PAK5-mediated PKM2 phosphorylation is critical for anaerobic glycolysis in endometriosis

Abstract

P21-activated kinase 5 (PAK5) belongs to the PAK-II subfamily, which is an important regulator of cell survival, adhesion, and motility. However, the functions of PAK5 in endometriosis remain unclear. Here, PAK5 is strikingly upregulated in endometriosis. Furthermore, the knockdown of PAK5 or its inhibitor GNE 2861 blocks the development of endometriosis, which is equally demonstrated in PAK5-knockout mice. In addition, PAK5 promotes glycolysis by enhancing the protein stability of pyruvate kinase 2 (PKM2) in endometriotic cells, which is a key enzyme for glucose metabolism. Moreover, the phosphorylation of PKM2 at Ser519 by PAK5 mediates endometriosis cell proliferation and metastasis. Collectively, PAK5 plays an indispensable role in endometriosis. Our findings demonstrate that PAK5 is an important target for the treatment of endometriosis.

Keywords

PAK5 / PKM2 / phosphorylation / endometriosis / glycolysis

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Acknowledgements

The study was supported by research grants from the National Natural Science Foundation of China (Nos. 81972489 and 82003201), the National Natural Science Foundation of Shandong Province (No. ZR2020YQ58), Shandong Province College Science and Technology Plan Project (No. J17KA254), Projects of medical and health technology development program in Shandong province (No. 2018WS057).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-024-1069-3 and is accessible for authorized users.

Compliance with ethics guidelines

Conflict of interest Jiayi Lu, Xiaoyun Wang, Xiaodan Shi, Junyi Jiang, Lan Liu, Lu Liu, Chune Ren, Chao Lu, and Zhenhai Yu declare that they have no conflict of interest.

This study was approved by the Ethics Committee of the Affiliated Hospital of Shandong Second Medical University and the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all patients for being included in the study. All institutional and national guidelines for the care and use of laboratory animals were followed.

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