The International Journal of Biochemistry & Cell Biology
ReviewUnraveling the mechanism of elastic fiber assembly: The roles of short fibulins
Introduction
Tissues such as the aorta, lungs and skin need to be resistant to mechanical strain and yet remain extensible throughout life to function. This characteristic feature of elastic tissues is provided by a network of elastic fibers, which allows the tissues to stretch and recoil without damage. Elastic fibers begin to form at midgestation and are completed during postnatal development, with no new elastic fiber formation in the adult (Ritz-Timme et al., 2003). Elastic fibers are generally considered to be non-self renewing extracellular structures. Defects in the elastic fiber formation or accelerated degradation of elastic fibers result in a myriad of pathological conditions, including cutis laxa, arterial tortuosity, pulmonary emphysema and pelvic organ prolapse. It is also known that elastic fibers undergo normal age-related changes, leading to loose skin, stiff vessels and an increase in pulse pressure. Elastic fibers are comprised of polymerized tropoelastin monomers surrounded by a mantle of microfibrils (reviewed in Wagenseil and Mecham (2007)). More than 30 elastic fiber-associated proteins have been identified and considerable effort has been put forth to determine biochemical and functional properties of these molecules (Kielty et al., 2002) (Table 1). Elastic fibers are formed in a regulated, stepwise manner, which includes the formation of a microfibrillar scaffold, deposition and integration of tropoelastin monomers into the scaffold, and cross-linking of the monomers to form an insoluble, functional polymer (Wagenseil and Mecham, 2007). As more information on the function of elastic fiber-associated proteins becomes available through protein–protein interaction studies and functional analyses, the molecular mechanisms of elastic fiber assembly will be revealed. Additionally, gene knockout studies in mice have revealed critical roles for elastic fiber-associated proteins in elastic fiber formation. In this review, we will focus on recent publications and update our knowledge on the role of the emerging family of fibulin proteins in the process of elastic fiber assembly. We will discuss how these proteins interact with components of elastic fibers and participate in formation and stabilization of the fiber. Lastly, we will discuss what we have learned from loss-of-function studies in mice and genetic studies in humans.
Section snippets
Short fibulins
Seven fibulins have been identified to date since the discovery of the fibulin-1 prototype (Argraves et al., 1989, de Vega et al., 2009). Fibulins can be divided into class I and class II based on length and domain structures (Yanagisawa et al., 2009). Class II fibulins, or so-called short fibulins, include fibulin-3 (encoded by the gene EFEMP1, also called S1-5), fibulin-4 (encoded by the gene EFEMP2, also called H411 or MBP1), fibulin-5 (also called EVEC or DANCE) and fibulin-7 (also called
Secretion and coacervation of tropoelastin
Tropoelastin is a 70-kDa protein and synthesized by elastogenic cells, including skin fibroblasts, lung alveolar cells, chondrocytes and vascular SMCs. Tropoelastin can bind cell surface galactosaminoglycans via its C-terminus (Broekelmann et al., 2005) or to cell surface αvβ3 integrins via a C-terminal GRKRK motif (Bax et al., 2009). Whereas assembly of fibronectin fibrils or collagen fibrils occurs near cell surface and involves matrix–cell interactions (Mao and Schwarzbauer, 2005),
Biochemical basis of the elastogenic activity of fibulins
Severe elastinopathic phenotypes in mice deficient in the short fibulin genes revealed their critical roles in elastogenesis in vivo. Fibulin-5 has been shown to exert strong elastogenic activity in various experimental systems. For example, recombinant fibulin-5 increases formation of elastic fibers in in vitro elastogenesis assays using primary human skin fibroblasts (Hirai et al., 2007b). Overexpression of Fbln5 increases deposition of elastic fibers and the level of the elastin-specific
Insight from knockout mouse models
Differences in biochemical properties, spatial and temporal gene expression and protein distribution among the short fibulins contribute to distinct phenotypes when perturbed in vivo. Knockout mice of elastogenic short fibulins have been generated and shown to exhibit non-overlapping phenotypes in vivo (McLaughlin et al., 2006, McLaughlin et al., 2007, Nakamura et al., 2002, Yanagisawa et al., 2002). Fbln3−/− mice have normal embryonic development but exhibit reduced reproductivity and show an
Conclusions and perspectives
Short fibulins possess potent elastogenic activity in vitro and in vivo and play essential roles in elastic fiber formation. As more information on protein–protein interactions and preferential binding partners for fibulins and other elastic fiber-associated proteins becomes available, the gaps in our current understanding of the process of elastic fiber assembly will be filled. In addition, how short fibulins are differentially expressed in the various elastogenic tissues and whether a
Acknowledgements
This work was supported by grants from National Institutes of Health (HL071157 to HY), American Heart Association (HY), Welch Foundation (HY), National Marfan Foundation (HY), Canadian Institutes of Health (MOP57663 and MOP86713 to ECD) and Natural Sciences and Engineering Research Council of Canada (RGPIN 35710-08 to ECD). ECD is a Canada Research Chair.
References (100)
- et al.
Fibulin, a novel protein that interacts with the fibronectin receptor beta subunit cytoplasmic domain
Cell
(1989) - et al.
Cell adhesion to tropoelastin is mediated via the C-terminal GRKRK motif and integrin alphaVbeta3
J Biol Chem
(2009) - et al.
Tropoelastin interacts with cell-surface glycosaminoglycans via its COOH-terminal domain
J Biol Chem
(2005) - et al.
Fibrillins 1 and 2 perform partially overlapping functions during aortic development
J Biol Chem
(2006) - et al.
