Nuclear translocation of an ICA512 cytosolic fragment couples granule exocytosis and insulin expression in β-cells

Trajkovski, Mirko; Mziaut, Hassan; Altkrüger, Anke; Ouwendijk, Joke; Knoch, Klaus-Peter; Solimena, Michele

doi:10.1083/jcb.200408172

Cited by 71 publications

(92 citation statements)

References 63 publications

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“…This lower rate of insulin production may be accounted for by the decreased insulin exocytosis rate and/or the long term REST-induced repression of key factors, such as the protein tyrosine phosphatase, receptor type, N (ICA512). Upon exocytosis, this LDCV-associated protein is cleaved and stimulates insulin synthesis through a retrograde pathway in order to adjust insulin production to its exocytosis [42]. The Ica512 gene is a bona fide RE-1 containing REST target gene, whose expression was decreased in both REST-expressing INS-1E cells and islets of RIP-REST transgenic mice (data not shown).…”

Section: Discussionmentioning

confidence: 97%

Functional significance of repressor element 1 silencing transcription factor (REST) target genes in pancreatic beta cells

et al. 2008

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Aims/hypothesis The expression of several neuronal genes in pancreatic beta cells is due to the absence of the transcription factor repressor element 1 (RE-1) silencing transcription factor (REST). The identification of these traits and their functional significance in beta cells has only been partly elucidated. Herein, we investigated the biological consequences of a repression of REST target genes by expressing REST in beta cells. Methods The effect of REST expression on glucose homeostasis, insulin content and release, and beta cell mass was analysed in transgenic mice selectively expressing REST in beta cells. Relevant target genes were identified in INS-1E and primary beta cells expressing REST. Results Transgenic mice featuring a beta cell-targeted expression of REST exhibited glucose intolerance and reduced beta cell mass. In primary beta cells, REST repressed several proteins of the exocytotic machinery, including synaptosomal-associated protein (SNAP) 25, synaptotagmin (SYT) IV, SYT VII, SYT IX and complexin II; it impaired first and second phases of insulin secretion. Using RNA interference in INS-1E cells, we showed that SYT IV and SYT VII were implicated in the control of insulin release.

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Section: Discussionmentioning

confidence: 97%

Functional significance of repressor element 1 silencing transcription factor (REST) target genes in pancreatic beta cells

et al. 2008

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“…Besides gene transduction experiments, interaction of the IA-2 cytoplasmic tail with spectrin and/or syntrophin was found in two-hybrid assay (25). Another function of IA-2 was also proposed, involving the regulation of gene expression in concert with signal transducer and activator of transcription (STAT)5b (26,27). Furthermore, phogrin and IA-2 are able to heterodimerize with other receptor-type PTPs, such as RPTP␣, and prevent its activity in a transient fashion (28).…”

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confidence: 99%

Gene Silencing of Phogrin Unveils Its Essential Role in Glucose-Responsive Pancreatic β-Cell Growth

