Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_565


 BM-90;  DANCE;  EFEMP1;  EFEMP2;  EVEC;  H411;  Hemicentin;  Him4;  MBP1;  S15;  T16;  TM14;  UP50;  UPH1

Historical Background

The extracellular matrix (ECM) is very diverse in its nature and composition in vertebrates, and is essential for normal development and maintenance of the microenvironment of embryonic and adult tissues. Many ECM proteins are secreted into extracellular milieu where they aggregate with existing matrix molecules to form supramolecular structures. The functions of the ECM include supporting cells, regulating intercellular communication, controlling cell motility, growth, and development, overseeing wound healing, and directing fibrosis (Albig and Schiemann 2005; de Vega et al. 2009; Timpl et al. 2003). These ECM proteins have been classified into several families based on their domain structures and/or functions, with fibulins now being recognized as one such family of ECM molecules. Fibulins share a common structural organization with tandem repeats of a calcium-binding epidermal growth factor (cbEGF)-like module and a unique C-terminal fibulin-type module (Albig and Schiemann 2005; Gallagher et al. 2005). The first fibulin (fibulin-1) was discovered two decades ago by affinity chromatography as an interacting molecule with the cytoplasmic tail of the ß subunit of the fibronectin receptor (also known as ß1 integrin receptor) (de Vega et al. 2009; Timpl et al. 2003). At first, fibulin-1 was considered to function as a bridging element between ß1 integrin and intracellular molecules. Later, fibulin-1 nucleotide sequencing and immunohistochemistry showed this ECM protein to be secreted and present in the fibril matrix in fibroblasts, and in the blood. Since the discovery of fibulin-1, six additional fibulin family members have been reported. Fibulin-2 was identified from a mouse fibroblast cDNA library by comparative sequence analysis. Fibulin-3 (also known as S1-5, Efemp1) was first isolated from the screening of differentially expressed genes between senescent and quiescent human fibroblasts, and fibulin-4 (also known as Efemp2) was identified as a member of the fibulin family by sequence homology. Fibulin-5 (also known as EVEC, DANCE) was identified independently by searching for genes that regulate the transition of vascular smooth muscle cells from quiescent to proliferative states, and by searching for novel secreted molecules involved in the control of cardiovascular development and disease using signal sequence trap method. Hemicentin-1, the gene product of the him-4 locus in Caenorhabditis elegans, has been designated as fibulin-6 based on its cbEGF-like domain and C-terminal fibulin-type module. Recently, fibulin-7 (also known as TM14) was identified as the newest member of fibulin family by differential hybridization using tooth germ cDNA microarrays (de Vega et al. 2009; Timpl et al. 2003; Gallagher et al. 2005).

Fibulins are ECM proteins that collectively play important roles in the biology of tissue organogenesis and vasculogenesis, as well as in the pathology of fibrogenesis, tumorigenesis, and other genetic diseases. Herein we describe the multifunctional nature of fibulins in regulating the development of cancer and genetic diseases in humans, as well as their interactions with other ECM molecules and regulation of cellular signaling systems.

Fibulin Protein Structure and Their Interaction with Other Proteins

Structurally, fibulins contain a N-terminal (Domain I), which is variable among fibulin family members, and sequential repeats of cbEGF-like modules (Domain II), which is followed by a globular C-terminal fibulin-type module (Domain III) (Fig. 1). The fibulin family can be further subdivided into two distinct subgroups based on their size and the absence or presence of additional functional domains (Albig and Schiemann 2005). For instance, subgroup 1 consists of fibulin-1, fibulin-2, and fibulin-6. Fibulin-1 and fibulin-2 are larger and more structurally complex because they house more cbEGF-like modules in Domain II and three anaphylatoxin (AT) modules in domain I, which are components of the complement system involved in inflammation and defense against parasites. In addition, fibulin-2 has an extra N-terminal domain with that contains cysteine-rich and cysteine-free segments. Fibulin-6 contains largest N-terminal domain with more than 40 repeats of immunoglobulin motifs, six thrombospondin type I repeats, and a von Willebrand factor domain. Subgroup 2 contains the remaining family members, namely, fibulin-3, 4, 5 and fibulin-7, which collectively are smaller and structurally simpler. Fibulin-7 contains a sushi domain, which is known to be involved in protein–protein interactions and in the regulation of the complement system and blood coagulation (de Vega et al. 2009; Timpl et al. 2003; Gallagher et al. 2005). Although fibulins represent a small gene family, their genetic and biological diversity is increased significantly by their propensity to undergo alternative mRNA splicing. Indeed, alternative splicing of fibulin-1 mRNA produces four splice variants (A, B, C, and D) in humans, and two splice variants (C and D) in mice, chickens, zebrafish, and nematodes. Splice variants of fibulin-1 differ exclusively in Domain III, such that fibulin-1A completely lacks this domain, while variants B, C, and D possess varying sequences throughout Domain III. In fibulin-2, the third EGF-like module is either or absent or present via alternative splicing; however, the functional consequences of these two variants remain unknown. Alternative splicing produces five variants of fibulin-3, all of which have a partial or complete absence of Domain I. Like fibulin-3, fibulin-4 also exhibits a splice variant that lacks a signal sequence in Domain I (de Vega et al. 2009; Gallagher et al. 2005).
Fibulins, Fig. 1

