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

J Clin Invest. 2018 Jan 2;128(1):517-530. doi: 10.1172/JCI95410. Epub 2017 Dec 11.


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.

Keywords: Cancer; Cell Biology; Melanoma; Oncology; Signal transduction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • HEK293 Cells
  • Humans
  • Melanoma / genetics
  • Melanoma / metabolism*
  • Melanoma / pathology
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Protein-Arginine N-Methyltransferases / genetics
  • Protein-Arginine N-Methyltransferases / metabolism*
  • SOXE Transcription Factors / genetics
  • SOXE Transcription Factors / metabolism
  • Ubiquitins / genetics
  • Ubiquitins / metabolism*


  • Neoplasm Proteins
  • SHARPIN protein, human
  • SOX10 protein, human
  • SOXE Transcription Factors
  • Ubiquitins
  • PRMT5 protein, human
  • Protein-Arginine N-Methyltransferases