Kin of IRRE-like Protein 2 Is a Phosphorylated Glycoprotein That Regulates Basal Insulin Secretion.
Direct interactions among pancreatic β-cells via cell surface proteins inhibit basal and enhance stimulated insulin secretion. Here, we functionally and biochemically characterized Kirrel2, an immunoglobulin superfamily protein with β-cell-specific expression in the pancreas. Our results show that Kirrel2 is a phosphorylated glycoprotein that co-localizes and interacts with the adherens junction proteins E-cadherin and β-catenin in MIN6 cells. We further demonstrate that the phosphosites Tyr(595-596) are functionally relevant for the regulation of Kirrel2 stability and localization. Analysis of the extracellular and intracellular domains of Kirrel2 revealed that it is cleaved and shed from MIN6 cells and that the remaining membrane spanning cytoplasmic domain is processed by γ-secretase complex. Kirrel2 knockdown with RNA interference in MIN6 cells and ablation of Kirrel2 from mice with genetic deletion resulted in increased basal insulin secretion from β-cells, with no immediate influence on stimulated insulin secretion, total insulin content, or whole body glucose metabolism. Our results show that in pancreatic β-cells Kirrel2 localizes to adherens junctions, is regulated by multiple post-translational events, including glycosylation, extracellular cleavage, and phosphorylation, and engages in the regulation of basal insulin secretion.
From the Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Otto-Stern-Weg 7, 8093 Zurich.
Burcak
B
Yesildag
the Department of Health Sciences and Technology, Institute of Molecular Systems Biology, Swiss Federal Institute of Technology Zurich, Auguste-Piccard-Hof 1, 8093 Zurich, and.
Thomas
T
Bock
From the Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Otto-Stern-Weg 7, 8093 Zurich.
Karolin
K
Herrmanns
the Department of Health Sciences and Technology, Institute of Molecular Systems Biology, Swiss Federal Institute of Technology Zurich, Auguste-Piccard-Hof 1, 8093 Zurich, and.
Bernd
B
Wollscheid
From the Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Otto-Stern-Weg 7, 8093 Zurich, the Department of Health Sciences and Technology, Institute of Molecular Systems Biology, Swiss Federal Institute of Technology Zurich, Auguste-Piccard-Hof 1, 8093 Zurich, and the Faculty of Medicine, University of Zurich, 8091 Zurich, Switzerland stoffel@biol.ethz.ch.
Markus
M
Stoffel
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D006031:Glycosylation; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017386:Sequence Homology, Amino Acid
D007136:Immunoglobulins; D007328:Insulin; D008565:Membrane Proteins; C546601:Neph3 protein, mouse
adherens junction; insulin secretion; kinase; membrane protein; phosphorylation; receptor protein serine/threonine kinase