Expression of the Scube3 epidermal growth factor-related gene during early embryonic development in the mouse

Haworth, Kim E.; Smith, Frances; Zoupa, Maria; Seppälä, Maisa; Sharpe, Paul T.; Cobourne, Martyn T.

doi:10.1016/j.modgep.2006.12.004

Cited by 24 publications

(49 citation statements)

References 10 publications

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“…SCUBE genes have been shown to be expressed predominantly in a variety of developing tissues, including gonads, the central nervous system, dermomyotome, digital mesenchyme, and limb buds during mouse embryogenesis (2,3,5), which implies that the proteins may play important roles in development. However, direct functional studies of the roles of the SCUBE genes during mammalian development are still lacking.…”

Section: Together Our Results Support the Dual Roles Of Scube1 On Brmentioning

confidence: 99%

Domain and Functional Analysis of a Novel Platelet-Endothelial Cell Surface Protein, SCUBE1

Yan

et al. 2008

Journal of Biological Chemistry

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SCUBE1 (signal peptide-CUB-EGF domain-containing protein 1) is a novel, secreted, cell surface glycoprotein expressed during early embryogenesis and found in platelet and endothelial cells. This protein is composed of an N-terminal signal peptide sequence followed by nine tandemly arranged epidermal growth factor (EGF)-like repeats, a spacer region, three cysteine-rich repeat motifs, and one CUB domain at the C terminus. However, little is known about its domain and biological function. Here, we generated a comprehensive panel of domain deletion constructs and a new genetic mouse model with targeted disruption of Scube1 (Scube1 ⌬cub/⌬cub ) to investigate the domain function and biological significance. A number of cellbased assays were utilized to define the critical role of the spacer region for membrane association and establish that the EGFlike repeats 7-9 are sufficient for the formation of SCUBE1-mediated homophilic adhesions in a calcium-dependent fashion. Biochemical and molecular analyses showed that the C-terminal cysteine-rich motifs and CUB domain could directly bind and antagonize the bone morphogenetic protein activity. Furthermore, genetic ablation of this C-terminal region resulted in brain malformation in the Scube1 ⌬cub/⌬cub embryos.Together, our results support the dual roles of SCUBE1 on brain morphogenesis and cell-cell adhesions through its distinct domain function.SCUBE1 (signal peptide-CUB-EGF domain-containing protein 1) is the founding member of an evolutionarily conserved SCUBE gene family (1, 2). To date, three distinct isoforms have been cloned and named SCUBE1 to SCUBE3 according to their order of discovery in mammals (1-4). These genes coding for polypeptide molecules of about 1000 amino acids share an organized protein domain structure of at least 5 recognizable motifs: an N-terminal signal peptide sequence, 9 tandem repeats of epidermal growth factor (EGF) 3 -like modules, a large N-glycosylated spacer region followed by three repeated stretches of 6-cysteine residues with unique and regular spacing, and one CUB domain at the C terminus (see Fig. 1A). Our previous study demonstrated that the signal peptide sequence is sufficient to direct the expressed SCUBE1 protein into the secretory pathway and results in a secreted and surface-associated protein (1). However, little is known about the functional significance of the other four domains in SCUBE1.SCUBE genes have been shown to be expressed predominantly in a variety of developing tissues, including gonads, the central nervous system, dermomyotome, digital mesenchyme, and limb buds during mouse embryogenesis (2, 3, 5), which implies that the proteins may play important roles in development. However, direct functional studies of the roles of the SCUBE genes during mammalian development are still lacking. In addition to its embryonic expression, SCUBE1 was found to be expressed in the endothelium and platelets (1, 6). Our recent study showed that SCUBE1 is stored in the platelet ␣-granules and exposed to the cell surface upon platel...

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Section: Together Our Results Support the Dual Roles Of Scube1 On Brmentioning

confidence: 99%

Domain and Functional Analysis of a Novel Platelet-Endothelial Cell Surface Protein, SCUBE1

Yan

et al. 2008

Journal of Biological Chemistry

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“…SCUBE3 has recently been discovered to be involved in murine cardiac hypertrophy, through TGF-b1-mediated transcriptional activation (Yang et al, 2007). SCUBE3 has also been implicated in murine embryogenesis and development, as scube3 transcripts are expressed prominently in developing tissues (Haworth et al, 2007). Our laboratory has recently discovered that SCUBE3 is also highly expressed in extremely invasive lung cancers, and we are interested in further investigating the role it may have in metastasis.…”

Section: Introductionmentioning

confidence: 99%

SCUBE3 is an endogenous TGF-β receptor ligand and regulates the epithelial-mesenchymal transition in lung cancer

