CSMD1 Is a Novel Multiple Domain Complement-Regulatory Protein Highly Expressed in the Central Nervous System and Epithelial Tissues

Kraus, Damian; Elliott, Gary; Chute, Hilary; Horan, Thomas P.; Pfenninger, Karl H.; Sanford, Staci D.; Foster, S. P.; Scully, Sheila; Welcher, Andrew A.; Holers, V. Michael

doi:10.4049/jimmunol.176.7.4419

Cited by 181 publications

(174 citation statements)

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“…Loss of CSMD1 expression increased cell proliferation. This agrees with studies that showed expression of the rat ortholog of CSMD1 is low in brain regions exhibiting high levels of cell proliferation (4). Similarly, a recent study has demonstrated that increasing miRNA-10b expression in HepG2 hepatocellular carcinoma cells resulted in decreased CSMD1 expression and increased proliferation (17).…”

Section: Discussionsupporting

confidence: 79%

“…Formation of such structures is an indicator of extensive actin polymerisation (23). Previous studies have revealed that the rat ortholog of CSMD1 colocalizes with F-actin (4,24). Thus CSMD1 may have an inhibitory effect on actin assembly or the signalling processes that impact upon the regulation of this process (25).…”

Section: Discussionmentioning

confidence: 99%

“…The function of CSMD1 is largely unknown. Although CSMD1 has been shown to inhibit C3 deposition onto the surface of cells leading to the inhibition of the classical complement pathway (4,5). The structure of CSMD1 predicts that CSMD1 is a receptor for unknown ligand(s) and is involved in signal transduction (1).…”

Section: Introductionmentioning

confidence: 99%

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Loss of CSMD1 expression disrupts mammary duct formation while enhancing proliferation, migration and invasion

et al. 2017

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Abstract. The CUB and sushi multiple domains 1 (CSMD1) gene maps to chromosome 8p23, a region deleted in many cancers. Loss of CSMD1 expression is associated with poor prognosis in breast cancer suggesting that it acts as a tumour suppressor in this cancer. However, the function of CSMD1 is largely unknown. Herein, we investigated CSMD1 functions in cell line models. CSMD1 expression was suppressed in MCF10A and LNCaP cells using short hairpin RNA. Functional assays were performed focusing on the 'normal' MCF10A cell line. Suppression of CSMD1 significantly increased the proliferation, cell migration and invasiveness of MCF10A cells compared to shcontrols. shCSMD1 cells also showed significantly reduced adhesion to Matrigel and fibronectin. In a three-dimensional Matrigel model of MCF10A cells, reduced CSMD1 expression resulted in the development of larger and more poorly differentiated breast acini-like structures that displayed impaired lumen formation. Loss of CSMD1 expression disrupts a model of mammary duct formation while enhancing proliferation, migration and invasion. Our data suggest that CSMD1 is involved in the suppression of a transformed phenotype. IntroductionCUB and sushi multiple domains-1 (CSMD1) is a very large gene which contains 71 exons that span over 2 Mb of genomic DNA on chromosome 8p23 (1). Multiple splice variants exist for CSMD1 and these encode proteins of varying length. The largest transcript is 14.3 kb long and this encodes a 3,565 amino acid protein (1). The full-length protein is a membrane protein with an extracellular region containing 14 CUB and 28 sushi domains, a single transmembrane domain and a short cytoplasmic domain that contains a putative tyrosine phosphorylation site. CSMD1 belongs to the CSMD gene family whose members also include the structurally similar proteins CSMD2 and CSMD3 (1-3). The function of CSMD1 is largely unknown. Although CSMD1 has been shown to inhibit C3 deposition onto the surface of cells leading to the inhibition of the classical complement pathway (4,5). The structure of CSMD1 predicts that CSMD1 is a receptor for unknown ligand(s) and is involved in signal transduction (1).CSMD1 is believed to act as a tumour suppressor based on a number of observations. CSMD1 is located on chromosome 8p23, a region that is frequently deleted in different types of cancer (1,6-10). In addition, reduced CSMD1 mRNA and protein expression has been observed in different cancers (11-17). An array comparative genomic hybridization study revealed a high rate of loss of 8p23.2 containing the CSMD1 gene in advanced prostrate cancer samples. A further small real-time PCR study identified a decrease in CSMD1 mRNA levels in higher stage prostrate cancer samples (11). Similarly reduced CSMD1 expression at the mRNA level has been identified in colorectal cancer associated with reduced patient survival (12). Furthermore, somatic mutations were detected in CSMD1 in 11% (6/54) of colorectal cancer patients along side DNA methylation and allele loss, predominantly in early onset ...

