Densin and filtrin in the pancreas and in the kidney, targets for humoral autoimmunity in patients with type 1 diabetes

Rinta-Valkama, Johanna; Aaltonen, Petri; Lassila, Markus; Palmén, Tuula; Tossavainen, Päivi; Knip, Mikael; Holthöfer, Harry

doi:10.1002/dmrr.655

Cited by 10 publications

(5 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with its location at the slit diaphragm in renal podocytes, Densin is also found at adherens junctions of testicular Sertoli cells (Lassila et al. 2007) and was further identified in pancreatic islet cells (Rinta‐Valkama et al. 2007).…”

Section: Densin‐180 In Non‐neuronal Tissuementioning

confidence: 63%

Densin‐180: revised membrane topology, domain structure and phosphorylation status

Thalhammer¹,

Trinidad

Burlingame

et al. 2009

Journal of Neurochemistry

View full text Add to dashboard Cite

Densin‐180 is a core component of post‐synaptic densities, the highly complex molecular assemblies that mediate signaling between neuronal cells. It is a multi‐domain scaffold protein characterized by multiple leucine‐rich repeat domains plus a single Psd95/Discs large/Zona occludens‐1 domain. In its original topology model a single transmembrane segment was proposed with an extracellular N‐terminus and an intracellular C‐terminus. However, recently discovered in vivo phosphorylation sites are incompatible with this topology. Here, we discuss an all‐intracellular and membrane‐associated localization of Densin‐180 that is consistent with and supported by all the latest experimental data. This revised topology which now includes also a phosphorylation‐rich area will have deciding influence on future research involving Densin‐180 and its signaling.

show abstract

Section: Densin‐180 In Non‐neuronal Tissuementioning

confidence: 63%

Densin‐180: revised membrane topology, domain structure and phosphorylation status

Thalhammer¹,

Trinidad

Burlingame

et al. 2009

Journal of Neurochemistry

View full text Add to dashboard Cite

show abstract

“…Recent studies have shown that over-expression of densin induces excessive neurite branching and outgrowth in cultured neurons: competitive binding of SHANK and dcatenin to the C-terminal domain appears to modulate this function (Quitsch et al 2005). Although densin was initially characterized as a brain-specific protein (Apperson et al 1996), recent studies have shown that densin is also expressed in the kidney and other peripheral tissues, where it is often localized to sites of cell-cell adhesion, suggesting key roles in modulating cell adhesion and cell-cell contacts (Ahola et al 2003;Heikkila et al 2007;Lassila et al 2007;Rinta-Valkama et al 2007).…”

mentioning

confidence: 99%

Developmentally regulated alternative splicing of densin modulates protein–protein interaction and subcellular localization

Jiao

Robison

Bass

et al. 2008

Journal of Neurochemistry

View full text Add to dashboard Cite

Densin is a member of the leucine‐rich repeat (LRR) and PDZ domain (LAP) protein family that binds several signaling molecules via its C‐terminal domains, including calcium/calmodulin‐dependent protein kinase II (CaMKII). In this study, we identify several novel mRNA splice variants of densin that are differentially expressed during development. The novel variants share the LRR domain but are either prematurely truncated or contain internal deletions relative to mature variants of the protein (180 kDa), thus removing key protein–protein interaction domains. For example, CaMKIIα coimmunoprecipitates with densin splice variants containing an intact C‐terminal domain from lysates of transfected HEK293 cells, but not with variants that only contain N‐terminal domains. Immunoblot analyses using antibodies to peptide epitopes in the N‐ and C‐ terminal domains of densin are consistent with developmental regulation of splice variant expression in brain. Moreover, putative splice variants display different subcellular fractionation patterns in brain extracts. Expression of green fluorescent protein (GFP)‐fused densin splice variants in HEK293 cells shows that the LRR domain can target densin to a plasma membrane‐associated compartment, but that the splice variants are differentially localized and have potentially distinct effects on cell morphology. In combination, these data show that densin splice variants have distinct functional characteristics suggesting multiple roles during neuronal development.

show abstract

“…Apart from the important roles of nephrin/Kirrel proteins in specialized cellcell contacts and formation of the size-selective filter barrier in the kidney, nephrin has also been localized to the surface of insulin granules and the plasma membrane of the pancreatic ␤-cells, where it was proposed to function as an active component of insulin vesicle machinery that may affect vesicle-actin interactions and mobilization of insulin granules to the plasma membrane (29). Autoantibodies against Kirrel2 have been detected in patients with type 1 diabetes (30), raising the possibility that shedding of this membrane protein within the pancreatic islet, uptake by resident or circulating macrophages or dendritic cells, and antigen presentation in lymph nodes draining the pancreas are some of the mechanisms contributing to autoimmunity (31).…”

mentioning

confidence: 99%

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

Yesildag

Bock

Herrmanns

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

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...

show abstract

Densin and filtrin in the pancreas and in the kidney, targets for humoral autoimmunity in patients with type 1 diabetes

Abstract: Densin is a novel molecule shared by the kidney glomerular podocytes and pancreatic islet cells. Densin and filtrin can act as autoantigens, and autoantibodies against these can be detected in patients with type 1 diabetes.

Cited by 10 publications

References 46 publications

Densin‐180: revised membrane topology, domain structure and phosphorylation status

Densin‐180: revised membrane topology, domain structure and phosphorylation status

Developmentally regulated alternative splicing of densin modulates protein–protein interaction and subcellular localization

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

Contact Info

Product

Resources

About