Download Gene Section FBLN5 (fibulin 5) Atlas of Genetics and Cytogenetics

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
INIST-CNRS
OPEN ACCESS JOURNAL
Gene Section
Review
FBLN5 (fibulin 5)
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 (MW, RAB)
Published in Atlas Database: May 2013
Online updated version : http://AtlasGeneticsOncology.org/Genes/FBLN5ID46779ch14q32.html
DOI: 10.4267/2042/51868
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2013 Atlas of Genetics and Cytogenetics in Oncology and Haematology
muscle cells. The expression of Fibulin-5 is downregulated in adult tissue but reactivated upon injury and
various disease conditions (Yanagisawa et al., 2009).
Fibulin-5 is essential for elastic fiber organization as
shown by generation of Fibulin-5 knockout (Fbln5-/-)
mice (Nakamura et al., 2002; Yanagisawa et al., 2002)
and biochemical analysis (Hirai et al., 2007; Zheng et
al., 2007). However, a mouse model with point
mutation (D to E) (Fbln5RGE/RGE) in the RGD domain
has exhibited intact elastic fibers (Budatha et al., 2011),
indicating that Fibulin-5-Integrin interaction is not
required for elastic fiber assembly. Fibulin-5 has also
been implicated in various pathological conditions
including cancer, cutis laxa and age-related macular
degeneration.
Identity
Other names: ADCL2, ARCL1A, ARMD3, DANCE,
EVEC, FIBL-5, UP50
HGNC (Hugo): FBLN5
Location: 14q32.12
Note
Fibulin-5 is a matricellular glycoprotein, belonging to
fibulin family which has 7 members (Yanagisawa et al.,
2009). Compared with other fibulins, it has a unique
arginine-glycine-aspartic acid (RGD) domain in the Nterminal region that mediates binding to integrins
(Nakamura et al., 1999). Fibulin-5 is produced and
secreted by endothelial cells, fibroblasts and vascular
smooth
The protein sequence of human Fibulin-5 (source database: UniProt).
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(12)
811
FBLN5 (fibulin 5)
Wang M, Brekken RA
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.
Localisation
DNA/RNA
Matricellular, secreted, extracellular matrix.
Description
Function
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.
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).
Protein
Description
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.
Expression
Mutations
The expression of Fibulin-5 is most prominent in
embryonic vasculature and neural crest cells and downregulated 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 HIF1αdependent 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).
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(12)
See table below.
Implicated in
Bladder cancer
Note
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 Fibulin5 (Hu et al., 2011).
812
FBLN5 (fibulin 5)
Wang M, Brekken RA
Breast cancer
Ovarian cancer
Note
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-mesenchymaltransition (EMT) in breast cancer cell lines in a MMPdependent 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).
Note
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.
Pancreatic cancer
Note
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).
Lung cancer
Age-related macular degeneration
(AMD)
Note
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).
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(12)
Note
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
813
FBLN5 (fibulin 5)
Wang M, Brekken RA
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).
Disease
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).
for elder women characterized by loss of pelvic floor
support leading to protrusion of pelvic organs like
uterus, bladder and vagina.
Thoracic aortic aneurysmal disease
(TAD)
Note
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).
Disease
Thoracic aortic aneurysmal disease (TAD) is an aortic
disorder characterized by loss of elastin in the wall of
aorta (Wang et al., 2005).
Charcot-Marie-Tooth disease (CMT)
Note
Missense mutations of Fbln5 were detected in CMT
neuropathy patients (Auer-Grumbach et al., 2011).
Disease
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).
References
Nakamura T, Ruiz-Lozano P, Lindner V, Yabe D, Taniwaki M,
Furukawa Y, Kobuke K, Tashiro K, Lu Z, Andon NL, Schaub R,
Matsumori A, Sasayama S, Chien KR, Honjo T. DANCE, a
novel secreted RGD protein expressed in developing,
atherosclerotic, and balloon-injured arteries. J Biol Chem. 1999
Aug 6;274(32):22476-83
Cutis laxa
Note
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).
Disease
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.
