FBLN5 (fibulin 5)

2013-05-01   Miao Wang , Rolf A Brekken 

Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390-8593, USA





According to Ensembl Genome Browser, human Fbln5 gene locates on Chromosome 14q between region 92335756 and 92414331. This gene has 9 splicing variants transcriptionally. The only one with known protein function has 11 exons and 1347 nucleotides.


Atlas Image
Figure 1: The protein sequence of human Fibulin-5 (source database: UniProt).


Fibulin-5 is a secreted protein belonging to the fibulin family. It contains 448 amino acids with an approximate 66-Kda molecular weight. It is mainly produced and secreted by endothelial cells, smooth muscle cells and fibroblasts (Yanagisawa et al., 2009). It has six calcium-binding epidermal growth factor (cb EGF)-like domains, the first one of which contains a RGD motif responsible for cell surface integrin binding.
Atlas Image
Schematic drawing of Fibulin-5 protein. It contains an evolutionally conserved RGD sequence in the first CB-EGF-like (Calcium Binding-Epidermal Growth Factor-like) motif and a fibulin module in the C-terminus of the protein.


The expression of Fibulin-5 is most prominent in embryonic vasculature and neural crest cells and down-regulated in most adult organs (Nakamura et al., 1999). Fibulin-5 mRNA is detected mainly in heart, ovary and colon of adult human tissue (Nakamura et al., 1999). However, Fibulin-5 expression can be reactivated upon tissue injury. It is reported that the expression of Fibulin-5 is elevated in human umbilical vein endothelial cells (HUVEC) by hypoxia in a HIF1α-dependent mechanism (Guadall et al., 2011). Transforming growth factors β (TGF-β) can also increase the expression of Fibulin-5 in human lung fibroblasts (Kuang et al., 2006).


Matricellular, secreted, extracellular matrix.


Fibulin-5 is essential for the assembly of elastic fibers. Biochemical analysis shows that Fibulin-5 preferentially binds to monomeric tropoelastin through N- and C-terminal elastin-binding regions (Zheng et al., 2007). Fbln5-/- mice exhibit severe elastic fibre disorganization throughout the whole body (Nakamura et al., 2002; Yanagisawa et al., 2002). Further studies have shown that Fibulin-5 regulates elastic fiber formation by increasing the efficacy of tropoelastin self-aggregation and cross-linking through direct binding to tropoelastin and lysyl oxidase like Loxl1, Loxl2 and Loxl4 (Yanagisawa et al., 2009). In addition, Fibulin-5 binds cell surface α4β1 and α5β1 integrins, but does not support receptor activation (Lomas et al., 2007). Additionally, Fibulin-5 competes with fibronectin for integrin binding. This competition serves to reduce fibronectin-mediated integrin-induced reactive oxygen species (ROS) generation (Schluterman et al., 2010).