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

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Loss of CSMD1 expression disrupts mammary duct formation while enhancing proliferation, migration and invasion

et al. 2017

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“…The other regulatory proteins, such as factor H, factor I, and C4 binding protein, also down-regulate complement activation . CUB and Sushi multiple domains 1 (CSMD1), CSMD2, and CSMD3 have been proposed to have a role in regulating complement activation and inflammation in the developing CNS (Nagase et al, 2001;Kraus et al, 2006). C4b, C3b, iC3b, C3dg, and C3d bind to CR1 and complement receptor type 2 (CR2) on B lymphocytes and enhance antibody response and long-term memory of B-cells.…”

Section: Introductionmentioning

confidence: 99%

Complement genetics, deficiencies, and disease associations

Mayilyan

2012

Protein Cell

150

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The complement system is a key component of innate immunity. More than 45 genes encoding the proteins of complement components or their isotypes and subunits, receptors, and regulators have been discovered. These genes are distributed throughout different chromosomes, with 19 genes comprising three significant complement gene clusters in the human genome. Genetic deficiency of any early component of the classical pathway (C1q, C1r/s, C2, C4, and C3) is associated with autoimmune diseases due to the failure of clearance of immune complexes (IC) and apoptotic materials, and the impairment of normal humoral response. Deficiencies of mannan-binding lectin (MBL) and the early components of the alternative (factor D, properdin) and terminal pathways (from C3 onward components: C5, C6, C7, C8, C9) increase susceptibility to infections and their recurrence. While the association of MBL deficiency with a number of autoimmune and infectious disorders has been well established, the effects of the deficiency of other lectin pathway components (ficolins, MASPs) have been less extensively investigated due to our incomplete knowledge of the genetic background of such deficiencies and the functional activity of those components. For complement regulators and receptors, the consequences of their genetic deficiency vary depending on their specific involvement in the regulatory or signalling steps within the complement cascade and beyond. This article reviews current knowledge and concepts about the genetic load of complement component deficiencies and their association with diseases. An integrative presentation of genetic data with the latest updates provides a background to further investigations of the disease association investigations of the complement system from the perspective of systems biology and systems genetics.

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“…CSMD2 is a recently cloned gene (39) whose functionality still needs to be identified. Recently, CSMD1, a gene with high structural similarity to CSMD2, has been implicated in the inhibition of complement activation (40), which could suggest a com-mon functionality. In addition, the results from our analysis along with previous genome-wide association studies also identified several SNPs from the newly associated TNFAIP3 locus (rs643571 at P ϭ 6 ϫ 10 Ϫ3 and rs6915853 at P ϭ 2 ϫ 10 Ϫ3 in our study).…”

Section: ϫ3mentioning

confidence: 99%

Genome‐wide association study of rheumatoid arthritis in the Spanish population: KLF12 as a risk locus for rheumatoid arthritis susceptibility

Juliá¹,

Ballina²,

Cañete³

et al. 2008

Arthritis & Rheumatism

101

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Objective. To identify new genes associated with susceptibility to rheumatoid arthritis (RA), using a 2-stage genome-wide association study.Methods. Following a liability-based study design, we analyzed 317,503 single-nucleotide polymorphisms (SNPs) in 400 patients with RA and 400 control subjects. We selected a group of candidate SNPs for replication in an independent group of 410 patients with RA and 394 control subjects. Using data from the 3 previous genome-wide association studies in RA, we also looked for genomic regions showing evidence of common association signals. Finally, we analyzed the presence of genome-wide epistasis using the binary test implemented in the PLINK program.Results. We identified several genomic regions showing evidence of genome-wide association (P < 1 ؋ ؊5). In the replication analysis, we identified KLF12 SNP rs1324913 as the most strongly associated SNP (P ‫؍‬ 0.01). In our study, we observed that this SNP showed higher significance than PTPN22 SNP rs2476601, in both the genome-wide association studies and the replication analyses. Furthermore, the integration of our data with those from previous genome-wide association studies showed that KLF12 and PTPRT are the unique loci that are commonly associated in 3 different studies (P ‫؍‬ 0.004 and P ‫؍‬ 0.002 for KLF12 in the Wellcome Trust Case Control Consortium study and the Brigham and Women's Rheumatoid Arthritis Sequential Study genome-wide association study, respectively). The genome-wide epistasis analysis identified several SNP pairs close to significance after multiple test correction.Conclusion. The present genome-wide association study identified KLF12 as a new susceptibility gene for RA. The joint analysis of our results and those from previous genome-wide association studies showed genomic regions with a higher probability of being genuine susceptibility loci for RA.Rheumatoid arthritis (RA) is one of the most prevalent autoimmune diseases in the world (1). In RA, chronic inflammation of the synovial joints leads to progressive articular damage, which can result in major functional disability (2). The etiology of RA is unknown, but several family aggregation and twin studies (3,4) clearly demonstrate a heritable component of the disease. Part of this genetic component of susceptibility has been consistently associated with the HLA class II locus variation. The remaining 50-75% of the genetic component includes several other genomic regions that are more difficult to identify due to their lower penetrance or more complex models of action (5,6).

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CSMD1 Is a Novel Multiple Domain Complement-Regulatory Protein Highly Expressed in the Central Nervous System and Epithelial Tissues

Cited by 181 publications

References 52 publications

Loss of CSMD1 expression disrupts mammary duct formation while enhancing proliferation, migration and invasion

Loss of CSMD1 expression disrupts mammary duct formation while enhancing proliferation, migration and invasion

Complement genetics, deficiencies, and disease associations

Genome‐wide association study of rheumatoid arthritis in the Spanish population: KLF12 as a risk locus for rheumatoid arthritis susceptibility

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