MST2 Methylation by PRMT5 Inhibits Hippo Signaling and Promotes Pancreatic Cancer Progression
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ABSTRACT:
PROVIDER: PRJNA1008073 | ENA |
REPOSITORIES: ENA
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Project description:As a classic tumor suppressor pathway, Hippo signaling axis is activated by various extra-pathway factors to regulate cell differentiation and organ development. However, recent studies have reported that the activation of Hippo signaling pathway may be more dependent on the autophosphorylation of its core kinase cassette. Here, we demonstrate that protein arginine methyltransferase 5 (PRMT5) is involved in inducing the inactivation of Hippo signaling pathway in pancreatic cancer. Our study shows that the initiator serine/threonine kinase 3 (STK3, also known as MST2) of Hippo signaling pathway can be symmetrically di-methylated at arginine-461 (R461) and arginine-467 (R467) in the SARAH domain by PRMT5, and the methylated MST2 suppresses its autophosphorylation and kinase activity by blocking the formation of homodimer, thereby inactivating Hippo signaling pathway in pancreatic cancer. Moreover, we also discover that the specific PRMT5 inhibitor GSK3326595 re-activates the dysregulated Hippo signaling pathway and inhibits the growth of human-derived pancreatic cancer xenografts in immunodeficient mice, which provides a theoretical foundation for the clinical application of PRMT5 inhibitor in pancreatic cancer.
2023-11-17 | GSE241402 | GEO
Project description: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.
| S-SCDT-10_15252-EMBJ_2023114558 | biostudies-other
Project description:As a classic tumor suppressor pathway, Hippo signaling axis is activated by various extra-pathway factors to regulate cell differentiation and organ development. However, recent studies have reported that the activation of Hippo signaling pathway may be more dependent on the autophosphorylation of its core kinase cassette. Here, we demonstrate that protein arginine methyltransferase 5 (PRMT5) is involved in inducing the inactivation of Hippo signaling pathway in pancreatic cancer. Our study shows that the initiator serine/threonine kinase 3 (STK3, also known as MST2) of Hippo signaling pathway can be symmetrically di-methylated at arginine-461 (R461) and arginine-467 (R467) in the SARAH domain by PRMT5, and the methylated MST2 suppresses its autophosphorylation and kinase activity by blocking the formation of homodimer, thereby inactivating Hippo signaling pathway in pancreatic cancer. Moreover, we also discover that the specific PRMT5 inhibitor GSK3326595 re-activates the dysregulated Hippo signaling pathway
2023-08-18 | PXD044671 |
Project description:Purpose: Richter’s Transformation (RT) is a poorly understood and often fatal progression of chronic lymphocytic leukemia (CLL) manifesting histologically as diffuse large B-cell lymphoma. PRMT5 is implicated in lymphomagenesis, but its role in CLL or RT progression is unknown. We demonstrate herein that tumors uniformly overexpress PRMT5 in patients with progression to RT. Furthermore, mice with B-specific overexpression of hPRMT5 developed a B-lymphoid expansion with increased risk of death, and Eµ-PRMT5/TCL1 double transgenic mice uniformly developed a highly aggressive disease that histologically resembles RT; where large-scale transcriptional profiling identified unique oncogenic pathways that mediate PRMT5-driven disease progression. Taken together, the discovery that PRMT5 drives oncogenic pathways promoting RT provides a compelling rationale for clinical investigation of PRMT5 inhibitors such as PRT382 in aggressive CLL/RT cases
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Project description:Purpose: Richter’s Transformation (RT) is a poorly understood and often fatal progression of chronic lymphocytic leukemia (CLL) manifesting histologically as diffuse large B-cell lymphoma. PRMT5 is implicated in lymphomagenesis, but its role in CLL or RT progression is unknown. We demonstrate herein that tumors uniformly overexpress PRMT5 in patients with progression to RT. Furthermore, mice with B-specific overexpression of hPRMT5 developed a B-lymphoid expansion with increased risk of death, and Eµ-PRMT5/TCL1 double transgenic mice uniformly developed a highly aggressive disease that histologically resembles RT; where large-scale transcriptional profiling identified unique oncogenic pathways that mediate PRMT5-driven disease progression. Taken together, the discovery that PRMT5 drives oncogenic pathways promoting RT provides a compelling rationale for clinical investigation of PRMT5 inhibitors such as PRT382 in aggressive CLL/RT cases
2022-12-07 | GSE183427 | GEO
Project description:Purpose: Richter’s Transformation (RT) is a poorly understood and often fatal progression of chronic lymphocytic leukemia (CLL) manifesting histologically as diffuse large B-cell lymphoma. PRMT5 is implicated in lymphomagenesis, but its role in CLL or RT progression is unknown. We demonstrate herein that tumors uniformly overexpress PRMT5 in patients with progression to RT. Furthermore, mice with B-specific overexpression of hPRMT5 developed a B-lymphoid expansion with increased risk of death, and Eµ-PRMT5/TCL1 double transgenic mice uniformly developed a highly aggressive disease that histologically resembles RT; where large-scale transcriptional profiling identified unique oncogenic pathways that mediate PRMT5-driven disease progression. Taken together, the discovery that PRMT5 drives oncogenic pathways promoting RT provides a compelling rationale for clinical investigation of PRMT5 inhibitors such as PRT382 in aggressive CLL/RT cases
2022-12-07 | GSE183426 | GEO
Project description:Purpose: Richter’s Transformation (RT) is a poorly understood and often fatal progression of chronic lymphocytic leukemia (CLL) manifesting histologically as diffuse large B-cell lymphoma. PRMT5 is implicated in lymphomagenesis, but its role in CLL or RT progression is unknown. We demonstrate herein that tumors uniformly overexpress PRMT5 in patients with progression to RT. Furthermore, mice with B-specific overexpression of hPRMT5 developed a B-lymphoid expansion with increased risk of death, and Eµ-PRMT5/TCL1 double transgenic mice uniformly developed a highly aggressive disease that histologically resembles RT; where large-scale transcriptional profiling identified unique oncogenic pathways that mediate PRMT5-driven disease progression. Taken together, the discovery that PRMT5 drives oncogenic pathways promoting RT provides a compelling rationale for clinical investigation of PRMT5 inhibitors such as PRT382 in aggressive CLL/RT cases
2022-12-07 | GSE205704 | GEO
Project description:Purpose: Richter’s Transformation (RT) is a poorly understood and often fatal progression of chronic lymphocytic leukemia (CLL) manifesting histologically as diffuse large B-cell lymphoma. PRMT5 is implicated in lymphomagenesis, but its role in CLL or RT progression is unknown. We demonstrate herein that tumors uniformly overexpress PRMT5 in patients with progression to RT. Furthermore, mice with B-specific overexpression of hPRMT5 developed a B-lymphoid expansion with increased risk of death, and Eµ-PRMT5/TCL1 double transgenic mice uniformly developed a highly aggressive disease that histologically resembles RT; where large-scale transcriptional profiling identified unique oncogenic pathways that mediate PRMT5-driven disease progression. Taken together, the discovery that PRMT5 drives oncogenic pathways promoting RT provides a compelling rationale for clinical investigation of PRMT5 inhibitors such as PRT382 in aggressive CLL/RT cases
2022-12-07 | GSE183425 | GEO
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| PRJNA760770 | ENA
Project description:Hippo kinases Mst1 and Mst2 act as molecular rheostats for the terminal maturation and effector differentiation programs of iNKT cells. Loss of Mst1 alone or with Mst2 impedes iNKT cell development, associated with defective IL-15-dependent cell survival
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