2. Academic Validation
  3. MST2 methylation by PRMT5 inhibits Hippo signaling and promotes pancreatic cancer progression

MST2 methylation by PRMT5 inhibits Hippo signaling and promotes pancreatic cancer progression

  • EMBO J. 2023 Oct 31:e114558. doi: 10.15252/embj.2023114558.
Yan Sun # 1 2,  Xin Jin # 3 4,  Junpeng Meng 1 2 5,  Feng Guo 1 2,  Taoyu Chen 1 2,  Xiaoyan Zhao 6,  Heshui Wu 1 2,  Dianyun Ren 1 2
Affiliations

Affiliations

  • 1 Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Sino-German Laboratory of Personalized Medicine for Pancreatic Cancer, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, China.
  • 4 Uro-Oncology Institute of Central South University, Changsha, China.
  • 5 Department of General Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, China.
  • 6 Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • # Contributed equally.
PMID: 37905571 DOI: 10.15252/embj.2023114558
Abstract

The Hippo signaling axis is a tumor suppressor pathway that is activated by various extra-pathway factors to regulate cell differentiation and organ development. Recent studies have reported that autophosphorylation of the core kinase cassette stimulates activation of the Hippo signaling cascade. Here, we demonstrate that protein arginine methyltransferase 5 (PRMT5) contributes to inactivation of the Hippo signaling pathway in pancreatic Cancer. We show that the Hippo pathway initiator serine/threonine kinase 3 (STK3, also known as MST2) of Hippo signaling pathway can be symmetrically di-methylated by PRMT5 at arginine-461 (R461) and arginine-467 (R467) in its SARAH domain. Methylation suppresses MST2 autophosphorylation and kinase activity by blocking its homodimerization, thereby inactivating Hippo signaling pathway in pancreatic Cancer. Moreover, we also show that the specific PRMT5 Inhibitor GSK3326595 re-activates the dysregulated Hippo signaling pathway and inhibits the growth of human pancreatic Cancer xenografts in immunodeficient mice, thus suggesting potential clinical application of PRMT5 inhibitors in pancreatic Cancer.

Keywords

MST2; PRMT5; dimerization; methylation; pancreatic cancer.

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