Schematic presentation of fibulin family proteins. Fibulins 1, 2, and 6 comprise subgroup 1, while fibulins 3, 4, 5, and 7 comprise subgroup 2. Although fibulins 1–4 are subject to alternative splicing, only fibulin-1 splice variants are shown. Fibulin-5 contains a unique evolutionarily conserved RGD (arginine-glycine-aspartic amino acid) sequence in the first cbEGF-like motif. The 44 immunoglobulin repeats in fibulin-6 are shown. Parenthesized number indicate amino acids present in alternatively spliced fibulin-1C-termini

As a member of the ECM, fibulins interact physically with a growing list of ECM and other secreted proteins in the matrix (Table 1). Fibulin-1 and fibulin-2 are localized in basement membranes in various tissues. Basement membranes are specialized sheet-like structures of the ECM that separates cells from the surrounding connective tissue; they also provide the essential scaffolding for cells and tissues during tissue morphogenesis that affects cell adhesion, migration, proliferation, and differentiation (Yanagisawa and Davis 2010). Basement membranes contain a vast array of proteins, such as laminin, perlecan, nidogen, and other molecules that interact with one another to form supramolecular structures (Yanagisawa and Davis 2010). Fibulin-1 and fibulin-2 bind to several basement membrane components including laminin, nidogen, perlecan, and fibronectin. The extensive network of interactions between basement membrane proteins and fibulin-1 and -2 plays an important scaffold function that supports the integrity and function of tissues. Fibulin-1 and fibulin-2 are also localized in elastic fibers, which provide the scaffold for connective tissues essential for the function of the skin, lungs, arteries, and other organs. The tropoelastins are deposited on microfibrils in an orderly manner and cross-linked by  lysyl oxidases (LOXs) during the elastic fiber assembly (de Vega et al. 2009; Yanagisawa and Davis 2010). Aggrecan and versican are expressed in cartilage and provide mechanical strength to resist compression in the joints through the formation of large aggregates with hyaluronan that link proteins in the cartilage matrix (de Vega et al. 2009; Yanagisawa and Davis 2010). The binding of fibulin-1 and fibulin-2 to tropoelastin, aggrecan, and versican suggests that these fibulins play an important role in elastic fiber assembly, as well as in the stabilization and function of cartilage matrix. While fibulin-1 and fibulin-2 interact with dozens of proteins, the other members of fibulin family typically display reduced ability to bind other proteins with the notable exception of fibulin-5, which exhibits overlapping binding affinities with fibulin-1 and fibulin-2. Fibulin-7 binds to dentin sialoprotein (Dsp), fibronectin, heparin, and fibulin-1, while no protein interactions have been reported for fibulin-6. Fibulin-3 and fibulin-4 bind to tropoelastin and play important roles in the assembly of elastic fibers during development (de Vega et al. 2009). Fibulin-5 not only binds to tropoelastin, but also interacts physically with a growing list of ECM and secreted proteins through three different mechanisms (Albig and Schiemann 2005; Yanagisawa et al. 2009). First, fibulin-5 binds αvß3, αvß5, α5ß1, α4ß1, and α9ß1 integrins through an integrin-binding RGD motif that is unique amongst the fibulin family. The integrin-binding RGD motif of fibulin-5 is conserved in chicken, mouse, and rat, suggesting an important function in fibulin-5 biology. Second, cbEGF-like domains bind calcium with moderate-to-high affinity, which aids in maintaining protein stability, and in mediating protein–protein interactions. Fibulin-5 binds to LTBP-2 (latent TGF-ß binding protein-2) through cbEGF-like modules, and in doing so, LTBP-2 may determine which microfibrils fibulin-5 becomes deposited on during elastic fiber assembly. The calcium-dependent binding of fibulin-5 to tropoelastin suggests that fibulin-5 structure and function also are dependent on calcium binding by its cbEGF-like domains. Fibulin-5 binds to the monomeric form of elastin through distinct N- and C-terminal elastin-binding regions, and to preexisting matrix scaffolds through cbEGF-like modules. Thus, fibulin-5 serves as an adaptor molecule that links monomeric elastin to matrix scaffolds to facilitate elastic fiber assembly. Fibulin-5 also binds the elastin-binding protein, elastin microfibril interface-located protein (EMILIN)-1, whose genetic ablation in mice induces mild elastinopathy reminiscent of that observed in fibulin-5-deficient mice. Whether fibulin-5 interacts physically with EMILIN-1 via its cbEGF-like domains remains to be determined. Finally, fibulin-5 interacts with apolipoprotein A, extracelluar superoxide dismutase (ecSOD), and lysyl oxidase-like 1, 2, and 3 (LOXL1-3) via its C-terminal fibulin-type module. The interaction between ecSOD and fibulin-5 is required for ecSOD binding to vascular tissues, thereby regulating vascular superoxide levels. The binding of fibulin-5 to LOXL1 appears essential for normal elastogenesis of the uterus, lung, skin, and vasculature. It has been reported that a fibulin-5 fragment lacking its C-terminus cannot be deposited on microfibrils and causes inactivation of the elastogenic activities of the full-length fibulin-5. Interestingly, the concentration of this fibulin-5 fragment actually increases with age, while the presence of full-length fibulin-5 is actually reduced in the skin of mouse. Since elasticity in tissue is thought be reduced with aging, C-terminal truncation of fibulin-5 by proteolysis may be involved in the deterioration of tissue elasticity during aging. Taken together, the extensive interactions of fibulins with other ECM proteins suggests that fibulins are indeed multifunctional proteins that couple the ECM to its formation of supramolecular structures, as well as its regulation of cellular processes.
Fibulins, Table 1