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Implicated in

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Bladder cancer
The expression of Fibulin-5 is downregulated in human bladder carcinoma samples (Hu et al., 2011). Increased proliferation and invasiveness were observed in a bladder cancer cell line with overexpression of Fibulin-5 (Hu et al., 2011).
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Breast cancer
The role of Fibulin-5 in breast cancer is still controversial. Oncomine database shows the reduction of Fibulin-5 mRNA in breast carcinomas, however, induction of Fibulin-5 expression is detected in breast cancer patient tissue by immunostaining (Lee et al., 2008). In addition, overexpression of Fibulin-5 can enhance tumor growth in an orthotopic mouse model of breast cancer (Lee et al., 2008). Meanwhile, overexpression of Fibulin-5 in breast cancer cells can reduce metastasis to liver and lung (Moller et al., 2011). The discrepancy between these studies could be due to cell line and mouse model differences. Fibulin-5 is also reported to participate in epithelial-mesenchymal-transition (EMT) in breast cancer cell lines in a MMP-dependent manner (Lee et al., 2008). However, the mechanism of Fibulin-5 regulation of MMP is unclear. For example, Fibulin-5 has been shown to inhibit and activate MMP9 activity, (Budatha et al., 2011; Lee et al., 2008; Moller et al., 2011).
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Lung cancer
Fibulin-5 expression is silenced in multiple lung cancer cell lines and human lung cancer samples by hypermethylation of the promoter region (Yue et al., 2009). Overexpression of Fibulin-5 reduces lung cancer invasion and metastasis through suppression of the MMP-7 expression and ERK phosphorylation (Yue et al., 2009).
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Ovarian cancer
The expression level of Fibulin-5 correlates inversely with the severity of disease (Wang et al., 2010). Expression of Fibulin-5 is also remarkably decreased in metastatic sites.
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Pancreatic cancer
Fibulin-5 is required for aggressive tumor growth and angiogenesis in a mouse model of pancreatic cancer (Schluterman et al., 2010). Tumor weight and blood vessel density in Fbln5-/- or Fbln5RGE/RGE mice are significantly reduced compared with wildtype mice in subcutaneous and orthotopic models. Increased level of ROS, DNA damage and apoptotic endothelial cells were detected in tumors grown in Fibulin-5 deficient mice. In vitro analysis identified that Fibulin-5 reduces ROS production in a fibronectin and integrin β1-dependent manner (Schluterman et al., 2010).
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Age-related macular degeneration (AMD)
DNA sequencing revealed 10 distinct heterozygous missense mutations in Fbln5 in 1-2% of AMD patients (Auer-Grumbach et al., 2011; Lotery et al., 2006; Stone et al., 2004). The underlying biochemical basis of two missense mutations, I169T and G267S was further studied by nuclear magnetic resonance (NMR) and chromophoric calcium chelation experiments. The results show that G267S substitution leads to protein misfolding and inhibition of secretion, but not the I169T substitution (Schneider et al., 2010).
Age-related macular degeneration (AMD) is an eye disease affecting the macula and is the main reason for irreversible version loss in elderly people (Lotery et al., 2006).
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Charcot-Marie-Tooth disease (CMT)
Missense mutations of Fbln5 were detected in CMT neuropathy patients (Auer-Grumbach et al., 2011).
Charcot-Marie-Tooth disease (CMT) is an autosomal dominantly inherited disorder of peripheral nervous system (Auer-Grumbach et al., 2011). It is characterized by lifelong disabilities because of muscle weakness and loss of touch sensation (Auer-Grumbach et al., 2011).
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Cutis laxa
Mutations in Fbln5 have been identified in hereditary and acquired forms of cutis laxa. Three homozygous mutations (C217R, S227P and R284X) in Fbln5 have been reported in autosomal recessive cutis laxa patients (Claus et al., 2008; Elahi et al., 2006; Loeys et al., 2002). In addition, a heterozygous in-frame tandem duplication of Fbln5 exon 5-8 has been discovered in a sporadic cutis laxa patient (Markova et al., 2003). Mutational analysis also shows that a cutis laxa patient has a heterozygous missense mutation (G202R) in Fbln5 and compound heterozygous mutation in elastin alleles (A55V and G773D) (Hu et al., 2006b). These findings further support that Fibulin-5 is essential for the formation and maturation of the tropoelastin self-aggregation process, which is required for elastic fiber assembly (Hu et al., 2006a).
Cutis laxa is a connective tissue disorder characterized by loose and redundant skin and multiple internal organ abnormalities due to fragmentation and paucity of elastic fibers.
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Pelvic organ prolapse (POP)
Lower level expression of Fibulin-5 was identified in patients with POP (Soderberg et al., 2009; Takacs et al., 2009). It is reported that Fibulin-5 can prevent the development of POP by regulating elastic fiber homeostasis and inactivating MMP-9 in the vaginal wall (Budatha et al., 2011).
Pelvic organ prolapse (POP) is a common disease for elder women characterized by loss of pelvic floor support leading to protrusion of pelvic organs like uterus, bladder and vagina.
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Thoracic aortic aneurysmal disease (TAD)
The expression of aortic Fibulin-5 is significantly decreased in patients with TAD. The low level of Fibulin-5 strongly correlates with disorganization of elastic fibers, which may contribute to aorta abnormality (Wang et al., 2005).
Thoracic aortic aneurysmal disease (TAD) is an aortic disorder characterized by loss of elastin in the wall of aorta (Wang et al., 2005).


