Proteolytic cleavage of PDZD2 generates a secreted peptide containing two PDZ domains

Yeung, M.R.; Tam, Tammy S M; Tsang, Anthony C. C.; Yao, KM

doi:10.1038/sj.embor.embor804

Cited by 24 publications

(24 citation statements)

References 19 publications

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“…Over a region of 215 amino acids, there is 39.5% identity and 58.1% similarity [31]. Consistent with this sequence similarity and the abundant expression of PDZD2 in the endoplasmic reticulum (ER) [31], we demonstrated that PDZD2 is proteolytically cleaved by caspase-3 [31,35] to generate the secreted form of PDZD2 (sPDZD2, Fig. 1), analogous to the processing of pro-IL-16 to generate the secreted cytokine IL-16 [36] (Fig.…”

Section: Pdzd2 Is Subjected To Proteolytic Cleavage To Generate Spdzdsupporting

confidence: 73%

“…This finding indicates that the NLS-like sequence is functional. The nuclear localization of PDZD2 [31] and the identification of a functional NLS suggest a nuclear function of PDZD2, consistent with its interaction with E2A proteins. Multi-PDZ proteins function by mediating the formation of multi-molecular complexes through their multiple PDZ domains.…”

Section: Pdzd2 Has a Functional Nlssupporting

confidence: 55%

“…1). Expression of sPDZD2 in pancreatic tissue extracts and the insulin-secreting cell line INS-1E [31,32] indicates an interesting extracellular signaling function for sPDZD2 (see below). Recent studies of Pdzd2 expression in pancreatic RNAs isolated from two gene-trap mouse lines deficient in full-length Pdzd2 suggested the existence of a shorter form of Pdzd2 (Tsang SW and Yao KM, unpublished data; shPdzd2 as shown in Fig.…”

Section: Pdzd2 Is Subjected To Proteolytic Cleavage To Generate Spdzdmentioning

confidence: 97%

“…PIN-1 was later named Pdzk3 and officially renamed as PDZD2 (PDZ Domain-containing protein 2) in 2006. PDZD2 is a ubiquitous protein expressed in a number of tissues, including heart, brain, liver, spleen, lung, kidney, but at an exceptional high level in the pancreas [31]. Within the pancreas, immunohistochemical analysis revealed a strong expression of PDZD2 in islet beta cells but not alpha cells [32].…”

Section: Pdz Domain-containing Protein 2 (Pdzd2)mentioning

confidence: 99%

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The Roles of the PDZ-containing Proteins Bridge-1 and PDZD2 in the Regulation of Insulin Production and Pancreatic Beta-Cell Mass

Thomas¹,

Tsang²,

Yeung³

et al. 2009

CPPS

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PDZ domains are versatile protein interaction modules with the ability to dimerize and to recognize internal and carboxy-terminal peptide motifs. Their function in mediating the formation of multi-molecular signaling complexes is best understood at neuronal and epithelial membranes. In a screen for interactors that regulate transcription factor function in pancreatic beta cells, we isolated two PDZ-containing proteins Bridge-1 (PSMD9) and PDZD2, which contain one and six PDZ domains, respectively. Here, we review their functions in the regulation of pancreatic beta cells as a nuclear coactivator or extracellular signaling molecule. Bridge-1 interacts with both E12 and PDX-1 to stimulate insulin promoter activity. Recent gain-of-function analysis in both cell and transgenic models has revealed its functions to regulate both insulin gene expression and pancreatic beta-cell survival. Little is known about the intracellular function of PDZD2 that is predominantly localized to the endoplasmic reticulum of INS-1E cells. Interestingly, PDZD2 is proteolytically processed by caspase-3 to generate a carboxy-terminal secreted protein (sPDZD2) containing two PDZ domains. Expressed in fetal pancreatic progenitor and INS-1E cells, sPDZD2 when added as recombinant protein exerts concentration-dependent mitogenic effects on beta-like cells. We propose that the PDZ domain proteins Bridge-1 and PDZD2 likely transduce signals that regulate insulin production, proliferation, and survival of pancreatic beta cells.