Loeys B, Van Maldergem L, Mortier G, Coucke P, Gerniers S,
Naeyaert JM, De Paepe A. Homozygosity for a missense
mutation in fibulin-5 (FBLN5) results in a severe form of cutis
laxa. Hum Mol Genet. 2002 Sep 1;11(18):2113-8
Nakamura T, Lozano PR, Ikeda Y, Iwanaga Y, Hinek A,
Minamisawa S, Cheng CF, Kobuke K, Dalton N, Takada Y,
Tashiro K, Ross Jr J, Honjo T, Chien KR. Fibulin-5/DANCE is
essential for elastogenesis in vivo. Nature. 2002 Jan
10;415(6868):171-5
Yanagisawa H, Davis EC, Starcher BC, Ouchi T, Yanagisawa
M, Richardson JA, Olson EN. Fibulin-5 is an elastin-binding
protein essential for elastic fibre development in vivo. Nature.
2002 Jan 10;415(6868):168-71
Markova D, Zou Y, Ringpfeil F, Sasaki T, Kostka G, Timpl R,
Uitto J, Chu ML. Genetic heterogeneity of cutis laxa: a
heterozygous tandem duplication within the fibulin-5 (FBLN5)
gene. Am J Hum Genet. 2003 Apr;72(4):998-1004
Stone EM, Braun TA, Russell SR, Kuehn MH, Lotery AJ,
Moore PA, Eastman CG, Casavant TL, Sheffield VC. Missense
variations in the fibulin 5 gene and age-related macular
degeneration. N Engl J Med. 2004 Jul 22;351(4):346-53
Wang X, LeMaire SA, Chen L, Carter SA, Shen YH, Gan Y,
Bartsch H, Wilks JA, Utama B, Ou H, Thompson RW, Coselli
JS, Wang XL. Decreased expression of fibulin-5 correlates with
reduced elastin in thoracic aortic dissection. Surgery. 2005
Aug;138(2):352-9
Pelvic organ prolapse (POP)
Note
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).
Disease
Pelvic organ prolapse (POP) is a common disease
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(12)
Elahi E, Kalhor R, Banihosseini SS, Torabi N, Pour-Jafari H,
Houshmand M, Amini SS, Ramezani A, Loeys B. Homozygous
missense mutation in fibulin-5 in an Iranian autosomal
recessive cutis laxa pedigree and associated haplotype. J
Invest Dermatol. 2006 Jul;126(7):1506-9
Hu Q, Loeys BL, Coucke PJ, De Paepe A, Mecham RP, Choi
J, Davis EC, Urban Z. Fibulin-5 mutations: mechanisms of
impaired elastic fiber formation in recessive cutis laxa. Hum
Mol Genet. 2006a Dec 1;15(23):3379-86
Hu Q, Reymond JL, Pinel N, Zabot MT, Urban Z. Inflammatory
destruction of elastic fibers in acquired cutis laxa is associated
814
FBLN5 (fibulin 5)
Wang M, Brekken RA
with missense alleles in the elastin and fibulin-5 genes. J
Invest Dermatol. 2006b Feb;126(2):283-90
inhibiting matrix metalloproteinase-7 expression. Cancer Res.
2009 Aug 1;69(15):6339-46
Kuang PP, Joyce-Brady M, Zhang XH, Jean JC, Goldstein RH.
Fibulin-5 gene expression in human lung fibroblasts is
regulated by TGF-beta and phosphatidylinositol 3-kinase
activity. Am J Physiol Cell Physiol. 2006 Dec;291(6):C1412-21
Schluterman MK, Chapman SL, Korpanty G, Ozumi K, Fukai T,
Yanagisawa H, Brekken RA. Loss of fibulin-5 binding to beta1
integrins inhibits tumor growth by increasing the level of ROS.
Dis Model Mech. 2010 May-Jun;3(5-6):333-42
Lotery AJ, Baas D, Ridley C, Jones RP, Klaver CC, Stone E,
Nakamura T, Luff A, Griffiths H, Wang T, Bergen AA, Trump D.
Reduced secretion of fibulin 5 in age-related macular
degeneration and cutis laxa. Hum Mutat. 2006 Jun;27(6):56874
Schneider R, Jensen SA, Whiteman P, McCullagh JS, Redfield
C, Handford PA. Biophysical characterisation of fibulin-5
proteins associated with disease. J Mol Biol. 2010 Aug
27;401(4):605-17
Wang Q, Li XG, Zhang Y, Cao LQ, Deng ZH, Chen Y.