Pubmed IDLast YearTitleAuthors
215761122011Fibulin-5 mutations link inherited neuropathies, age-related macular degeneration and hyperelastic skin.Auer-Grumbach M et al
215191422011Extracellular matrix proteases contribute to progression of pelvic organ prolapse in mice and humans.Budatha M et al
181855372008A p.C217R mutation in fibulin-5 from cutis laxa patients is associated with incomplete extracellular matrix formation in a skin equivalent model.Claus S et al
166912022006Homozygous missense mutation in fibulin-5 in an Iranian autosomal recessive cutis laxa pedigree and associated haplotype.Elahi E et al
211933902011Fibulin-5 is up-regulated by hypoxia in endothelial cells through a hypoxia-inducible factor-1 (HIF-1α)-dependent mechanism.Guadall A et al
173718352007Fibulin-5/DANCE has an elastogenic organizer activity that is abrogated by proteolytic cleavage in vivo.Hirai M et al
170352502006Fibulin-5 mutations: mechanisms of impaired elastic fiber formation in recessive cutis laxa.Hu Q et al
163744722006Inflammatory destruction of elastic fibers in acquired cutis laxa is associated with missense alleles in the elastin and fibulin-5 genes.Hu Q et al
197672202011Fibulin-5 is down-regulated in urothelial carcinoma of bladder and inhibits growth and invasion of human bladder cancer cell line 5637.Hu Z et al
168376502006Fibulin-5 gene expression in human lung fibroblasts is regulated by TGF-beta and phosphatidylinositol 3-kinase activity.Kuang PP et al
187138382008Fibulin-5 initiates epithelial-mesenchymal transition (EMT) and enhances EMT induced by TGF-beta in mammary epithelial cells via a MMP-dependent mechanism.Lee YH et al
121891632002Homozygosity for a missense mutation in fibulin-5 (FBLN5) results in a severe form of cutis laxa.Loeys B et al
174725762007Fibulin-5 binds human smooth-muscle cells through alpha5beta1 and alpha4beta1 integrins, but does not support receptor activation.Lomas AC et al
166523332006Reduced secretion of fibulin 5 in age-related macular degeneration and cutis laxa.Lotery AJ et al
126189612003Genetic heterogeneity of cutis laxa: a heterozygous tandem duplication within the fibulin-5 (FBLN5) gene.Markova D et al
214543782011Role of fibulin-5 in metastatic organ colonization.Møller HD et al
118058352002Fibulin-5/DANCE is essential for elastogenesis in vivo.Nakamura T et al
201974182010Loss of fibulin-5 binding to beta1 integrins inhibits tumor growth by increasing the level of ROS.Schluterman MK et al
205995472010Biophysical characterisation of fibulin-5 proteins associated with disease.Schneider R et al
192517632009Gene expressions of small leucine-rich repeat proteoglycans and fibulin-5 are decreased in pelvic organ prolapse.Söderberg MW et al
152693142004Missense variations in the fibulin 5 gene and age-related macular degeneration.Stone EM et al
189896072009Fibulin-5 expression is decreased in women with anterior vaginal wall prolapse.Takacs P et al
211223822010[Expression of EVEC in ovarian carcinoma and its biological significance].Wang Q et al
161534472005Decreased expression of fibulin-5 correlates with reduced elastin in thoracic aortic dissection.Wang X et al
118058342002Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivo.Yanagisawa H et al
195842782009Fibulin-5 suppresses lung cancer invasion by inhibiting matrix metalloproteinase-7 expression.Yue W et al
171302422007Molecular analysis of fibulin-5 function during de novo synthesis of elastic fibers.Zheng Q et al

Other Information

Locus ID:

NCBI: 10516
MIM: 604580
HGNC: 3602
Ensembl: ENSG00000140092


dbSNP: 10516
ClinVar: 10516
TCGA: ENSG00000140092


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Extracellular matrix organizationREACTOMER-HSA-1474244
Elastic fibre formationREACTOMER-HSA-1566948
Molecules associated with elastic fibresREACTOMER-HSA-2129379

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
152693142016Aberrant hippocampal Atp8a1 levels are associated with altered synaptic strength, electrical activity, and autistic-like behavior.97
152693142016Aberrant hippocampal Atp8a1 levels are associated with altered synaptic strength, electrical activity, and autistic-like behavior.97
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
173718352007Fibulin-5/DANCE has an elastogenic organizer activity that is abrogated by proteolytic cleavage in vivo.58
172551082007Fibrillin-1 interactions with fibulins depend on the first hybrid domain and provide an adaptor function to tropoelastin.54
175816312007Latent TGF-beta-binding protein 2 binds to DANCE/fibulin-5 and regulates elastic fiber assembly.52
190152242009Polymorphisms in C2, CFB and C3 are associated with progression to advanced age related macular degeneration associated with visual loss.46
215191422011Extracellular matrix proteases contribute to progression of pelvic organ prolapse in mice and humans.46
202019262010Human variation in alcohol response is influenced by variation in neuronal signaling genes.45
155284652004Fibulin-5 is a novel binding protein for extracellular superoxide dismutase.43


Miao Wang ; Rolf A Brekken

FBLN5 (fibulin 5)

Atlas Genet Cytogenet Oncol Haematol. 2013-05-01

Online version: http://atlasgeneticsoncology.org/gene/46779/fbln5