Overview of fibulins: interaction, human pathologies, and cancer association



Interacting proteins

Heritable disease

Cancer association



Fibronectin, fibrinogen, nidogen



Laminin, aggrecan, versican

Giant platelet syndrome

Extracellular matrix protein1 (ECM1)

Vitroretinal dystrophy

Angiogenin, tropoelastin

ADAMTS-1(disintegrin-like and metalloproteinase with thrombospondin motifs), fibulin-7,

Sex-hormone binding globulin (SHBG)

ß-amyloid precursor protein



αIIß3, αVß3 integrin, laminin,



Fibrilin, fibronectin, nidogen

Aggrecan, versican, prelecan, SHBG




Malattia leventinese



Doyne honeycomb retinal dystrophy


Age-related macular degeneration




Autosomal recessive cutis laxa



Mutant p53



Aortic aneyrysm




Tropoelastin, Lox-like protein-1 (Loxl-1), Loxl-2, Loxl-4, emilin-1, fibrilin-1

Autosomal dominant cutis laxa



Latent TGF-ß binding protein 2 (LTBP2)

Age-related macular degeneration


Extracellular superoxide dismutase

(ecSOD), Lipoprotein A,

αVß1, αVß3, αVß5, α4ß1, α9ß1 integrin



Not available

Age-related macular degeneration (uncertain)

Not described




Fibronectin, heparin, fibulin-1


Not described

Dentin sialoprotein (DSP)