[Expression of EVEC in ovarian carcinoma and its biological
significance]. Zhonghua Zhong Liu Za Zhi. 2010
Sep;32(9):676-80
Hirai M, Ohbayashi T, Horiguchi M, Okawa K, Hagiwara A,
Chien KR, Kita T, Nakamura T. Fibulin-5/DANCE has an
elastogenic organizer activity that is abrogated by proteolytic
cleavage in vivo. J Cell Biol. 2007 Mar 26;176(7):1061-71
Auer-Grumbach M, Weger M, Fink-Puches R, Papić L, Fröhlich
E, Auer-Grumbach P, El Shabrawi-Caelen L, Schabhüttl M,
Windpassinger C, Senderek J, Budka H, Trajanoski S,
Janecke AR, Haas A, Metze D, Pieber TR, Guelly C. Fibulin-5
mutations link inherited neuropathies, age-related macular
degeneration and hyperelastic skin. Brain. 2011 Jun;134(Pt
6):1839-52
Lomas AC, Mellody KT, Freeman LJ, Bax DV, Shuttleworth
CA, Kielty CM. Fibulin-5 binds human smooth-muscle cells
through alpha5beta1 and alpha4beta1 integrins, but does not
support receptor activation. Biochem J. 2007 Aug
1;405(3):417-28
Zheng Q, Davis EC, Richardson JA, Starcher BC, Li T, Gerard
RD, Yanagisawa H. Molecular analysis of fibulin-5 function
during de novo synthesis of elastic fibers. Mol Cell Biol. 2007
Feb;27(3):1083-95
Budatha M, Roshanravan S, Zheng Q, Weislander C,
Chapman SL, Davis EC, Starcher B, Word RA, Yanagisawa H.
Extracellular matrix proteases contribute to progression of
pelvic organ prolapse in mice and humans. J Clin Invest. 2011
May;121(5):2048-59
Claus S, Fischer J, Mégarbané H, Mégarbané A, Jobard F,
Debret R, Peyrol S, Saker S, Devillers M, Sommer P, Damour
O. A p.C217R mutation in fibulin-5 from cutis laxa patients is
associated with incomplete extracellular matrix formation in a
skin equivalent model. J Invest Dermatol. 2008
Jun;128(6):1442-50
Guadall A, Orriols M, Rodríguez-Calvo R, Calvayrac O, Crespo
J, Aledo R, Martínez-González J, Rodríguez C. Fibulin-5 is upregulated by hypoxia in endothelial cells through a hypoxiainducible factor-1 (HIF-1α)-dependent mechanism. J Biol
Chem. 2011 Mar 4;286(9):7093-103
Lee YH, Albig AR, Regner M, Schiemann BJ, Schiemann WP.
Fibulin-5 initiates epithelial-mesenchymal transition (EMT) and
enhances EMT induced by TGF-beta in mammary epithelial
cells via a MMP-dependent mechanism. Carcinogenesis. 2008
Dec;29(12):2243-51
Hu Z, Ai Q, Xu H, Ma X, Li HZ, Shi TP, Wang C, Gong DJ,
Zhang X. Fibulin-5 is down-regulated in urothelial carcinoma of
bladder and inhibits growth and invasion of human bladder
cancer cell line 5637. Urol Oncol. 2011 Jul-Aug;29(4):430-5
Söderberg MW, Byström B, Kalamajski S, Malmström A,
Ekman-Ordeberg G. Gene expressions of small leucine-rich
repeat proteoglycans and fibulin-5 are decreased in pelvic
organ prolapse. Mol Hum Reprod. 2009 Apr;15(4):251-7
Møller HD, Ralfkjær U, Cremers N, Frankel M, Pedersen RT,
Klingelhöfer J, Yanagisawa H, Grigorian M, Guldberg P,
Sleeman J, Lukanidin E, Ambartsumian N. Role of fibulin-5 in
metastatic organ colonization. Mol Cancer Res. 2011
May;9(5):553-63
Takacs P, Nassiri M, Viciana A, Candiotti K, Fornoni A, Medina
CA. Fibulin-5 expression is decreased in women with anterior
vaginal wall prolapse. Int Urogynecol J Pelvic Floor Dysfunct.
2009 Feb;20(2):207-11
This article should be referenced as such:
Wang M, Brekken RA. FBLN5 (fibulin 5). Atlas Genet
Cytogenet Oncol Haematol. 2013; 17(12):811-815.
Yue W, Sun Q, Landreneau R, Wu C, Siegfried JM, Yu J,
Zhang L. Fibulin-5 suppresses lung cancer invasion by
Atlas Genet Cytogenet Oncol Haematol. 2013; 17(12)
815