Identification of chicken and C. elegans fibulin-1 homologs and characterization of the C. elegans fibulin-1 gene

doi:10.1016/S0945-053X(98)90114-7

Matrix Biology

Volume 17, Issues 8–9, December 1998, Pages 635-646

https://doi.org/10.1016/S0945-053X(98)90114-7 Get rights and content

Abstract

Fibulin-1, a member of the emerging family of fibulin proteins, is a component of elastic extracellular matrix fibers, basement membranes and blood. Homologs of fibulin-1 have been described in man, mouse and zebrafish. In this study, we describe the isolation and sequencing of chicken fibulin-1C and D cDNA variants. We also describe identification of a C. elegans cDNA encoding fibulin-1D and cosmids containing the C. elegans fibulin-1 gene. Using the cDNA, RT-PCR and computer-based analysis of genomic sequences, the exon/intron organization of the C. elegans fibulin-1 gene was determined. The C. elegans fibulin-1 gene is located on chromosome IV, is approximately 6 kb in length, contains 16 exons and encodes fibulin-1C and D variants. Comparative analysis of the deduced amino acid sequences of nematode and chicken fibulin-1 variants with other known vertebrate fibulin-1 polypeptides showed that the number and organization of structural modules are identical. The results of this study indicate that the structure of the fibulin-1 protein has remained highly conserved over a large period of evolution, suggestive of functional conservation.

