite being put on HFHFHC diet. Collectively, these demonstrate the important role of PTPRK inhibition in preventing metabolic disease onset and progression, and demonstrates that our PTP mass spectrometry-based assay is highly relevant in the screening and rational design of clinical therapy.