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FBLN2 (fibulin 2)

Written2014-10Santiago Cal, Alvaro J Obaya
Departamento de Bioquimica y Biologia Molecular, Instituto Universitario de Oncologia (IUOPA), Universidad de Oviedo, 33006, Asturias, Spain (SC); Departamento de Biologia Funcional, Instituto Universitario de Oncologia (IUOPA), Universidad de Oviedo, 33006, Asturias, Spain (AJO)

Abstract Fibulin-2 is an extracellular matrix glycoprotein with an important function in maintaining elastic properties in different tissues. Fibulin-2 belongs to a protein family with seven members characterized by sharing a globular domain at the carboxy-terminus, which is called "fibulin-like", "FC domain" or domain III. Together with fibulin-1, fibulin-2 forms the so called subgroup 1 in the fibulin family which contains three anaphylatoxin modules in their sequence. Fibulin-2 does not only form part of elastic fibers but is also present in basement membranes and other connective tissue structures. Besides its structural function, alterations in fibulin-2 expression have also been related to several pathological processes. Thus, fibulin-2 has been shown to be implicated in blood pressure regulation, vascular injury protection or with a protective role in some heart malfunctioning. Also, fibulin-2 participation has been described in cancer showing both oncogenic or tumor-suppressor properties.

Keywords Extracellular matrix, elastic fibers.

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Identity

Other alias
HGNC (Hugo) FBLN2
LocusID (NCBI) 2199
Atlas_Id 52662
Location 3p25.1  [Link to chromosome band 3p25]
Location_base_pair Starts at 13549125 and ends at 13638422 bp from pter ( according to hg19-Feb_2009)  [Mapping FBLN2.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
NUP210 (3p25.1) / FBLN2 (3p25.1)

DNA/RNA

Note According to NCBI (National Center for Biotechnology Information) fibulin-2 (NC_000003.12) is encoded in 19 exons in chromosome 3, spans approximately 89.3 Kb of genomic DNA in the telomere-to-centromere orientation. The translation initiation codon is located to exon 3, and the stop codon to exon 19.
Transcription Northern blot analysis of mRNA from various human tissues reveals an abundant 4.5-kb transcript in heart, placenta, and ovary tissue (Zhang et al., 1994).

Protein

Note The open reading frame encodes a 1231 amino acid protein, with an estimated molecular weight of 131,9 kDa. Fibulin-2 shares a structural multidomain complex architecture with the rest of the members of the fibulin family, specially with fibulin-1. This organization includes a signal peptide, a cystein rich domain, a cystein free domain, three anaphylotoxyn domains, an EGF-like (Epidermal Growth Factor) domain following the first out of a total of ten cbEGF (calcium-binding Epidermal Growht Factor) domains and finally, at the carboxy-terminus the fibulin-like domain, characteristic of the fibulin family (Figure 1) (Timpl et al., 2003; de Vega et al., 2009; Obaya et al., 2012). An alternative splicing has been described for fibulin-2 mRNA by which exon 10 is removed resulting in a short fibulin-2 (FBLN2S) of 1184 amino which lacks the third EFG-like domain in comparison to the long fibulin-2 (FBLN2L) (Zhang et al., 1994; Grassel et al., 1999; Law et al., 2012). It has been described that fibulin-2 forms anti-paralel homodimers stabilized by a single disulfide bond throug a cysteine residue located in the second anaphylotoxin domain. As seen by electron microscopy, fibulin-2 homodimerization produces a set of star-like particles consisting in two-, three- or four-arm structures as well as some larger aggregates. Thus, the complexity of fibulin-2 structure allows different combinations and possibilities to interact with other extracellular matrix proteins (Pan et al., 1993; Sasaki et al., 1997).
 
