title: Transthyretin binds to glucose-regulated proteins and is subjected to endocytosis by the pancreatic β-cell.
abstract: Transthyretin (TTR) is a functional protein in the pancreatic β-cell. It promotes insulin release and protects against β-cell death. We now demonstrate by ligand blotting, adsorption to specific magnetic beads, and surface plasmon resonance that TTR binds to glucose-regulated proteins (Grps)78, 94, and 170, which are members of the endoplasmic reticulum chaperone family, but Grps78 and 94 have also been found at the plasma membrane. The effect of TTR on changes in cytoplasmic free Ca(2+) concentration ([Ca(2+)](i)) was abolished if the cells were treated with either dynasore, a specific inhibitor of dynamin GTPase that blocks clathrin-mediated endocytosis, or an antibody against Grp78, that prevents TTR from binding to Grp78. The conclusion is that TTR binds to Grp78 at the plasma membrane, is internalized into the β-cell via a clathrin-dependent pathway, and that this internalization is necessary for the effects of TTR on β-cell function.
authors.affiliation: The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Nancy
authors.initials: N
authors.lastname: Dekki
authors.forename: Essam
authors.initials: E
authors.lastname: Refai
authors.forename: Rebecka
authors.initials: R
authors.lastname: Holmberg
authors.forename: Martin
authors.initials: M
authors.lastname: Köhler
authors.forename: Hans
authors.initials: H
authors.lastname: Jörnvall
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
authors.forename: Lisa
authors.initials: L
authors.lastname: Juntti-Berggren
mesh_terms: D000818:Animals; D022163:Clathrin-Coated Vesicles / Q000378:metabolism; D004705:Endocytosis; D000091342:Endoplasmic Reticulum Chaperone BiP; D006023:Glycoproteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D011228:Prealbumin / Q000378:metabolism*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006023:Glycoproteins; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011228:Prealbumin; C053387:endoplasmin; C098410:glucose-regulated protein 170