Multimerization of the Protein-tyrosine Phosphatase (PTP)-like Insulin-dependent Diabetes Mellitus Autoantigens IA-2 and IA-2β with Receptor PTPs (RPTPs)

Gross, Steffen; Blanchetot, Christophe; Schepens, Jan; Albet, Sabrina; Lammers, Reiner; Hertog, Jeroen den; Hendriks, Wiljan

doi:10.1074/jbc.m208228200

Cited by 38 publications

(38 citation statements)

References 57 publications

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“…At 2 wk postlesion the average SFI was still Ϫ55 Ϯ 4.3%. [23][24][25] in the fourth week, the SFI value remained at Ϫ16 Ϯ 4%, indicating that not all PTP-BL ⌬P/⌬P animals had reached complete recovery (Fig. 7B).…”

Section: Delayed Motor But Not Sensory Function Recovery Following mentioning

confidence: 97%

Mild impairment of motor nerve repair in mice lacking PTP-BL tyrosine phosphatase activity

Wansink

Peters

Schaafsma

et al. 2004

Physiological Genomics

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Mouse PTP-BL is a large, nontransmembrane protein tyrosine phosphatase of unclear physiological function that consists of a KIND domain, a FERM domain, five PDZ domains, and a COOH-terminal catalytic PTP domain. PTP-BL and its human ortholog PTP-BAS have been proposed to play a role in the regulation of microfilament dynamics, cytokinesis, apoptosis, and neurite outgrowth. To investigate the biological function of PTP-BL enzyme activity, we have generated mice that lack the PTP-BL PTP moiety. These PTP-BL ⌬P/⌬P mice are viable and fertile and do not present overt morphological alterations. Although PTP-BL is expressed in most hematopoietic cell lineages, no alterations of thymocyte development in PTP-BL ⌬P/⌬P mice could be detected. Sciatic nerve lesioning revealed that sensory nerve recovery is unaltered in these mice. In contrast, a very mild but significant impairment of motor nerve repair was observed. Our findings exclude an essential role for PTP-BL as a phosphotyrosine phosphatase and rather are in line with a role as scaffolding or anchoring molecule.

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Section: Delayed Motor But Not Sensory Function Recovery Following mentioning

confidence: 97%

Mild impairment of motor nerve repair in mice lacking PTP-BL tyrosine phosphatase activity

Wansink

Peters

Schaafsma

et al. 2004

Physiological Genomics

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“…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). Unfortunately, it is still unknown whether all of their interactions physiologically associate with a secretion defect in knockout mice.…”

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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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“…Immunoelectron microscopic analyses have revealed the localization of IA-2 on dense-core granules in mouse posterior pituitary [2] and colocalization of IA-2β with insulin in pancreatic β-cells [36] (Figure 2). Although a physiological role is unclear, IA-2 and IA-2β are suggested to form a heterodimer in a cell [21], such as a pancreatic β-cell (Torii, unpublished observation). These localization studies suggest that both proteins appear functionally similar.…”

Section: +mentioning

confidence: 99%

“…Three spliced transcripts of human IA-2β/ phogrin gene have been reported (GenBank database), and Drosophila ia2 has been found to have two isoforms as well [12], although the functional difference of each isoform is unknown. On the other hand, a splice variant of human IA-2/ICA512 lacking exon 13 (encodes the transmembrane region) has been discovered in thymus and spleen as well as in pancreas, and et al has demonstrated that the PTP portion of IA-2 and IA-2β is able to heterodimerize with other receptor-type PTPs such as RPTPα and RPTPε and prevent their activity in a transient expression system [21], however, this function remains to be established at the physiological level.…”

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confidence: 99%

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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Multimerization of the Protein-tyrosine Phosphatase (PTP)-like Insulin-dependent Diabetes Mellitus Autoantigens IA-2 and IA-2β with Receptor PTPs (RPTPs)

Cited by 38 publications

References 57 publications

Mild impairment of motor nerve repair in mice lacking PTP-BL tyrosine phosphatase activity

Mild impairment of motor nerve repair in mice lacking PTP-BL tyrosine phosphatase activity

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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