Fibulins and Cancer

Oncogenic and tumor suppressive roles of fibulin family members have been proposed (Albig and Schiemann 2005; Gallagher et al. 2005; Argraves et al. 2003). A tumor suppressive role for fibulin-1 was proposed due to the fact that the overexpression of fibulin-1D in fibrosarcoma cells lowered their ability to grow in soft agar and invade reconstituted basement membranes in vitro. More importantly, expression of fibulin-1D delayed tumor formation in vivo and inhibited papillomavirus-E6 protein-mediated transformation. These findings support the conclusion that fibulin-1D acts as a tumor suppressor. However, fibulin-1 protein expression is progressively increased in the stroma adjacent to carcinoma cells during ovarian tumor progression. In addition, increased expression of fibulin-1 mRNA and protein was observed in primary breast carcinomas as compared with normal breast tissue. Furthermore, findings from DNA microarray studies of lung adenocarcinomas showed that fibulin-1 is consistently associated with matrix metalloproteinase 2 expression, a protein that promotes tumor invasion and metastasis (Gallagher et al. 2005; Argraves et al. 2003). These findings seem paradoxical to the idea that fibulin-1 is the product of a tumor suppressor gene. An explanation may come from findings that fibulin-1C and fibulin-1D splice variants are differentially expressed in ovarian carcinomas. Of the four fibulin-1 splice variants, fibulin-1C and -1D transcripts are predominately expressed in most cell and tissue types, and it was shown that the ratio of fibulin-1C to -1D mRNA is increased in ovarian carcinomas relative to normal ovaries, suggesting that the fibulin-1C variant might play a role in carcinogenesis. In fact, it has been hypothesized that fibulin-1C variants possess oncogenic properties, while fibulin-1D variants exhibit tumor suppressive properties. Along these lines, genetic alterations of fibulin-1D have been linked to a congenital disorder that is typified by limb malformations, suggesting a functional independence of fibulin-1C and fibulin-1D variants. Precisely how fibulin-1C and fibulin-1D differentially impact cell behavior remains unknown. The splice variants of fibulin-1 all share the first 566 residues from the N-terminus, at which point they diverge to encode differing C-terminal polypeptide segments that add 0 (1A), 35 (1B), 117 (1C), and 137 (1D) residues, respectively. Thus, the difference in the C-terminal fibulin-type modules between fibulin-1 splice variants may account for the differential functions of fibulin-1C and fibulin-1D, possibly by modifying the repertoire of protein–protein interaction signatures. Likewise, a second possible mechanism to explain the imbalances that favor fibulin-1C expression over that of fibulin-1D in tumors has recently been proposed. Indeed, fibulin-1 expression is regulated by estrogen and its receptor at both the transcriptional and posttranscriptional levels in ovarian cancer cell lines. While estradiol treatment selectively decreased the half-life of fibulin-1D mRNA, the same treatment had no effect on fibulin-1C mRNA in ovarian cancer cells in vitro. This suggests that the oncogenic and tumor suppressive roles of fibulin-1 are governed by variant-specific expression in response to estrogens, which specifically destabilizes fibulin-1D mRNA. At present, the generality of this mechanism to other types of tumors, including those of breast, remains to be determined definitively.

