SHARPIN-mediated regulation of protein arginine methyltransferase 5 controls melanoma growth

Hironari Tamiya, Hyungsoo Kim, Oleksiy Klymenko, Heejung Kim, Yongmei Feng, Tongwu Zhang, Ji Yun Han, Ayako Murao, Scott J. Snipas, Lucia Jilaveanu, Kevin Brown, Harriet Kluger, Hao Zhang, Kazuhiro Iwai, Zeev A. Ronai

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

SHARPIN, an adaptor for the linear ubiquitin chain assembly complex (LUBAC), plays important roles in NF-κB signaling and inflammation. Here, we have demonstrated a LUBAC-independent role for SHARPIN in regulating melanoma growth. We observed that SHARPIN interacted with PRMT5, a type II protein arginine methyltransferase, and increased its multiprotein complex and methyltransferase activity. Activated PRMT5 controlled the expression of the transcription factors SOX10 and MITF by SHARPIN-dependent arginine dimethylation and inhibition of the transcriptional corepressor SKI. Activation of PRMT5 by SHARPIN counteracted PRMT5 inhibition by methylthioadenosine, a substrate of methylthioadenosine phosphorylase, which is codeleted with cyclin-dependent kinase inhibitor 2A (CDKN2A) in approximately 15% of human cancers. Collectively, we identified a LUBAC-independent role for SHARPIN in enhancing PRMT5 activity that contributes to melanomagenesis through the SKI/SOX10 regulatory axis.

Original languageEnglish
Pages (from-to)517-530
Number of pages14
JournalJournal of Clinical Investigation
Volume128
Issue number1
DOIs
StatePublished - 2 Jan 2018
Externally publishedYes

Fingerprint

Dive into the research topics of 'SHARPIN-mediated regulation of protein arginine methyltransferase 5 controls melanoma growth'. Together they form a unique fingerprint.

Cite this