Magnesium-dependent-Protein Phosphatase 1B Regulates the Protein Arginine Methyltransferase 5 Through the Modulation of Myosin Phosphatase.

Abstract

Dysregulation of the expression levels and the activity of kinases/phosphatases is an intrinsic hallmark of tumor transformation and progression, as either as a primary cause or consequence. The myosin phosphatase (MP)/protein arginine methyltransferase 5 (PRMT5)/histone (H4) pathway is an oncogenic signaling pathway downregulating the gene expression of tumor suppressors. However, the upstream regulators of the pathway are unknown. We show that the Mg²⁺-dependent protein phosphatase 1 B (PP2Cb or PPM1B) interacts and regulates MP through the MYPT1 regulatory subunit, and this interplay results in the inactivation of the tumorigenic pathway driven by PRMT5. The phospho-Thr696 inhibitory residues of the MYPT1 regulatory subunit of MP was dephosphorylated by PPM1B. The inhibition of PPM1B by sanguinarine (SNG) resulted in the deactivation of MP and the increased activity of PRMT5 leading to increased symmetric dimethylation of histone H4 in HeLa cells. The overexpression of the PPM1B had the opposite action. The overexpression of PPM1B decreased the colonization activity of HeLa cells through modulation of MP. Finally, human cervical carcinoma biopsies showed almost complete elimination of PPM1B compared to their healthy control counterparts. The phosphorylation of the inhibitory MYPT1^pT696 and the regulatory PRMT5^pT80 residues and the symmetric dimethylation of H4 were elevated in the cancer biopsies and it resulted in a decrease in retinoblastoma protein expression. The results indicate a tumor suppressor role of the PPM1B/MP axis via inhibition of PRMT5, thereby regulating gene expression through H4 arginine dimethylation. Collectively, PPM1B is a tumor suppressor and a possible tumor marker for cervical carcinoma.