The TRPM7 chanzyme is cleaved to release a chromatin-modifying kinase

Cell. 2014 May 22;157(5):1061-72. doi: 10.1016/j.cell.2014.03.046.

Abstract

TRPM7 is a ubiquitous ion channel and kinase, a unique "chanzyme," required for proper early embryonic development. It conducts Zn(2+), Mg(2+), and Ca(2+) as well as monovalent cations and contains a functional serine/threonine kinase at its carboxyl terminus. Here, we show that in normal tissues and cell lines, the kinase is proteolytically cleaved from the channel domain in a cell-type-specific manner. These TRPM7 cleaved kinase fragments (M7CKs) translocate to the nucleus and bind multiple components of chromatin-remodeling complexes, including Polycomb group proteins. In the nucleus, the kinase phosphorylates specific serines/threonines of histones. M7CK-dependent phosphorylation of H3Ser10 at promoters of TRPM7-dependent genes correlates with their activity. We also demonstrate that cytosolic free [Zn(2+)] is TRPM7 dependent and regulates M7CK binding to transcription factors containing zinc-finger domains. These findings suggest that TRPM7-mediated modulation of intracellular Zn(2+) concentration couples ion-channel signaling to epigenetic chromatin covalent modifications that affect gene expression patterns. PAPERCLIP:

MeSH terms

  • Animals
  • Cell Line
  • Cell Nucleus / metabolism
  • Chromatin Assembly and Disassembly
  • Cytosol / metabolism
  • Gene Expression
  • Histones / metabolism
  • Humans
  • Mice
  • Phosphorylation
  • Protein-Serine-Threonine Kinases
  • TRPM Cation Channels / metabolism*
  • Zinc / metabolism
  • Zinc Fingers

Substances

  • Histones
  • TRPM Cation Channels
  • Trpm7 protein, mouse
  • Protein-Serine-Threonine Kinases
  • TRPM7 protein, human
  • Zinc