To date, there exists little evidence that links fibulin-2, -6, and -7 with cancer; however, elevated fibulin-2 expression has been associated with the acquisition of metastatic phenotypes during adenocarcinoma progression. Fibulin-3 expression is altered in some human tumors and its constitutive expression in endothelial cells inhibited their proliferation, invasion, and angiogenic sprouting, as well as their response to vascular endothelial growth factor (Albig et al. 2006). The rat homologue of fibulin-3 associates with DA41, which interacts with the tumor suppressor protein DAN. Thus, fibulin-3 might have an indirect role in regulating cell growth through a network of molecular interactions. In addition, fibulin-3 prevented angiogenesis and vessel infiltration, as well as decreased vessel growth and density in tumors produced by MCA102 fibrosarcoma cells (Albig et al. 2006). Fibulin-4 expression is elevated in human colon tumors. Although fibulin-4 is clearly a secreted protein, recent work has identified a mutation in its signal sequence (i.e., Ala5Thr) that prevents its efficient secretion from cells, raising the possibility that aberrant subcellular localization of fibulin-4 contributes to tumorigenesis in humans. Accordingly, the intracellular form of fibulin-4 enhances cellular transformation and proliferation by interacting physically with mutant  p53 proteins. Fibulin-5 was identified independently as a novel fibroblast and endothelial cell gene target of the tumor suppressor, transforming growth factor (TGF)-ß (Albig and Schiemann 2005). Fibulin-5 mRNA expression is downregulated dramatically in the majority of human tumors, such as kidney, breast, ovary, and colon compared to corresponding normal tissues. Also, fibulin-5 has been established as a multifunctional signaling molecule that (1) regulates the proliferation, motility, and invasion of normal and malignant cells both in vitro and in vivo; (2) antagonizes endothelial cell activities coupled to angiogenesis both in vitro and in vivo; and (3) inhibits the growth of fibrosarcomas in mice (Lee et al. 2008). These findings suggest that the loss or inactivation of fibulin-5 may participate in cancer progression. Epithelial-mesenchymal transition (EMT) is a normal physiological process that regulates tissue development, remodeling, and repair; however, aberrant EMT also elicits disease development in humans, including lung fibrosis, rheumatoid arthritis, and cancer metastasis (Wendt et al. 2009). TGF-ß is a master regulator of EMT in normal mammary epithelial cells (MECs), wherein this pleiotropic cytokine also functions as a potent suppressor of mammary tumorigenesis (Tian and Schiemann 2009). Since fibulin-5 is expressed in a developmentally regulated manner to regions of EMT during tissue development, and is a target of TGF-ß, fibulin-5 has been considered an important and novel regulator of normal EMT during embryonic development, as well as an inducer of oncogenic EMT during the development and progression of human breast cancers. Indeed, mammary epithelial cells engineered to ectopically expression fibulin-5 acquired an EMT phenotype as measured by monitoring alterations in the actin cytoskeleton, as well as by alterations in the expression of various markers of EMT (Lee et al. 2008). In addition, overexpression of fibulin-5 in 4T1 breast cancer cells increased their invasiveness by enhancing TGF-®-induced EMT and matrix metalloproteinase (MMP) expression (Lee et al. 2008). These alterations led to increased tumor growth in vivo when these cells were implanted into normal wild-type mice. Given the differential effects of fibulin-5 on cells of epithelial versus mesenchymal origin, the overall effect of fibulin-5 on tumor development must be carefully evaluated. Taken together, these findings suggest that fibulins play important roles in tumor development by functioning as tumor suppressors or tumor promoters through mechanisms that remain to be fully elucidated.

Fibulins and Human Genetic Diseases

Several human genetic diseases associated with the mutation of fibulin genes have been identified (Table 1). For instance, the fibulin-1 gene is disrupted in patients from one family with a rare dominantly inherited malformation of the distal limbs. Moreover, it has been reported that a defect in fibulin-1D expression is associated with the autosomal dominant giant platelet syndromes, which represent a group of disorders with combinations of deafness, renal disease, and eye abnormalities (de Vega et al. 2009; Gallagher et al. 2005; Argraves et al. 2003). Both genetic diseases are caused by the specific absence fibulin-1D transcripts, suggesting that the C-terminal fibulin-type motif of fibulin-1 plays an important causative role in initiating these pathologies. Along these lines, mice lacking fibulin-1 expression die shortly after birth, suggesting an essential function of this ECM in organism survival. In stark contrast, no human diseases have been linked to fibulin-2, and as such, fibulin-2 knockout mice are viable, fertile, and free of anatomic abnormalities (de Vega et al. 2009; Gallagher et al. 2005; Argraves et al. 2003). These findings suggest that fibulin-2 possesses functional redundancy with other matrix proteins that compensate for the absence of fibulin-2 during development. A fibulin-3 missense mutation (R345W) is associated with malattia leventinese (ML), which is a dominant macular degenerative disease characterized by the appearance of yellow deposits beneath the retinal pigment epithelium. The association of fibulin-3 mutation with ML was further supported by knock-in mice containing the R345W mutation, which develop early onset of macular degeneration in both heterozygous and homozygous mice. A fibulin-4 missense mutation (G169A) is associated with autosomal recessive cutis laxa, which is a connective tissue disorder characterized by cutaneous abnormalities such as loose skin. This mutation also affects elastic fiber densities in internal organs, such as the lung and the arteries. Moreover, fibulin-4 knockout mice showed lung and vascular malformations due to defects in elastic fiber formation, indicating a key role of fibulin-4 in vascular homeostasis.

