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

Abstract

Background: Surface proteins fine-tune insulin secretion from pancreatic ␤-cells. Results: Kirrel2 is regulated by multiple post-translational modifications, and its expression influences basal insulin secretion. Conclusion: Kirrel2 expression is tightly regulated by phosphorylation and suppresses basal insulin secretion. Significance: Genetic and biochemical characterization of Kirrel2 in pancreatic ␤-cells reveals insight into regulation of protein stability and insulin secretion. Direct interactions among pancreatic ␤-cells via cell surface proteins inhibit basal and enhance stimulated insulin secretion.Here, we functionally and biochemically characterized Kirrel2, an immunoglobulin superfamily protein with ␤-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 ␤-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 ␥-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 ␤-cells, with no immediate influence on stimulated insulin secretion, total insulin content, or whole body glucose metabolism. Our results show that in pancreatic ␤-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.Pancreatic ␤-cells sense fluctuations in metabolic demand, particularly minute changes in circulating glucose levels, and uniquely respond by secreting adequate amounts of insulin to regulate glucose homeostasis and metabolism (1). Loss of ␤-cell mass or impairment of normal insulin secretion results in diabetes, the most common metabolic disease in man that is characterized by hyperglycemia over a prolonged period (1). Hence, uncovering molecular mechanisms underlying normal ␤-cell function as well as those that lead to its dysfunction is crucial for understanding the pathology of diabetes and developing novel approaches for its treatment.During embryonic development, scattered ␤-cells aggregate with other ␤-cells and endocrine cells into small clusters that subsequently mature through a series of morphogenetic events to form endocrine micro-organs of the pancreas termed islets of Langerhans (2, 3). In pancreatic islets, several surface proteins mediate direct communication among ␤-cells and their neighbors (4). These integral membrane proteins selectively interact to adopt one or more of the following functions: establishment of adhesive links among adjacent cells (5, 6); assistance in the formation o...

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“…Kin of IRRE-like protein 2 (Kirrel2, GB45525) encodes pancreatic islet β-cell-expressed protein. It is an integral part of the extracellular adhesion scaffold required for normal basal insulin secretion ( Yesildag et al, 2015 ). Insect insulin-like peptides and their signal pathways play important roles in metabolism, longevity, growth, and development ( Antonova et al, 2012 ; Fridell, 2013 ; Yesildag et al, 2015 ).…”

“…It is an integral part of the extracellular adhesion scaffold required for normal basal insulin secretion ( Yesildag et al, 2015 ). Insect insulin-like peptides and their signal pathways play important roles in metabolism, longevity, growth, and development ( Antonova et al, 2012 ; Fridell, 2013 ; Yesildag et al, 2015 ). Queen brain-selective protein-1 (QBP-1, GB45741) plays a role in determining honeybee longevity ( Grönke and Partridge, 2010 ), and its isoforms function in phase transition ( Vanhems et al, 1990 ; Claeys et al, 2005 ) in locusts.…”

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