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Section: Pdzd2 Is Subjected To Proteolytic Cleavage To Generate Spdzdsupporting

confidence: 73%

Section: Pdzd2 Has a Functional Nlssupporting

confidence: 55%

Section: Pdzd2 Is Subjected To Proteolytic Cleavage To Generate Spdzdmentioning

confidence: 97%

Section: Pdz Domain-containing Protein 2 (Pdzd2)mentioning

confidence: 99%

See 2 more Smart Citations

The Roles of the PDZ-containing Proteins Bridge-1 and PDZD2 in the Regulation of Insulin Production and Pancreatic Beta-Cell Mass

Thomas¹,

Tsang²,

Yeung³

et al. 2009

CPPS

View full text Add to dashboard Cite

show abstract

“…In vitro treatment with recombinant sPDZD2 induces p53 up-regulation in human prostate cancer (DU-145), breast adenocarcinoma (MCF-7), and liver cancer (Hep-G2) cell lines, 64 and such altered p53 activity may inhibit epithelial-mesenchymal transition. 65 More important, though, PDZD2 is expressed in the nucleus and also secreted after cleavage, 66 suggesting a potentially complex role in these processes.…”

Section: Discussionmentioning

confidence: 99%

miR-21 Promotes Fibrogenesis in Peritoneal Dialysis

Lopez-Anton

Lambie

López–Cabrera

et al. 2017

The American Journal of Pathology

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Peritoneal dialysis (PD) is a life-saving form of renal replacement therapy for those with end-stage kidney disease. Mesothelial cells (MCs) line the peritoneal cavity and help define peritoneal response to treatment-associated injury, a major reason for treatment failure. miRNAs are important regulators, but their roles in peritoneal fibrosis are largely unknown. In this study, miR-21 was one of the most abundant miRNAs in primary MCs, and was up-regulated by the profibrotic cytokine transforming growth factor-β1 and in PD effluent-derived MCs exhibiting mesenchymal phenotypic change. Increased miR-21 was found in peritoneal membrane biopsy specimens from PD patients compared to healthy controls (PD biocompatible, 5.86×, P = 0.0001; PD conventional, 7.09×, P < 0.0001, n = 11 per group). In PD effluent from a cohort of 230 patients, miR-21 was higher in those receiving the therapy long-term compared to new starters (n = 230, miR-21 3.26×, P = 0.001) and associated with icodextrin use (R = 0.52; 95% CI, 0.20-0.84), peritonitis count (R = 0.16; 95% CI, 0.03-0.29), and dialysate cytokines. miR-21 down-regulated programmed cell death 4 and programmed cell death 4 protein was decreased in peritoneal membrane biopsy specimens from PD patients compared to healthy controls. New miR-21 targets were identified that may be important during PD fibrogenesis. These data identify miR-21 as an important effector of fibrosis in the peritoneal membrane, and a promising biomarker in the dialysis effluent for membrane change in patients receiving PD.

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Structural Genomic Variation as Risk Factor for Idiopathic Recurrent Miscarriage

et al. 2014

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Recurrent miscarriage (RM) is a multifactorial disorder with acknowledged genetic heritability that affects ß3% of couples aiming at childbirth. As copy number variants (CNVs) have been shown to contribute to reproductive disease susceptibility, we aimed to describe genome-wide profile of CNVs and identify common rearrangements modulating risk to RM. Genome-wide screening of Estonian RM patients and fertile controls identified excessive cumulative burden of CNVs (5.4 and 6.1 Mb per genome) in two RM cases possibly increasing their individual disease risk. Functional profiling of all rearranged genes within RM study group revealed significant enrichment of loci related to innate immunity and immunoregulatory pathways essential for immune tolerance at fetomaternal interface. As a major finding, we report a multicopy duplication (61.6 kb) at 5p13.3 conferring increased maternal risk to RM in Estonia and Denmark (meta-analysis, n = 309/205, odds ratio = 4.82, P = 0.012). Comparison to Estonian population-based cohort (total, n = 1000) confirmed the risk for Estonian female cases (P = 7.9 × 10 −4 ). Datasets of four cohorts from the Database of Genomic Variants (total, n = 5,846 subjects) exhibited similar low duplication prevalence worldwide (0.7%-1.2%) compared to RM cases of this study (6.6%-7.5%). The CNV disrupts PDZD2 and GOLPH3 genes predomiAdditional Supporting Information may be found in the online version of this article.

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Proteolytic cleavage of PDZD2 generates a secreted peptide containing two PDZ domains

Cited by 24 publications

References 19 publications

The Roles of the PDZ-containing Proteins Bridge-1 and PDZD2 in the Regulation of Insulin Production and Pancreatic Beta-Cell Mass

The Roles of the PDZ-containing Proteins Bridge-1 and PDZD2 in the Regulation of Insulin Production and Pancreatic Beta-Cell Mass

miR-21 Promotes Fibrogenesis in Peritoneal Dialysis

Structural Genomic Variation as Risk Factor for Idiopathic Recurrent Miscarriage

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