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Allosterically activating SHP2 by oleanolic acid inhibits STAT3-Th17 axis for ameliorating colitis
1State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Drum Tower Hospital, School of Life Sciences, Nanjing University, Nanjing 210093, China.
Acta Pharmaceutica Sinica. B
|June 3, 2024
Summary
Oleanolic acid activates Src homology 2 domain-containing tyrosine phosphatase 2 (SHP2), inhibiting inflammatory Th17 cell differentiation and mitigating colitis in mice.
Area of Science:
- Biochemistry
- Immunology
- Pharmacology
Background:
- Src homology 2 domain-containing tyrosine phosphatase 2 (SHP2) is crucial for cell signaling, with therapeutic potential in inflammatory diseases.
- Identifying SHP2 activators and understanding their mechanisms is essential for developing new treatments.
Purpose of the Study:
- To identify novel allosteric activators of SHP2.
- To elucidate the mechanism of SHP2 activation by oleanolic acid.
- To evaluate the therapeutic potential of oleanolic acid in colitis models.
Main Methods:
- A two-step screening assay was employed to identify SHP2 activators.
- The binding site and conformational changes induced by oleanolic acid were analyzed.
- The effect of oleanolic acid on Th17 differentiation and STAT3 activation was investigated.
- Colitis was induced in mice to assess the therapeutic efficacy of oleanolic acid, with SHP2 knockout and inhibitor controls.
Main Results:
- Oleanolic acid was identified as a novel allosteric activator of SHP2, stabilizing its open conformation.
- Oleanolic acid binds to specific residues (R362, K364, K366) in the PTP domain, facilitating substrate interaction.
- Activated SHP2 by oleanolic acid inhibited STAT3 activation and Th17 cell differentiation by disrupting the STAT3-IL-6Rα interaction.
- Oleanolic acid treatment significantly ameliorated colitis in mice, an effect dependent on SHP2 activity.
Conclusions:
- Oleanolic acid is a potent SHP2 activator with a defined mechanism of action.
- SHP2 activation by oleanolic acid provides a novel therapeutic strategy for inflammatory bowel diseases.
- Oleanolic acid demonstrates significant potential as a treatment for colitis.
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