TY - JOUR
T1 - Transthyretin binds to glucose-regulated proteins and is subjected to endocytosis by the pancreatic β-cell
AU - Dekki, Nancy
AU - Refai, Essam
AU - Holmberg, Rebecka
AU - Köhler, Martin
AU - Jörnvall, Hans
AU - Berggren, Per Olof
AU - Juntti-Berggren, Lisa
N1 - Funding Information:
We thank Prof Tomas Kirchhausen, Harvard Medical School, who kindly provided us with dynasore, synthesized by Dr Henry E Pelish. This work was supported by grants from The Family Erling-Persson Foundation, The Swedish Research Council, the Novo Nordisk Foundation, Swedish Diabetes Association, Barndiabetesfonden, Karolinska Institutet, Magnus Bergwalls Foundation, The Knut and Alice Wallenberg Foundation, the Skandia Insurance Company Ltd., VIBRANT (FP7-228933-2), Strategic Research Program in Diabetes at Karolinska Institutet and Berth von Kantzow’s Foundation.
PY - 2012/5
Y1 - 2012/5
N2 - Transthyretin (TTR) is a functional protein in the pancreatic b-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.
AB - Transthyretin (TTR) is a functional protein in the pancreatic b-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.
KW - Dynasore
KW - Glucose-regulated proteins
KW - Pancreatic β-cell
KW - Surface plasmon resonance
KW - Transthyretin
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U2 - 10.1007/s00018-011-0899-8
DO - 10.1007/s00018-011-0899-8
M3 - Article
C2 - 22183612
AN - SCOPUS:84863603027
VL - 69
SP - 1733
EP - 1743
JO - Cellular and Molecular Life Sciences
JF - Cellular and Molecular Life Sciences
SN - 1420-682X
IS - 10
ER -