Kin of IRRE-like Protein 2 Is a Phosphorylated Glycoprotein That Regulates Basal Insulin Secretion

J Biol Chem. 2015 Oct 23;290(43):25891-906. doi: 10.1074/jbc.M115.684704. Epub 2015 Aug 31.


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.

Keywords: adherens junction; insulin secretion; kinase; membrane protein; phosphorylation; receptor protein serine/threonine kinase.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Glycosylation
  • Immunoglobulins / genetics
  • Immunoglobulins / metabolism
  • Immunoglobulins / physiology*
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Mutation
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Sequence Homology, Amino Acid


  • Immunoglobulins
  • Insulin
  • Membrane Proteins
  • Neph3 protein, mouse