  Figure 1. Fibulin-2 domain organization. EGF : Epidermal Growth Factor.
Expression Northern blot analysis of mRNA from various human tissues reveals the presence of fibulin-2 transcript in heart, placenta and ovary tissue (Zhang et al., 1994). Fibulin-2 expression is restricted to certain tissues and partially overlaps with that of fibulin-1. Both proteins are localized in basement membranes, elastic fibers, and other connective tissue structures (Pan et al., 1993; Roark et al., 1995; Miosge et al., 1996; Reinhardt et al., 1996; Zhang et al., 1996). Both proteins can be detected in early stages of embryonic development although fibulin-2 synthesis is delayed with respect to fibulin-1. However, both are at relatively high levels at the onset of organogenesis in mouse and humans (Miosge, 1996; Zhang et al., 1996). Fibulin-2 is expressed during the epithelial to mesenchymal transformation in the endocardial cushion matrix, aortic arch vessels and coronary vessels during embryonic heart development (Zhang et al., 1995; Tsuda et al., 2001). Fibulin-1 and fibulin-2 are also expressed and deposited in several, although different neuronal structures. Specifically, fibulin-2 was detected primarily within the neuropithelium, spinal ganglia and peripheral nerves (Zhang et al., 1996). Furthermore, fibulin-2 has also been detected during skin wound healing, in the developing cartilage (perichondrium) or deposited in the organization of corneal structures (Zhang et al., 1995; Ducros et al., 2007; Kobayashi et al., 2007).
Localisation Secreted, extracellular matrix.
Function Fibulin-2 as well as other members of the fibulin family play essential role for the correct assembly of elastic fibers in connective tissues (Kielty et al., 2002). In particular, fibulin-2 is localized in the interface between the two main components of elastic fibers, microfibrils and the elastin core (Reinhardt et al., 1996; Kobayashhi et al., 2007). In its structural function, fibulin-2 is able to interact with several other extracellular components to maintain specific connective tissues properties. Thus, fibulin-2 is able to interact with troposlatin-2 (Sasaki et al., 1999), aggrecan and versican (Olin et al., 2001), fibronectin and nidogen-1 (Sasaki et al., 1995). All those bindings partners overlap with those of fibulin-1 but, fibulin-2 is also able to specifically interact with fibrillin-1 and perlecan (Reinhardt et al., 1996; Hopf et al., 2001).
Fibulin-2 is also suggested to regulate steroid hormone action since it is able to interact with sex hormone globulin (SHBG) (Ng et al., 2006). Mutations in SHGB alter its binding capacities to fibulin-2 and sex hormones suggesting participation in human diseases (Wu and Hammond, 2014). In relation with steroid hormones, progesterone, dexamethasone, estradiol and glucocorticoids are able to regulate fibulin-2 expression levels in different tissues and contexts (Talts et al., 1995; Gu et al., 2001; Okada et al., 2003; Eyster et al., 2014 ; Olijnyk et al., 2014).
Homology The FBLN2 gene is conserved in chimpanzee (Refseq: NC_006490.3), dog (Refseq: NC_006602.3), cow (Refseq: AC_000179.1), mouse (Refseq: NC_000072.6), rat (Refseq: NC_005103.4), chicken (Refseq: NC_006099.3), and zebrafish (Refseq: NC_007122.5).

Implicated in

Note
  
Entity Various cancers
Note Fibulin-2 was early related to cancer in a study aimed to look for genes differently expressed between adenocarcinoma metastases of multiple tumor types and the unmatched primary adenocarcinomas (breast, prostate, lung, colon, uterus and ovary) (Ramaswamy et al., 2003).
  
  
Entity Nasopharyngeal carcinoma
Note Genome-wide Human Mapping Array analysis showed that the chromosome 3p25 region, where FBLN2 maps, is often deleted in esophageal squamous cell carcinoma patients (Chattopadhyay et al., 2010). More recently, fibulin-2 RNA downregulation has been described in 100% of nasopharingeal carcinoma cell lines as well as 46.7% of biopsies tested. Deletion and promoter hypermethylation events contribute to the silencing of FBLN2 expression (Law et al., 2012). Functional analysis of fibulin-2 role as a tumor suppressor gene showed angio-inhibitory and tumor-suppressive properties that are linked to a short isoform of FBLN2, FBLN2S, in nasopharingeal carcinoma (Law et al., 2012). Interestingly, FBLN2-associated anti-angiogenic activity is concomitant with a downregulation of two pro-angiogenic factors such as VEGF and matrix-metalloprotease-2 (MMP-2).
  
  
Entity Breast cancer
Note Fibulin-2 was suggested to be a putative biomarker of breast cancer attending to the proteomic analysis performed in a breast cancer mouse model (Whiteaker et al., 2007). A role of fibulin-2 as a tumor suppressor gene in breast cancer came after the observation of its down-regulation in several cancer cell lines (Yi et al., 2007). Exogenous expression of fibulin-2 in breast cancer cell lines was able to reduce cell motility as well as invasion capacities, some of the tumor properties of those cells (Yi et al., 2007). One of the mechanisms to reduce FBLN2 gene expression is throuh promoter hypermethylation as it has been described in breast cancer cell lines (60%), primary breast tumors (34%) and matched tumor/normal pairs (32%) biopsies (Hill et al., 2010). Fibulin-2 might exert its tumor suppressor function by interaction with other proteins of the extracellular matrix as is the case of ADAMTS-12 (Fontanil et al., 2014). ADAMTS-12 is a secreted metalloprotease (Cal et al., 2001; Cal and Obaya, 2014) and different studies have suggested a role for this metalloprotease in tissue remodeling and cell migration or adhesion (Noel et al., 2012). Fibulin-2/ADAMTS-12 interaction has been shown to inhibit the migration, invasion and tumorigenicity properties of cancer breast cell lines after exogenous expression of ADAMTS-12 (Fontanil et al., 2014).
  