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The clinical value of Fibulin-1 for prognosis and its prospective mechanism in intrahepatic cholangiocarcinoma
2019, HPB
Citation Excerpt :
Fibulin-1, a widespread component of the extracellular matrix (ECM), can mediate cell signal transduction events by binding to ECM proteins, such as laminin-1, fibronectin, and versican. Fibulin-1 has been reported able to regulate cell morphology, adhesion, growth and mobility.4–7 More importantly, Fibulin-1 is up-regulated in ovarian and breast carcinomas, and the expression level is related to tumor progression in breast, ovarian and prostate cancers.8–10
Intrahepatic cholangiocarcinoma (ICC) is the second most common malignancy arising from the liver. Fibulin-1 has been demonstrated to be involved in various cancers, however, its role in ICC remains unclear.
To study the clinical value and potential molecular mechanism of Fibulin-1 in ICC, immunohistochemistry and bioinformatic analyses were performed using data in the Gene Expression Omnibus Datasets and The Cancer Genome Atlas database.
Fibulin-1 expression was overexpressed in ICC tissues compared with adjacent non-cancerous tissues, and was significantly associated with unfavorable overall survival. Moreover, similar genes were identified by Gene Expression Profiling Interactive Analysis and microarray data set. Next, functional and pathway enrichment analysis demonstrated that Fibulin-1 was overrepresented in the pathways of extracellular matrix organization and angiogenesis, which are associated with tumor progression and potential for metastasis. Gene set enrichment analysis indicated that the gene sets of epithelial mesenchymal transition, TGF-beta signaling pathway and angiogenesis were enriched in tissues with high Fibulin-1 level. Furthermore, Fibulin-1 silencing suppressed the ability of ICC tumor cells to form colonies and siFibulin-1 repressed the endogenous protein level of p-AKT.
Collectively, this study suggests that Fibulin-1 overexpression may play key roles in the carcinogenesis and progression of ICC via regulation of tumor-related pathways.
Calumenin and fibulin-1 on tumor metastasis: Implications for pharmacology
2015, Pharmacological Research
Tumor metastasis is a key cause of cancer mortality, and inhibiting migration of cancer cells is one of the major directions of anti-metastatic drug development. Calumenin and fibulin-1 are two extracellular proteins that synergistically inhibit cell migration and tumor metastasis, and could potentially be served as targets for pharmacological research of anti-metastatic drugs. This review briefly introduces the multi-function of these two proteins, and discusses the mechanism of how they regulate cell migration and tumor metastasis.
Distinct regions within fibulin-1D modulate interactions with hemicentin
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Three anaphylatoxin repeats precede the tandem EGF repeats in fibulins 1 and 2. Two alternate splicing events within the C. elegans fibulin-1 gene produce distinct carboxy terminal FC modules and second EGF repeats in fibulin-1C and fibulin-1D [9,10]; Fig. 1. Although no specific function has been identified for the second EGF of fibulin-1D (EGF2D), the second EGF of fibulin-1C (EGF2C) is necessary to rescue the growth and body size defects of a fibulin-1 null mutant and the synthetic larval arrest defect of a fibulin-1; gon-1 double mutant, suggesting that it may have growth factor, or growth factor binding activity [14].
Fibulins are evolutionarily conserved extracellular matrix (ECM) proteins that assemble in elastic fibers and basement membranes. Caenorhabditis elegans has a single fibulin gene that produces orthologs of vertebrate fibulin-1 C and D splice forms. In a structure-function analysis of fibulin-1 domains, a series of deletion constructs show that EGF repeats 4 and 5 are required for the hemicentin-dependent assembly and function of fibulin-1D in native locations. In contrast, constructs missing the second EGF repeat of fibulin-1D (EGF2D) assemble in ectopic locations in a hemicentin dependent manner. Constructs that contain EGF2D are cleaved into two fragments, but constructs with EGF2D missing are not, suggesting that a protease binds and/or cleaves fibulin-1D at a site that is likely within EGF2D. Together, the data suggests that EGF repeats 4 and 5 promote interaction with hemicentin while a region within EGF2D suppresses ectopic interactions with hemicentin and this suppression may be protease dependent.
Hemicentin 2 and Fibulin 1 are required for epidermal-dermal junction formation and fin mesenchymal cell migration during zebrafish development
2012, Developmental Biology
Citation Excerpt :
Interestingly, of all vertebrate fibulins, only Hemicentin and Fibulin 1 are present in C. elegans. For Fibulin 1, structural conservation even extends to the Fbln1C and Fbln1D splice isoforms (Barth et al., 1998). Most strikingly, Hmcn and the two Fbln1 isoforms display specific interactions during multiple processes of nematode development (Muriel et al., 2005; Vogel et al., 2006).
