JAK2V617F-Mediated Phosphorylation of PRMT5 Downregulates Its Methyltransferase Activity and Promotes Myeloproliferation

Abstract

SUMMARY The JAK2V617F constitutively activated tyrosine kinase is found in most patients with myeloproliferative neoplasms. While examining the interaction between JAK2 and PRMT5, an arginine methyltransferase originally identified as JAK2 binding protein 1, we found that JAK2V617F (and JAK2K539L) bound PRMT5 more strongly than did wild-type JAK2. These oncogenic kinases also acquired the ability to phosphorylate PRMT5, greatly impairing its ability to methylate its histone substrates, and representing a specific gain-of-function that allows them to regulate chromatin modifications. We readily detected PRMT5 phosphorylation in JAK2V617F-positive patient samples and when we knocked down PRMT5 in human CD34+ cells using shRNA, we observed increased colony formation and erythroid differentiation. These results indicate that phosphorylation of PRMT5 contributes to the mutant JAK2-induced myeloproliferative phenotype.

Protein Arginine Methyltransferase 5 (PRMT5) Signaling Suppresses Protein Kinase Cδ- and p38δ-dependent Signaling and Keratinocyte Differentiation

“…The possibility that PRMT5-related regulation is increased is an important area for further investigation in skin cancer. PRMT5 may also link the p38␦ complex to other signaling cascades, as PRMT5 associates with Janus kinases and STAT (54,56). Thus, the knowledge that PRMT5 is part of the p38␦ complex helps us in our effort to assembly the signaling network that controls keratinocyte differentiation.…”

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

“…JAK2 is known to phosphorylate histone H3, thereby disrupting the binding of heterochromatin protein 1 alpha (HP1α) to chromatin [21,22]. Furthermore, JAK2 phosphorylates the arginine methyltransferase PRMT5, impairing its ability to methylate histone substrates, ultimately driving myeloproliferation [22]. …”

Identification of a Dual Inhibitor of Janus Kinase 2 (JAK2) and p70 Ribosomal S6 Kinase1 (S6K1) Pathways

“…Stimulation of JAK2 by cytokines and growth factors subsequently leads to activation of STAT 3/5, promoting transcription of STAT-dependent genes (5). In addition, recent findings have shown that JAK2-mediated STAT-independent epigenetic up-regulation promotes tumor formation (6,7). Various solid and hematological cancers have been reported to exhibit constitutive activation of JAK2/STAT3 signaling due in part to JAK2 activating mutations, elevated cytokine/growth factor levels, and inactivation of endogenous sup-pressors of the pathway (4).…”