Peck

Chang

et al. 2011

Oncogene

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Signal peptide-CUB-EGF-like domain-containing protein 3 (SCUBE3) is a secreted glycoprotein that is overexpressed in lung cancer tumor tissues and is correlated with the invasive ability in a lung cancer cell line model. These observations suggest that SCUBE3 may have a role in lung cancer progression. By exogenous SCUBE3 treatment or knockdown of SCUBE3 expression, we found that SCUBE3 could promote lung cancer cell mobility and invasiveness. Knockdown of SCUBE3 expression also suppressed tumorigenesis and cancer metastasis in vivo. The secreted SCUBE3 proteins were cleaved by gelatinases (matrix metalloprotease-2 (MMP-2) and MMP-9) in media to release two major fragments: the N-terminal epidermal growth factor-like repeats and the C-terminal complement proteins C1r/C1s, Uegf and Bmp1 (CUB) domain. Both the purified SCUBE3 protein and the C-terminal CUB domain fragment, bound to transforming growth factor-b (TGF-b) type II receptor through the C-terminal CUB domain, activated TGF-b signaling and triggered the epithelial-mesenchymal transition (EMT). This process includes the induction of Smad2/3 phosphorylation, the increase of Smad2/3 transcriptional activity and the upregulation of the expression of target genes involved in EMT and cancer progression (such as TGF-b1, MMP-2, MMP-9, plasminogen activator inhibitor type-1, vascular endothelial growth factor, Snail and Slug), thus promoting cancer cell mobility and invasion. In conclusion, in lung cancer cells, SCUBE3 could serve as an endogenous autocrine and paracrine ligand of TGF-b type II receptor, which could regulate TGF-b receptor signaling and modulate EMT and cancer progression.

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“…The signal peptide CUB EGF-like domain-containing protein (SCUBE) gene family, which encodes secreted cell-surface proteins, contains 3 members (SCUBE1-3) and is evolutionarily conserved from zebrafish to humans (Wu et al, 2004;Woods and Talbot, 2005;Haworth et al, 2007;Xavier et al, 2013). All three human SCUBE proteins have been found to homodimerize, while SCUBE1 has additionally been shown to heterodimerize with other SCUBE proteins (Wu et al, 2004;Johnson et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Transcripts of the SCUBE genes have been detected in a range of tissues in mouse, rat, and zebrafish embryos (Hollway et al, 2006;Haworth et al, 2007;Xavier et al, 2010). The SCUBE1 protein is present at high levels in human endothelial cells, and in the central nervous system, somites, and gonads of mouse embryos (Grimmond et al, 2000;Yang et al, 2002;Tu et al, 2006;Xavier et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…The SCUBE1 protein is present at high levels in human endothelial cells, and in the central nervous system, somites, and gonads of mouse embryos (Grimmond et al, 2000;Yang et al, 2002;Tu et al, 2006;Xavier et al, 2009). SCUBE 2 has been found in the zebrafish you-type mutant and in human endothelial smooth-muscle, fibroblast, and renal mesangial cells, as well as in the forebrain, trunk neuroepithelium, and anterior hindbrain of mice (Grimmond et al, 2001;Haworth et al, 2007). SCUBE3, which is a secreted glycoprotein, forms either homo-or hetero-oligomers that are tethered to the cell surface and can act either locally or distantly in a paracrine or endocrine manner (Wu et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Molecular cloning, tissue expression pattern, and copy number variation of porcine SCUBE3

et al. 2016

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ABSTRACT. The signal peptide CUB EGF-like domain-containing protein 3 (SCUBE3) gene is a member of SCUBE gene family and plays important roles in bone cell biology and the determination of limb bone length. In this study, the full-length transcript of porcine SCUBE3 was cloned using reverse transcription-polymerase chain reaction and rapid amplification of cDNA ends. The full-length sequence of porcine SCUBE3 cDNA was 4131 base pairs and included 21 exons. The SCUBE3 gene contained a 2895-base pair open reading frame that encoded a peptide of 965 amino acids. Comparison of the deduced amino acid sequences of porcine SCUBE3 with those of human, mouse, zebrafish, and rat showed 96, 95, 73, and 95% identities, respectively. Porcine SCUBE3 mRNA expression levels were highest in the backfat, bone marrow, and cartilage tissues. Copy number variation was detected in porcine SCUBE3 and validated by real-time quantitative polymerase chain reaction. Different copy number variations were present in randomly selected individuals and may, therefore, be a good marker for identifying phenotypic traits. Our findings provide a basis for further investigation of the functions and regulatory mechanisms of SCUBE3 in pigs.

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Expression of the Scube3 epidermal growth factor-related gene during early embryonic development in the mouse

Cited by 24 publications

References 10 publications

Domain and Functional Analysis of a Novel Platelet-Endothelial Cell Surface Protein, SCUBE1

Domain and Functional Analysis of a Novel Platelet-Endothelial Cell Surface Protein, SCUBE1

SCUBE3 is an endogenous TGF-β receptor ligand and regulates the epithelial-mesenchymal transition in lung cancer

Molecular cloning, tissue expression pattern, and copy number variation of porcine SCUBE3

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