The novel complement inhibitor human CUB and Sushi multiple domains 1 (CSMD1) protein promotes factor I‐mediated degradation of C4b and C3b and inhibits the membrane attack complex assembly

Escudero-Esparza, Astrid; Kalchishkova, Nikolina; Kurbasic, Emila; Jiang, Wen Guo; Blom, Anna M.

doi:10.1096/fj.13-230706

Cited by 91 publications

(81 citation statements)

References 35 publications

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“…The expression of CSMD1 was confirmed by flow cytometry analysis with a specific antibody (Figure 2Cii and 2Dii). In order to knock down the expression of CSMD1 in T47D cells, we used a ribozyme transgene generated previously in which a reduction of CSMD1 was confirmed on both the RNA and the protein levels [3]. …”

Section: Resultsmentioning

confidence: 99%

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Complement inhibitor CSMD1 acts as tumor suppressor in human breast cancer

et al. 2016

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Human CUB and Sushi multiple domains 1 (CSMD1) is a membrane-bound complement inhibitor suggested to act as a putative tumor suppressor gene, since allelic loss of this region encompassing 8p23 including CSMD1 characterizes various malignancies. Here, we assessed the role of CSMD1 as a tumor suppressor gene in the development of breast cancer in vitro and in vivo. We found that human breast tumor tissues expressed CSMD1 at lower levels compared to that in normal mammary tissues. The decreased expression of CSMD1 was linked to a shorter overall survival of breast cancer patients. We also revealed that expression of CSMD1 in human breast cancer cells BT-20 and MDA-MB-231 significantly inhibited their malignant phenotypes, including migration, adhesion and invasion. Conversely, stable silencing of CSMD1 expression in T47D cells enhanced cancer cell migratory, adherent and clonogenic abilities. Moreover, expression of CSMD1 in the highly invasive MDA-MB-231 cells diminished their signaling potential as well as their stem cell-like properties as assessed by measurement of aldehyde dehydrogenase activity. In a xenograft model, expression of CSMD1 blocked the ability of cancer cells to metastasize to secondary sites in vivo, likely via inhibiting local invasion but not the extravasation into distant tissues. Taken together, these findings demonstrate the role of CSMD1 as a tumor suppressor gene in breast cancer.

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Section: Resultsmentioning

confidence: 99%

“…Human CUB and Sushi multiple domains 1 (CSMD1) is a large (∼ 390 kDa) membrane-bound complement inhibitor [3]. It is composed of 14 N-terminal CUB domains separated by single complement control protein (CCP) domains and followed by 15 consecutive CCP domains.…”

Section: Introductionmentioning

confidence: 99%

Complement inhibitor CSMD1 acts as tumor suppressor in human breast cancer

et al. 2016

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“…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%

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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“…However, exploration of the TreatOA GWAS data set for hip and for knee OA showed no association for rs9657371 (data not shown). The rat homologue of CSMD1 was identified in a search for proteins of the ‘regulators of complement activation’ family,39 and it was shown that CSMD1 blocked the classical complement pathway activation 39 40. It may therefore be speculated that innate dysregulated expression of CSMD1 results in a (slight) activation of the complement cascade in articular cartilage independent of OA, leading to changes in the release of CTX-II.…”

Section: Discussionmentioning

confidence: 99%