  
Entity Lung adenocarcinoma
Note Based on the previous study of Ramaswamy et al. comparing primary a metastatic tumors in the search of a gene metastatic signature (Ramaswamy et al., 2003), a proteomic screen of highly and poorly metastatic tumor cell lines derived from mice that develop lung adenocarcinoma revealed that fibulin-2 was preferentially expressed in highly metastatic cells (Schliekelman et al., 2011). A more profound and functional study revealed that fibulin-2 shows an oncogenic potential in lung adenocarcinoma (Baird et al., 2013). Fibulin-2 is found expressed in metastatic-derived cell lines and tumor growth depends on the endogenously expressed fibulin-2 since they are able to grow equally in Fbln2-null and wild-type mice. Furthermore, fibulin-2 requires the presence of collagen in the extracellular matrix in order to promote tumorigenic properties of these cells lines (Baird et al., 2013).
  
  
Entity Pancreatic cancer
Note Expression of MUC4, a transmembrane type I glycoprotein, is elevated in pancreatic cancer. It is also known that MUC4 is able to interact through its nidogen-like domain with fibulin-2 and authors suggest that this association contributes to the MUC4-mediated metastasis of pancreatic tumor cells (Senapati et al., 2012).
  
  
Entity Kaposí's sarcoma
Note Infection of dermal microvascular endothelial cells (DMVEC) with Kaposi's sarcoma-associated herpesvirus (KSHV) reduced fibulin-2 protein and RNA. Furthermore, a decrease in the expression of fibronectin and tropoelastin, binding partners of fibulin-2, was also detected in infected cells (Alcendor et al., 2011). Since downregulataion of other fibulins is observed, authors suggest that dysregulation of fibulin family members such as fibulin-2, fibulin-3, fibulin-5, fibulin 1C, and fibulin 1D likely contribute to KSHV-induced pathogenesis in Kaposi's sarcoma (Alcendor et al., 2011).
  
  
Entity Various diseases
Note Fibulin-2 participation in disease has been somehow elusive due to functional redundacy with other members of the fibulin family. Thus, fibulin-1 staining is highly detected in the absence of fibulin-2 in the viable, fertile and free of anatomic abnormalities fibulin-2 knock-out mice (Sicot et al., 2008; Olijnyk et al.,2014). However, several studies support fibulin-2 functions in disease and cancer. In the case of cancer, fibulin-2 shows a dual function, showing either suppresor gene or oncogenic activities (Obaya et al., 2012).
  
  
Entity Skin damage
Note In normal skin, regulation of skin elastogenesis depends on the association between fibulin-2 and fibulin-5 with fibrillin-1 matrix (Lemaire et al., 2004). Fibulin-2 is not only known to participate in the elastic structure of the skin but also participates in skin wound healing where it shows an increased expression with mRNA levels returning to normal after skin repair (Fässler el al., 1996). Fibulin-2 deposition is also high in a mice model of chronic contact dermatitis as well as in models of solar elastosis which suggests a protective role of fibulin-2 in skin formation and maintenance (Kusubata et al., 1999; Hunzelmann et al., 2001). Furthermore, fibulin-2 reduction in fbln2 null mice or due to the lack of integrin α3β1-laminin interaction contributes to loss of the integrity of basement membrane and skin blistering (Sicot et al., 2008; Longmate el al., 2014). In fact, the latest occurs since fibulin-2 is one of the genes regulated by integrin α3β1 in inmortalized keratinocytes and seems to be one of the mediators in the invasive capacities exerted by integrin α3β1 (Missan et al., 2014).
  