et al. 2009

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1OBJECTIVE-Phogrin and IA-2, autoantigens in insulin-dependent diabetes, have been shown to be involved in insulin secretion in pancreatic ␤-cells; however, implications at a molecular level are confusing from experiment to experiment. We analyzed biological functions of phogrin in ␤-cells by an RNA interference technique. RESEARCH DESIGN AND METHODS-Adenovirus-mediated expression of short hairpin RNA specific for phogrin (shPhogrin) was conducted using cultured ␤-cell lines and mouse islets. Both glucose-stimulated insulin secretion and cell proliferation rate were determined in the phogrin-knockdown cells. Furthermore, protein expression was profiled in these cells. To see the binding partner of phogrin in ␤-cells, coimmunoprecipitation analysis was carried out. RESULTS-Adenoviral expression of shPhogrin efficiently decreased its endogenous expression in pancreatic ␤-cells. Silencing of phogrin in ␤-cells abrogated the glucose-mediated mitogenic effect, which was accompanied by a reduction in the level of insulin receptor substrate 2 (IRS2) protein, without any changes in insulin secretion. Phogrin formed a complex with insulin receptor at the plasma membrane, and their interaction was promoted by high-glucose stimulation that in turn led to stabilization of IRS2 protein. Corroboratively, phogrin knockdown had no additional effect on the proliferation of ␤-cell line derived from the insulin receptor-knockout mouse. CONCLUSIONS-Phogrin is involved in ␤-cell growth via regulating stability of IRS2 protein by the molecular interaction with insulin receptor. We propose that phogrin and IA-2 function as an essential regulator of autocrine insulin action in pancreatic ␤-cells. Diabetes 58:682-692, 2009 G lucose is a principle regulator of pancreatic ␤-cell survival and growth as well as insulin secretion (1). It is a potent mitogen on pancreatic ␤-cells and regulates islet ␤-cell mass through their replication (2). Recent studies have suggested that insulin secreted in response to elevated glucose exerts autocrine/paracrine effects, including promotion of insulin biosynthesis and proliferation of ␤-cells (3,4). The importance of insulin signaling in maintaining ␤-cell mass was demonstrated by targeted knockouts of the insulin receptor and insulin receptor substrate 2 (IRS2) (5-8). Although insulin receptor knockout had a restricted effect on ␤-cell mass (7), its mitogenic function on ␤-cells was clearly shown by short interfering RNA (siRNA)-based silencing of insulin receptor in ␤-cell-derived MIN6 cells (9,10). More recently, another pathway was demonstrated showing that glucose metabolism leads to increased ␤-cell mass through the transcriptional activation of IRS2 (11). Calcium/calmodulin-dependent protein kinases and increased cAMP levels were suggested to contribute to IRS2 expression, and this pathway has been shown to be modulated by the incretin hormone glucagonlike peptide 1 (GLP-1) (12,13). In both cases, IRS2 must be a key mediator for glucose-responsive ␤-cell growth (14).Phogrin (IA-2␤) and IA-2 (ICA51...

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“…2, #12, and Fig. S1D) enters the nucleus and acts as a transcriptional regulator (30,31). Lys609-Ica512 was shortlived in reticulocyte extract (postpulse t 1/2 of ∼6 min), in contrast to Val609-Ica512, which was completely stable (Fig.…”

Section: (A) the Ubiquitin Reference Technique (Urt) (B)mentioning

confidence: 98%

“…Lys609-Ica512. Ica512 (Ptprn) is a member of the receptor protein phosphatase (PTP) family of integral membrane proteins, except that the cytosolic domain of Ica512 lacks phosphatase activity (30). Ica512 is expressed largely in neurons and neuroendocrine cells and is a major target of autoreactive antibodies in type I diabetes.…”

Section: (A) the Ubiquitin Reference Technique (Urt) (B)mentioning

confidence: 99%

Calpain-generated natural protein fragments as short-lived substrates of the N-end rule pathway

Piatkov

Liu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Calpains are Ca 2+ -dependent intracellular proteases. We show here that calpain-generated natural C-terminal fragments of proteins that include G protein-coupled receptors, transmembrane ion channels, transcriptional regulators, apoptosis controllers, kinases, and phosphatases (Phe-GluN2a, Lys-Ica512, Arg-Ankrd2, Tyr-Grm1, Arg-Atp2b2, Glu-Bak, Arg-Igfbp2, Glu-IκBα, and Arg-cFos), are short-lived substrates of the Arg/N-end rule pathway, which targets destabilizing N-terminal residues. We also found that the identity of a fragment's N-terminal residue can change during evolution, but the residue's destabilizing activity is virtually always retained, suggesting selection pressures that favor a short half-life of the calpain-generated fragment. It is also shown that a self-cleavage of a calpain can result in an N-end rule substrate. Thus, the autoprocessing of calpains can control them by making active calpains short-lived. These and related results indicate that the Arg/N-end rule pathway mediates the remodeling of oligomeric complexes by eliminating protein fragments that are produced in these complexes through cleavages by calpains or other nonprocessive proteases. We suggest that this capability of the Arg/N-end rule pathway underlies a multitude of its previously known but mechanistically unclear functions.proteolysis | calpain substrates | ubiquitin

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Nuclear translocation of an ICA512 cytosolic fragment couples granule exocytosis and insulin expression in β-cells

Cited by 71 publications

References 63 publications

Functional significance of repressor element 1 silencing transcription factor (REST) target genes in pancreatic beta cells

Functional significance of repressor element 1 silencing transcription factor (REST) target genes in pancreatic beta cells

Gene Silencing of Phogrin Unveils Its Essential Role in Glucose-Responsive Pancreatic β-Cell Growth

Calpain-generated natural protein fragments as short-lived substrates of the N-end rule pathway

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