title: Inositol polyphosphates intersect with signaling and metabolic networks via two distinct mechanisms.
abstract: Inositol-based signaling molecules are central eukaryotic messengers and include the highly phosphorylated, diffusible inositol polyphosphates (InsPs) and inositol pyrophosphates (PP-InsPs). Despite the essential cellular regulatory functions of InsPs and PP-InsPs (including telomere maintenance, phosphate sensing, cell migration, and insulin secretion), the majority of their protein targets remain unknown. Here, the development of InsP and PP-InsP affinity reagents is described to comprehensively annotate the interactome of these messenger molecules. By using the reagents as bait, >150 putative protein targets were discovered from a eukaryotic cell lysate (Saccharomyces cerevisiae). Gene Ontology analysis of the binding partners revealed a significant overrepresentation of proteins involved in nucleotide metabolism, glucose metabolism, ribosome biogenesis, and phosphorylation-based signal transduction pathways. Notably, we isolated and characterized additional substrates of protein pyrophosphorylation, a unique posttranslational modification mediated by the PP-InsPs. Our findings not only demonstrate that the PP-InsPs provide a central line of communication between signaling and metabolic networks, but also highlight the unusual ability of these molecules to access two distinct modes of action.
authors: Department of Chemistry, Princeton University, Princeton, NJ 08544.
authors: Mingxuan
authors: M
authors: Wu
authors: Division of Neurosurgery, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.|Department of Chemical Biology, Leibniz-Institut für Molekulare Pharmakologie, 13125 Berlin, Germany.
authors: Lucy S
authors: LS
authors: Chong
authors: Department of Molecular Biology, Princeton University, Princeton, NJ 08544.
authors: David H
authors: DH
authors: Perlman
authors: Division of Neurosurgery, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.
authors: Adam C
authors: AC
authors: Resnick
authors: Department of Chemistry, Princeton University, Princeton, NJ 08544; fiedler@fmp-berlin.de.|Department of Chemical Biology, Leibniz-Institut für Molekulare Pharmakologie, 13125 Berlin, Germany.
authors: Dorothea
authors: D
authors: Fiedler
mesh_terms: D011756:Diphosphates / Q000378:metabolism; D005057:Eukaryotic Cells / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism*; D008274:Magnesium; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D009711:Nucleotides / Q000378:metabolism; D010766:Phosphorylation; D011122:Polyphosphates / Q000378:metabolism*; D020543:Proteome; D012270:Ribosomes / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D011756:Diphosphates; D007295:Inositol Phosphates; D009711:Nucleotides; D011122:Polyphosphates; D020543:Proteome; D008274:Magnesium; D005947:Glucose
keywords: affinity reagents; inositol pyrophosphates; metabolism; protein pyrophosphorylation; signal transduction