Defects in the fibulin-5 gene are associated with cutis laxa and age-related macular degeneration (AMD). Two homozygous missense mutations (S227P and C217R) have been found in autosomal recessive cutis laxa families. Both fibulin-5 mutations decrease its binding to tropoelastin; they also significantly decreased its synthesis and secretion from cells, as well as impaired its association with fibrillin-1. As expected, defects in elastic fiber development were also evident under these conditions, suggesting that fibulin-5 is essential for proper elastic fiber formation. Accordingly, fibulin-5 knockout mice developed disorganized elastic fibers, which is reminiscent of the cutis laxa syndrome observed in humans that express fibulin-5 mutants. Heterozygous missense variations in fibulin-5 (G412E, G267S, I169 T, and Q124P) are associated with AMD and showed decreased fibulin-5 secretion. However, the causal relationship between heterozygous missense mutations in fibulin-5 and AMD needs to be further investigated. Fibulin-6 mutation (Q5346R) is proposed as a causal mutation for AMD pedigree; however, there is no supporting evidence for this hypothesis. At present, no human diseases have yet to be associated with the fibulin-7.


The fibulin family is comprised of matricellular proteins that clearly contribute to the structural development of elastogenic tissues, as well as mediate various cellular functions required for the maintenance of tissue homeostasis. Seven fibulin family members have been found in mammals, all of which interact with various ECM molecules to stabilize supramolecular structures and to oversee various cellular processes, such as cell growth, differentiation, angiogenesis, and tumorigenesis. The variety of cellular activities attributed to fibulins are often cell-type specific and/or in a context-dependent manner, suggesting that the specific interactions between fibulins and ECM proteins leads to various cell behaviors and outcomes. Therefore, it remains to be determined precisely how fibulins mediate or antagonize intracellular signaling events and whether the modulation of fibulins possesses therapeutic potential to alleviate fibulins-related pathologies. Finally, new insight into the regulated steps of elastic fiber assembly from the study of fibulins may provide new opportunities to explore novel therapeutic regimens, including the regeneration of damaged elastic fibers, the prevention of elastic fiber-degenerative conditions, and the development of efficient artificial blood vessels.


  1. Albig AR, Schiemann WP. Fibulin-5 function during tumorigenesis. Future Oncol. 2005;1(1):23–35.PubMedCrossRefGoogle Scholar
  2. Albig AR, Neil JR, Schiemann WP. Fibulins 3 and 5 antagonize tumor angiogenesis in vivo. Cancer Res. 2006;66(5):2621–9.PubMedCrossRefGoogle Scholar
  3. Argraves WS, Greene LM, Cooley MA, Gallagher WM. Fibulins: physiological and disease perspectives. EMBO Rep. 2003;4(12):1127–31.PubMedPubMedCentralCrossRefGoogle Scholar
  4. de Vega S, Iwamoto T, Yamada Y. Fibulins: multiple roles in matrix structures and tissue functions. Cell Mol Life Sci. 2009;66(11–12):1890–902.PubMedCrossRefGoogle Scholar
  5. Gallagher WM, Currid CA, Whelan LC. Fibulins and cancer: friend or foe? Trends Mol Med. 2005;11(7):336–40.PubMedCrossRefGoogle Scholar
  6. 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;29(12):2243–51.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Tian M, Schiemann WP. The TGF-beta paradox in human cancer: an update. Future Oncol. 2009;5(2):259–71.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Timpl R, Sasaki T, Kostka G, Chu ML. Fibulins: a versatile family of extracellular matrix proteins. Nat Rev Mol Cell Biol. 2003;4(6):479–89.PubMedCrossRefGoogle Scholar
  9. Wendt MK, Allington TM, Schiemann WP. Mechanisms of the epithelial-mesenchymal transition by TGF-beta. Future Oncol. 2009;5(8):1145–68.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Yanagisawa H, Davis EC. Unraveling the mechanism of elastic fiber assembly: the roles of short fibulins. Int J Biochem Cell Biol. 2010;42(7):1084–93.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Yanagisawa H, Schluterman MK, Brekken RA. Fibulin-5, an integrin-binding matricellular protein: its function in development and disease. J Cell Commun Signal. 2009;3(3–4):337–47.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Case Comprehensive Cancer CenterCase Western Reserve UniversityClevelandUSA