fibulins: a versatile family of extracellular matrix proteins

REVIEWSTable 3 | The binding properties of fibulin-1 and fibulin-2 for extracellular proteinsInteracting ligand Affinity (K d)* Calcium dependence ‡ Epitope mapped ReferencesFibulin-1Fibronectin 139 nM + Yes 19,45,46Nidogen-1 2–60 nM + Yes 19,50Laminin-1 80 nM + Yes 19Fibrinogen 3 µM ND Yes 63Aggregan, versican 10–30 nM + Yes 61Tropoelastin 18 nM + No 37Endostatin 46 nM – No 57Laminin γ2 chain 20 nM ND Yes 56Laminin α2 chain 14 nM ND Yes 54Connective-tissue growth factor ND ND Yes 66β-amyloid precursor protein ND + Yes 35Fibulin-2Fibronectin 1 µM + Yes 7Nidogen-1 0.5 µM – No 7Perlecan 22 nM ND Yes 52Fibrillin-1 56 nM + Yes 36Tropoelastin 0.6 nM + Yes 37Endostatin 33 nM – No 57Aggrecan, versican 0.1 nM + Yes 62Laminin γ2 chain 20–40 nM ND Yes 56Laminin α2 chain 13 nM ND Yes 54*The affinities were determined using surface plasmon resonance. ‡ The calcium dependence was examined by the addition of EDTA.ND, not determined.MACULAR DEGENERATIVEDISEASEAn incurable eye disease that iscaused by the deterioration ofthe central portion of the retina,which is known as the macula.The disease is heterogeneousand includes the rare heritableforms, the sporadic early-onsetform and the age-related form.expression of the D, but not the C, variant of fibulin-1in patients’ fibroblasts. As fibulin-1 is expressed in thedigits of the developing limb, altering the expression offibulin-1 splice variants is thought to be responsiblefor the digit abnormality 75 . This possibility, however,remains to be tested.As a result of positional cloning, a single mutationin the fibulin-3 gene (FBLN3), which results in anR345W substitution (where W is tryptophan), wasfound to be the cause of two inherited forms of MACULARDEGENERATIVE DISEASE — so-called Malattia Leventineseand Doyne honeycomb retinal dystrophy 21 . Maculardegenerative disease is characterized by extracellulardeposits, which are known as drusen, beneath theretinal pigment epithelium. R345 is located in the lastcbEGF-like domain of fibulin-3 and follows the secondcysteine residue. Interestingly, this mutation infibulin-3 was found in 161 patients from 37 familiesin the initial study, although recent evidence indicatesthat there is molecular heterogeneity within theinherited forms of macular degenerations 76 .Mutations in fibulin-3 are not associated with thesporadic form of early onset drusen or with agerelatedmacular degeneration, which is the mostcommon cause of blindness and is also characterizedby drusen deposition 21 . In both inherited and agerelatedmacular degeneration diseases, fibulin-3 isnot located at the site of drusen formation, but is aberrantlyaccumulated with and/or beneath the retinalpigment epithelium 77 . A R345W mutant fibulin-3protein produced by a mammalian expression systemis misfolded, secreted inefficiently and retained incells 77 . It has therefore been postulated that the misfoldingand aberrant accumulation of fibulin-3 mighthave a role in the etiology of macular degeneration 77 .An essential role for fibulin-5 in elastic-fibre assemblyin vivo was highlighted by the abnormal phenotypesof mice lacking fibulin-5 (REFS 22,23). The mutantmice showed markedly disrupted and disorganizedelastic fibres, which resulted in loose skin, emphysematouslungs and tortuous aortas with loss of function.Fibulin-5, which is expressed in tissues that areenriched in elastic fibres and binds tropoelastin andcell-surface integrins in vitro, is thought to anchor elasticfibres to cells and to be required for elastic-fibreassembly during development. It has also been postulatedthat fibulin-5 might function as a chaperone thattethers tropoelastin to the cell surface during elasticfibreassembly 78 .Although Fbln5-null mice have highly disorganizedelastic fibres in their internal organs, they survive toadulthood. The phenotypes of the mutant mice resemblethose of human patients with cutis laxa — a heterogeneousgroup of disorders that are characterized byloose skin and that have variable internal-organ involvement,such as pulmonary emphysema and cardiovascularabnormalities. This phenotype similarity led to theidentification of a homozygous missense mutationNATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 4 | JUNE 2003 | 487© 2003 Nature PublishingGroup