Tyrosine phosphorylation of CARM1 promotes its enzymatic activity and alters its target specificity

• Published in: Nature communications Vol. 15; no. 1; p. 3415
• Main Authors: Itonaga, Hidehiro, Mookhtiar, Adnan K., Greenblatt, Sarah M., Liu, Fan, Martinez, Concepcion, Bilbao, Daniel, Rains, Masai, Hamard, Pierre-Jacques, Sun, Jun, Umeano, Afoma C., Duffort, Stephanie, Chen, Chuan, Man, Na, Mas, Gloria, Tottone, Luca, Totiger, Tulasigeri, Bradley, Terrence, Taylor, Justin, Schürer, Stephan, Nimer, Stephen D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.04.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 38/15; 38/39; 38/70; 631/1647/296; 631/337/458/1648; 631/337/458/1733; 631/45/607/1172; 82/58; 82/80; Acute myeloid leukemia; Apoptosis; Arginine; Cell Cycle; Cell Line, Tumor; Cell proliferation; Core Binding Factor Alpha 2 Subunit - genetics; Core Binding Factor Alpha 2 Subunit - metabolism; Enzymatic activity; Epigenetics; Gene expression; HEK293 Cells; Histones; Humanities and Social Sciences; Humans; Janus kinase; Janus kinase 2; Janus Kinase 2 - genetics; Janus Kinase 2 - metabolism; Kinases; Leukemia; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Malignancy; Methylation; multidisciplinary; Mutation; Myeloid cells; Phosphorylation; Protein arginine methyltransferase; Protein-Arginine N-Methyltransferases - genetics; Protein-Arginine N-Methyltransferases - metabolism; Runx1 protein; Science; Science (multidisciplinary); Substrate Specificity; Substrates; Tyrosine; Tyrosine - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-47689-4

An important epigenetic component of tyrosine kinase signaling is the phosphorylation of histones, and epigenetic readers, writers, and erasers. Phosphorylation of protein arginine methyltransferases (PRMTs), have been shown to enhance and impair their enzymatic activity. In this study, we show that the hyperactivation of Janus kinase 2 (JAK2) by the V617F mutation phosphorylates tyrosine residues (Y149 and Y334) in coactivator-associated arginine methyltransferase 1 (CARM1), an important target in hematologic malignancies, increasing its methyltransferase activity and altering its target specificity. While non-phosphorylatable CARM1 methylates some established substrates (e.g. BAF155 and PABP1), only phospho-CARM1 methylates the RUNX1 transcription factor, on R223 and R319. Furthermore, cells expressing non-phosphorylatable CARM1 have impaired cell-cycle progression and increased apoptosis, compared to cells expressing phosphorylatable, wild-type CARM1, with reduced expression of genes associated with G2/M cell cycle progression and anti-apoptosis. The presence of the JAK2-V617F mutant kinase renders acute myeloid leukemia (AML) cells less sensitive to CARM1 inhibition, and we show that the dual targeting of JAK2 and CARM1 is more effective than monotherapy in AML cells expressing phospho-CARM1. Thus, the phosphorylation of CARM1 by hyperactivated JAK2 regulates its methyltransferase activity, helps select its substrates, and is required for the maximal proliferation of malignant myeloid cells. Coactivator-associated arginine methyltransferase 1 (CARM1) is an important target in hematologic malignancies. In this work, the authors show that the hyperactivation of Janus kinase 2 (JAK2) by the V617F mutation phosphorylates CARM1 which regulates its methyltransferase activity and alters its target specificity.