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

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. image Activation of the YAP transcriptional co‐activator, frequently occurring in pancreatic cancer, is suppressed by the Hippo pathway initiated by the MST2 kinase. Here, arginine methylation via PRMT5 is found to inhibit MST2 activation and may present a target for cancer treatment. MST2 is dimethylated at R461 and R467 in its C‐terminal SARAH domain. MST2 dimethylation decreases its homodimerization, suppressing MST2 autophosphorylation and kinase activity. PRMT5 catalyzes the symmetrical SARAH domain dimethylation of MST2. The PRMT5 inhibitor GSK3326595 re‐activates Hippo signaling in human pancreatic cancer‐derived xenografts.