title: The TRPM7 chanzyme is cleaved to release a chromatin-modifying kinase.
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:
authors.affiliation: Howard Hughes Medical Institute, Department of Cardiology, Boston Children's Hospital, Enders Building 1309, 320 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Grigory
authors.initials: G
authors.lastname: Krapivinsky
authors.affiliation: Howard Hughes Medical Institute, Department of Cardiology, Boston Children's Hospital, Enders Building 1309, 320 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Luba
authors.initials: L
authors.lastname: Krapivinsky
authors.affiliation: Howard Hughes Medical Institute, Department of Cardiology, Boston Children's Hospital, Enders Building 1309, 320 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Yunona
authors.initials: Y
authors.lastname: Manasian
authors.affiliation: Howard Hughes Medical Institute, Department of Cardiology, Boston Children's Hospital, Enders Building 1309, 320 Longwood Avenue, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. Electronic address: dclapham@enders.tch.harvard.edu.
authors.forename: David E
authors.initials: DE
authors.lastname: Clapham
mesh_terms: D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D003600:Cytosol / Q000378:metabolism; D015870:Gene Expression; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D050053:TRPM Cation Channels / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism; D016335:Zinc Fingers
chemical_list: D006657:Histones; D050053:TRPM Cation Channels; C421903:Trpm7 protein, mouse; D017346:Protein Serine-Threonine Kinases; C486583:TRPM7 protein, human; D015032:Zinc