ICA512 signaling enhances pancreatic β-cell proliferation by regulating cyclins D through STATs

Mziaut, Hassan; Kersting, Stephan; Knoch, Klaus-Peter; Fan, Wan-Hung; Trajkovski, Mirko; Erdmann, Katja; Bergert, H.; Ehehalt, Florian; Saeger, Hans‐Detlev; Solimena, Michele

doi:10.1073/pnas.0710931105

Cited by 54 publications

(61 citation statements)

References 55 publications

(59 reference statements)

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“…Previous studies have shown that the deletion of IA-2 or phogrin gene or in combination in mice resulted in mild impairment of GSIS but did not affect ␤-cell mass (19 -21). However, more recent studies have suggested that islets from double knockout mice failed to show any secretion defect (45), and ␤-cell regeneration was reduced in partially pancreatectomized ICA512 (IA-2) knockout mice (46). Therefore, it is possible that the alteration in GSIS in knockout mice is indirect and that ␤-cell mass is recovered by compensatory function of other genes.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2009

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“…Disruption of gut-specific ia2 expression reveals a role of IA-2 for modulating both exon SGs are distributed to the plasma membrane when hormones are secreted, then enter into endosomes (or related organelles), and recycle back to SGs. Other reports have proposed that upon insulin secretion in β-cells, IA-2 protein is cleaved by calpain at the site specific to IA-2 [42] but absent in IA-2β [40], and the PTP-containing fragment then enters into the nucleus [43,44]. Although an almost identical fragment (~40 kDa) has been found in the bovine pituitary extracts [10], it remains to be elucidated whether the calpainmediated cleavage similarly occurs in physiological conditions and whether the cleaved transmembrane protein (~30 kDa) is recycled back to SGs.…”

Section: +mentioning

confidence: 99%

“…In this case, scrupulous attention should be paid to the possibility that the stable clone obtained such a potency independent of IA-2, because MIN6 cells are heterogenous in hormone contents [52] and the insulin content per cell is changeable during the cloning steps [27,53,54]. On the other hand, Mziaut et al has demonstrated that insulin gene transcription is promoted by prolonging STAT5 activity through the action of calpain-cleaved IA-2 tail [44], although this retrograde pathway does not seem to apply to IA-2β. Taken together with the results by DKO islets [49], these data partly support the idea that IA-2 and IA-2β contribute to the maintenance of insulin content presumably through regulating expression of insulin and/or SG-associated proteins in pancreatic β-cells.…”

Section: Physiological Function Of Ia-2 Family Proteinsmentioning

confidence: 99%

“…Thus, IA-2 and IA-2β may positively regulate pancreatic β-cell growth under a specific condition or a kind of pathological state. Regarding the molecular action of IA-2 protein, one group gives the hypothesis that, when insulin exocytosis is promoted, the cytoplasmic tail of IA-2 is cleaved by a Ca 2+ -dependent calpain and translocates to the nucleus where it promotes transcription of the insulin and other SG genes, and it also promotes up-regulation of cyclin D via STATs activation [43,44,56]. However, this series of studies awaits independent examination because most of the experimental condition was demonstrated by overexpression of the cytoplasmic fragment.…”

Section: Physiological Function Of Ia-2 Family Proteinsmentioning

confidence: 99%

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Expression and Function of IA-2 Family Proteins, Unique Neuroendocrine-specific Protein-tyrosine Phosphatases

Torii

2009

Endocr J

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Abstract. IA-2 (also known as islet cell antigen ICA-512) and IA-2β (also known as phogrin, phosphatase homologue in granules of insulinoma) are major autoantigens in insulin-dependent diabetes mellitus (IDDM). Autoantibodies against both proteins are expressed years before clinical onset, and they become predictive markers for high-risk subjects. However, the role of these genes in the IDDM pathogenesis has been reported fairly negative by recent studies. IA-2 and IA-2β are type I transmembrane proteins that possess one inactive protein-tyrosine phosphatase (PTP) domain in the cytoplasmic region, and act as one of the constituents of regulated secretory pathways in various neuroendocrine cell types including pancreatic β-cells. Existence of IA-2 homologues in different species suggests a fundamental role in neuroendocrine function. Studies of knockout animals have shown their involvement in maintaining hormone content, however, their specific steps in the secretory pathway IA-2 functions as well as their molecular mechanisms in the hormone content regulation are still unknown. More recent studies have suggested a novel function showing that they contribute to pancreatic β-cell growth. This review attempts to show the possible biological functions of IA-2 family, focusing on their expression and localization in the neuroendocrine cells.

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“…T4 polynucleotide kinase was obtained from New England Biolabs (Ipswich, MA). [␥- 32 P]ATP (specific activity 3000 Ci/mmol) was from MP Biomedicals (Irvine, CA). [ 3 H]Thymidine (specific activity 20 Ci/mmol) was obtained from PerkinElmer Life Sciences.…”

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confidence: 99%

Novel Interactions between NFATc1 (Nuclear Factor of Activated T Cells c1) and STAT-3 (Signal Transducer and Activator of Transcription-3) Mediate G Protein-coupled Receptor Agonist, Thrombin-induced Biphasic Expression of Cyclin D1, with First Phase Influencing Cell Migration and Second Phase Directing Cell Proliferation

Kundumani‐Sridharan

Quyền

Singh

et al. 2012

Journal of Biological Chemistry

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Background: NFATc1 and STAT-3 associate with each other constitutively and regulate cyclin D1 expression in response to thrombin, a G protein-coupled receptor agonist. Results: NFATc1 exists in complex with STAT-3 and modulates its acetylation via recruiting p300 in the biphasic expression of cyclin D1 facilitating VSMC migration and proliferation. Conclusion: NFATc1-STAT-3 cooperatively binds to cyclin D1 promoter and modulates its activity. Significance: NFATc1-STAT-3 interactions may play a role in vascular diseases and cancer.

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ICA512 signaling enhances pancreatic β-cell proliferation by regulating cyclins D through STATs

Cited by 54 publications

References 55 publications

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

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

Expression and Function of IA-2 Family Proteins, Unique Neuroendocrine-specific Protein-tyrosine Phosphatases

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