  
Entity Cardiaovascular pathologies
Note Fibulin-2 has been detected in the endocardial cushion tissue, endocardium and the basement membrane zones and adventitia of blood vessels of developing human and mouse embryo (Zhang et al., 1995; Miosge et al., 1996). Fibulin-2 is also up-regulated in transformed cells that migrate into the extracellular matrix of cardiac valves and aortic arch vessels and authors suggest that fibulin-2 is also required for the correct formation of coronary arteries and veins in postnatal life (Tsuda et al., 2001). However, although mice lacking fibulin-2 do not show any obvious phenotypic anomalies (Sicot et al., 2008), loss of fibulin-2 significantly improved the survival rate after experimental myocardial infarction through attenuating progressive ventricular dysfunction accompanied by reduced activation of the TGFβ-dependent pathway (Tsuda et al., 2012). The modulation of this signalling pathway by fibulin-2 in heart homeostasis has also been described in an angiotensin II-induced heart hypertrophy model (Zhang et al., 2014). In both cases, fibulin-2 deficiency results in a better outcome of the pathologies.
Fibulin-2 is required, in cooperation with fibulin-5, in the maintenance of vessel integrity as well as in vessel recovery after injury (Chapman et al., 2010). In this regard, participation of fibulin-2 in artery integrity and stiffnes is also important in order to control blood pressure and it has been described the existence of some polymorphisms of FBLN2 associated with reduced levels of systolic blood pressure and decreased risk of hypertension (Vallvé et al., 2012).
  

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Dev Dyn. 1996 Mar;205(3):348-64.
PMID 8850569
 
Fibulin-2 (FBLN2): human cDNA sequence, mRNA expression, and mapping of the gene on human and mouse chromosomes.
Zhang RZ, Pan TC, Zhang ZY, Mattei MG, Timpl R, Chu ML.
Genomics. 1994 Jul 15;22(2):425-30.
PMID 7806230
 
Fibulins: multiple roles in matrix structures and tissue functions.
de Vega S, Iwamoto T, Yamada Y.
Cell Mol Life Sci. 2009 Jun;66(11-12):1890-902. doi: 10.1007/s00018-009-8632-6. (REVIEW)
PMID 19189051
 

Citation

This paper should be referenced as such :
Santiago Cal, Alvaro J, Obaya
FBLN2 (fibulin 2)
Atlas Genet Cytogenet Oncol Haematol. 2015;19(10):605-610.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/FBLN2ID52662ch3p25.html