Analysis of dermal elastic fibers in the absence of fibulin-5 reveals potential roles for fibulin-5 in elastic fiber assembly
Matrix Biol
(2009) - et al.
Differential regulation of elastic fiber formation by fibulin-4 and -5
J Biol Chem
(2009) - et al.
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) - et al.
TM14 is a new member of the fibulin family (fibulin-7) that interacts with extracellular matrix molecules and is active for cell binding
J Biol Chem
(2007) - et al.
Pelvic organ prolapse in Fibulin-5 knockout mice: pregnancy changes in elastic fiber homeostasis in mouse vagina
Am J Pathol
(2007) - et al.
Cloning, expression and characterization of the murine Efemp1, a gene mutated in Doyne–Honeycomb retinal dystrophy
Gene Exp Patterns
(2003)
Fibrillin-1 interactions with fibulins depend on the first hybrid domain and provide an adaptor function to tropoelastin
J Biol Chem
Homozygous missense mutation in fibulin-5 in an Iranian autosomal recessive cutis laxa pedigree and associated haplotype
J Invest Dermatol
Cellular fibronectin binds to lysyl oxidase with high affinity and is critical for its proteolytic activation
J Biol Chem
Human fibulin-4: analysis of its biosynthetic processing and mRNA expression in normal and tumour tissues
FEBS Lett
Sequence, recombinant expression and tissue localization of two novel extracellular matrix proteins, fibulin-3 and fibulin-4
Matrix Biol
Structural and functional properties of the human notch-1 ligand binding region
Structure
Bacterial lipopolysaccharide induces expression of the stress response genes hop and H411
J Biol Chem
LTBP-2 specifically interacts with the amino-terminal region of fibrillin-1 and competes with LTBP-1 for binding to this microfibrillar protein
Matrix Biol
Lysyl oxidase is required for vascular and diaphragmatic development in mice
J Biol Chem
Fibronectin binds and enhances the activity of bone morphogenetic protein 1
J Biol Chem
Fibulin-4: a novel gene for an autosomal recessive cutis laxa syndrome
Am J Hum Genet
Elastic fiber assembly is disrupted by excessive accumulation of chondroitin sulfate in the human dermal fibrotic disease, keloid
Biochem Biophys Res Commun
Versican interacts with fibrillin-1 and links extracellular microfibrils to other connective tissue networks
J Biol Chem
Latent transforming growth factor beta-binding protein 1 interacts with fibrillin and is a microfibril-associated protein
J Biol Chem
Vascular extracellular matrix and aortic development
Curr Top Dev Biol
Tissue inhibitor of metalloproteinases-3 (TIMP-3) is a binding partner of epithelial growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1): implications for macular degenerations
J Biol Chem
A comparative analysis of the fibulin protein family. Biochemical characterization, binding interactions, and tissue localization
J Biol Chem
Microfibril-associated MAGP-2 stimulates elastic fiber assembly
J Biol Chem
Fibulin-2 and fibulin-5 alterations in tsk mice associated with disorganized hypodermal elastic fibers and skin tethering
J Invest Dermatol
Fibronectin fibrillogenesis, a cell-mediated matrix assembly process
Matrix Biol
Genetic heterogeneity of cutis laxa: a heterozygous tandem duplication within the fibulin-5 (FBLN5) gene
Am J Hum Genet
Structural and functional aspects of calcium binding in extracellular matrix proteins
Matrix Biol
Fibulin-5 distribution in human eyes: relevance to age-related macular degeneration
Exp Eye Res
DANCE, a novel secreted RGD protein expressed in developing, atherosclerotic, and balloon-injured arteries
J Biol Chem
DANCE/fibulin-5 promotes elastic fiber formation in a tropoelastin isoform-dependent manner
Clin Biochem
Latent transforming growth factor beta-binding proteins and fibulins compete for fibrillin-1 and exhibit exquisite specificities in binding sites
J Biol Chem
Effects of fibulin-5 on attachment, adhesion, and proliferation of primary human endothelial cells
Biochem Biophys Res Commun
Failure of pelvic organ support in mice deficient in fibulin-3
Am J Pathol
Distinct steps of cross-linking, self-association, and maturation of tropoelastin are necessary for elastic fiber formation
J Mol Biol
Phenotypic alteration of vascular smooth muscle cells precedes elastolysis in a mouse model of Marfan syndrome
Circ Res
Fibulin-2 and fibulin-5 cooperatively function to form the internal elastic lamina and protect from vascular injury
Arterioscler Throm Vasc Biol
Mutation of the gene encoding fibrillin-2 results in syndactyly in mice
Hum Mol Genet
Fibrillins, fibulins, and matrix-associated glycoprotein modulate the kinetics and morphology of in vitro self-assembly of a recombinant elastin-like polypeptide
Biochemistry
Elastic fiber macro-assembly is a hierarchical, cell motion-mediated process
J Cell Physiol
Dual functions for LTBP in lung development: LTBP-4 independently modulates elastogenesis and TGF-beta activity
J Cell Physiol
Compound heterozygous mutations in fibulin-4 causing neonatal lethal pulmonary artery occlusion, aortic aneurysm, arachnodactyly, and mild cutis laxa
Am J Med Genet A
Fibulins: multiple roles in matrix structures and tissue functions
Cell Mol Life Sci
Fibulin-5 interacts with fibrillin-1 molecules and microfibrils
Biochem J
MBP1: a novel mutant p53-specific protein partner with oncogenic properties
Oncogene
Latent TGF-beta-binding protein 2 binds to DANCE/fibulin-5 and regulates elastic fiber assembly
EMBO J
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