Hemicentin 1 (Hmcn1) and Hemicentin 2 (Hmcn2) belong to the fibulin family of extracellular matrix (ECM) proteins that play pivotal roles during development and homeostasis of a variety of vertebrate tissues. Recently, we have shown that mutations in zebrafish Hmcn1, also called Fibulin 6, lead to massive fin blistering, similar to the defects caused by the Fraser syndrome gene Fras1. In contrast, the role of Hmcn2 during vertebrate development has thus far been uncharacterized. In zebrafish, hmcn2, like fibulin 1 (fbln1), another member of the fibulin family, is predominantly expressed in fin mesenchymal cells and developing somites, contrasting the strict epithelial expression of hmcn1. While antisense morpholino oligonucleotide (MO)-based knockdown of hmcn2 did not yield any discernable defects, hmcn2/fbln1 double knockdown fish displayed blistering in the trunk, pointing to an essential contribution of these proteins from mesodermal sources for proper epidermal–dermal junction formation. In contrast, and unlike hmcn1 mutants, epidermal–dermal junctions in the fin folds of hmcn2/fbln1 double knockdown fish were only moderately affected. Instead, they displayed impaired migration of fin mesenchymal cells into the fin folds, pointing to a crucial role of Hmcn2 and Fbln1 to remodel the ECM of the fin fold interepidermal space, which is a prerequisite for fibroblast ingrowth. TEM analyses suggest that this ECM remodeling occurs at the level of actinotrichia, the collageneous migration substrate of mesenchymal cells, and at the level of cross fibers, which resemble mammalian microfibers. This work provides first insights into the role of Hmcn2 during vertebrate development, identifying it as an evolutionary conserved protein that acts in functional redundancy with Fbln1C and/or Fbln1D isoforms to regulate tissue adhesion and cell migration, while extending the current knowledge of the functions of vertebrate Fbln1.
Molecular evolution of the fibulins: Implications on the functionality of the elastic fibulins
2010, Gene
The fibulins form a family of secreted proteins associated with the basement membrane, cell adhesive structures, and elastic fibers characterized by the presence of a unique fibulin-like C-terminal domain preceded by a rod-like tandem array of calcium-binding EGF modules. We traced the origin of the fibulin gene family to the base of the metazoans. In invertebrates, Fibulin-1 and Hemicentin comprise the fibulin gene set. Diversification of the fibulins took place in the last common ancestor to the chordates by gene duplication of an ancestral Fibulin-1 gene. Further duplications at the vertebrate stem and in teleost fishes increased the number of fibulin genes to nine, including the novel Fibulin-8. Extensive gene loss has happened repeatedly, including Fibulin-8 in placental mammals and Fibulin-4 in birds. The Fibulin-3/4/5 clade of elastic fibulins branched out at the sequence level after relaxation of selective constraints immediately after the two gene duplication events in quick succession that originated the individual vertebrate Fibulin-3, -4, and -5 genes. Divergence took place mostly in the Fibulin-5 branch, at the atypical first EGF module and at the fibulin-like C-terminal region. Differentiation in gene expression further split Fibulin-5 from the other elastic fibulins, likely contributing to its nonredundant role in elastic fiber assembly.
ADAMTS Metalloproteases Generate Active Versican Fragments that Regulate Interdigital Web Regression
2009, Developmental Cell
Citation Excerpt :
Fibulin-1, a modular ECM protein interacting with the G3 domain of versican, was previously reported to be a cofactor for ADAMTS1 proteolysis of aggrecan (Lee et al., 2005). In addition, the C.elegans fibulin gene, which is most closely related to mammalian fibulin-1 (Barth et al., 1998), interacts genetically with the ADAMTS proteases Mig-17 and Gon-1 during gonadal morphogenesis (Hesselson et al., 2004; Kubota et al., 2004). Versican and fibulin-1 localization was analyzed by immunofluorescence in E14.5 wt and Adamts5−/−;bt/bt hindlimbs.
We show that combinatorial mouse alleles for the secreted metalloproteases Adamts5, Adamts20 (bt), and Adamts9 result in fully penetrant soft-tissue syndactyly. Interdigital webs in Adamts5^−/−;bt/bt mice had reduced apoptosis and decreased cleavage of the proteoglycan versican; however, the BMP-FGF axis, which regulates interdigital apoptosis was unaffected. BMP4 induced apoptosis, but without concomitant versican proteolysis. Haploinsufficiency of either Vcan or Fbln1, a cofactor for versican processing by ADAMTS5, led to highly penetrant syndactyly in bt mice, suggesting that cleaved versican was essential for web regression. The local application of an aminoterminal versican fragment corresponding to ADAMTS-processed versican, induced cell death in Adamts5^−/−;bt/bt webs. Thus, ADAMTS proteases cooperatively maintain versican proteolysis above a required threshold to create a permissive environment for apoptosis. The data highlight the developmental significance of proteolytic action on the ECM, not only as a clearance mechanism, but also as a means to generate bioactive versican fragments.

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Regular paperIdentification of chicken and C. elegans fibulin-1 homologs and characterization of the C. elegans fibulin-1 gene

Abstract

J Biol Chem.

Mol. Biochem. Parasitol.

J. Biol. Chem.

Neuron

Biochem. Biophys. Res. Commun.

J. Mol. Biol.

Dev. Biol.

J. Biol. Chem.

J. Biol. Chem.

Matrix Biol.

J. Biol. Chem.

Differentiation

Sensory control of dauer larva formation in Caenorhabditis elegans

J. Comp. Neurol.

Fibulin is an extracellular matrix and plasma glycoprotein with repeated domain structure

J. Cell Biol.

The DIG User's Guide for Filter Hybridation

Regular paper
Identification of chicken and C. elegans fibulin-1 homologs and characterization of the C. elegans fibulin-1 gene