External links

Nomenclature
HGNC (Hugo)FBLN2   3601
Cards
AtlasFBLN2ID52662ch3p25
Entrez_Gene (NCBI)FBLN2  2199  fibulin 2
Aliases
GeneCards (Weizmann)FBLN2
Ensembl hg19 (Hinxton)ENSG00000163520 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000163520 [Gene_View]  chr3:13549125-13638422 [Contig_View]  FBLN2 [Vega]
ICGC DataPortalENSG00000163520
TCGA cBioPortalFBLN2
AceView (NCBI)FBLN2
Genatlas (Paris)FBLN2
WikiGenes2199
SOURCE (Princeton)FBLN2
Genetics Home Reference (NIH)FBLN2
Genomic and cartography
GoldenPath hg38 (UCSC)FBLN2  -     chr3:13549125-13638422 +  3p25.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)FBLN2  -     3p25.1   [Description]    (hg19-Feb_2009)
EnsemblFBLN2 - 3p25.1 [CytoView hg19]  FBLN2 - 3p25.1 [CytoView hg38]
Mapping of homologs : NCBIFBLN2 [Mapview hg19]  FBLN2 [Mapview hg38]
OMIM135821   
Gene and transcription
Genbank (Entrez)AK129883 AK300913 AK304777 AK304827 AL050095
RefSeq transcript (Entrez)NM_001004019 NM_001165035 NM_001998
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)FBLN2
Cluster EST : UnigeneHs.198862 [ NCBI ]
CGAP (NCI)Hs.198862
Alternative Splicing GalleryENSG00000163520
Gene ExpressionFBLN2 [ NCBI-GEO ]   FBLN2 [ EBI - ARRAY_EXPRESS ]   FBLN2 [ SEEK ]   FBLN2 [ MEM ]
Gene Expression Viewer (FireBrowse)FBLN2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)2199
GTEX Portal (Tissue expression)FBLN2
Human Protein AtlasENSG00000163520-FBLN2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP98095   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP98095  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP98095
Splice isoforms : SwissVarP98095
PhosPhoSitePlusP98095
Domaine pattern : Prosite (Expaxy)ANAPHYLATOXIN_1 (PS01177)    ANAPHYLATOXIN_2 (PS01178)    ASX_HYDROXYL (PS00010)    EGF_2 (PS01186)    EGF_3 (PS50026)    EGF_CA (PS01187)   
Domains : Interpro (EBI)Anaphylatoxin/fibulin    cEGF    EGF-like_Ca-bd_dom    EGF-like_CS    EGF-like_dom    EGF-type_Asp/Asn_hydroxyl_site    EGF_Ca-bd_CS    Growth_fac_rcpt_   
Domain families : Pfam (Sanger)ANATO (PF01821)    cEGF (PF12662)    EGF_CA (PF07645)   
Domain families : Pfam (NCBI)pfam01821    pfam12662    pfam07645   
Domain families : Smart (EMBL)ANATO (SM00104)  EGF (SM00181)  EGF_CA (SM00179)  
Conserved Domain (NCBI)FBLN2
DMDM Disease mutations2199
Blocks (Seattle)FBLN2
SuperfamilyP98095
Human Protein Atlas [tissue]ENSG00000163520-FBLN2 [tissue]
Peptide AtlasP98095
HPRD00630
IPIIPI01010639   IPI00465038   IPI00927720   IPI00926485   IPI00926729   IPI01018299   
Protein Interaction databases
DIP (DOE-UCLA)P98095
IntAct (EBI)P98095
FunCoupENSG00000163520
BioGRIDFBLN2
STRING (EMBL)FBLN2
ZODIACFBLN2
Ontologies - Pathways
QuickGOP98095
Ontology : AmiGOextracellular matrix structural constituent  calcium ion binding  extracellular region  proteinaceous extracellular matrix  extracellular space  positive regulation of cell-substrate adhesion  extracellular matrix  extracellular matrix  extracellular matrix binding  extracellular exosome  extracellular vesicle  
Ontology : EGO-EBIextracellular matrix structural constituent  calcium ion binding  extracellular region  proteinaceous extracellular matrix  extracellular space  positive regulation of cell-substrate adhesion  extracellular matrix  extracellular matrix  extracellular matrix binding  extracellular exosome  extracellular vesicle  
REACTOMEP98095 [protein]
REACTOME PathwaysR-HSA-2129379 [pathway]   
NDEx NetworkFBLN2
Atlas of Cancer Signalling NetworkFBLN2
Wikipedia pathwaysFBLN2
Orthology - Evolution
OrthoDB2199
GeneTree (enSembl)ENSG00000163520
Phylogenetic Trees/Animal Genes : TreeFamFBLN2
HOVERGENP98095
HOGENOMP98095
Homologs : HomoloGeneFBLN2
Homology/Alignments : Family Browser (UCSC)FBLN2
Gene fusions - Rearrangements
Fusion : MitelmanNUP210/FBLN2 [3p25.1/3p25.1]  [t(3;3)(p25;p25)]  
Fusion: TCGA_MDACCNUP210 3p25.1 FBLN2 3p25.1 LUAD
Tumor Fusion PortalFBLN2
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerFBLN2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)FBLN2
dbVarFBLN2
ClinVarFBLN2
1000_GenomesFBLN2 
Exome Variant ServerFBLN2
ExAC (Exome Aggregation Consortium)ENSG00000163520
GNOMAD BrowserENSG00000163520
Genetic variants : HAPMAP2199
Genomic Variants (DGV)FBLN2 [DGVbeta]
DECIPHERFBLN2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisFBLN2 
Mutations
ICGC Data PortalFBLN2 
TCGA Data PortalFBLN2 
Broad Tumor PortalFBLN2
OASIS PortalFBLN2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICFBLN2  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDFBLN2
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch FBLN2
DgiDB (Drug Gene Interaction Database)FBLN2
DoCM (Curated mutations)FBLN2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)FBLN2 (select a term)
intoGenFBLN2
NCG5 (London)FBLN2
Cancer3DFBLN2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM135821   
Orphanet
DisGeNETFBLN2
MedgenFBLN2
Genetic Testing Registry FBLN2
NextProtP98095 [Medical]
TSGene2199
GENETestsFBLN2
Target ValidationFBLN2
Huge Navigator FBLN2 [HugePedia]
snp3D : Map Gene to Disease2199
BioCentury BCIQFBLN2
ClinGenFBLN2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD2199
Chemical/Pharm GKB GenePA28014
Clinical trialFBLN2
Miscellaneous
canSAR (ICR)FBLN2 (select the gene name)
Probes
Litterature
PubMed38 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineFBLN2
EVEXFBLN2
GoPubMedFBLN2
iHOPFBLN2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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