Disease relevance of MFAP2

• In the lesional skin of pseudoxanthoma elasticum which is an elastin-related disorder, immunoreactivity of MAGP-36 was found in the accumulation of disintegrated elastic fibers [1].
• These results provide evidence that the expression of terminal galactose (beta 1-3)N-acetyl galactosamine structure, positioned on MAGP1 and MAGP2 glycoproteins, is associated with the metastatic potential of human melanoma cells [2].

High impact information on MFAP2

• 2. Here we report the identification of a novel gene encoding a human microfibril-associated glycoprotein (MFAP4), which has been mapped to the SMS region [3].
• Based on the high level of homology, we predicted and further showed that MAGP-1 can also bind to Notch1, cause the release of the extracellular domain, and activate signaling [4].
• Together these results demonstrate for the first time that the microfibrillar proteins MAGP-1 and MAGP-2 can function outside of their role in elastic fibers to activate a cellular signaling pathway [4].
• The interactions of microfibril-associated glycoprotein (MAGP)-2 have been investigated with fibrillins and fibrillin-containing microfibrils [5].
• Co-immunoprecipitation experiments showed that MAGP-1 interacted with biglycan but not decorin in the solution phase [6].

Biological context of MFAP2

• Characterization of the human gene for microfibril-associated glycoprotein (MFAP2), assignment to chromosome 1p36.1-p35, and linkage to D1S170 [7].
• Fragments of tropoelastin corresponding to the N-terminal, C-terminal, and central regions of the molecule were used to characterize the MAGP-1 binding site [8].
• Like the bovine and murine loci, the human gene has eight coding exons, but it contains two alternatively used 5' untranslated exons, whereas only one untranslated exon was described in the bovine and murine Magp genes [7].
• In contrast, approximately 10-fold more MAGP-1 was required to support comparable levels of cell adhesion [9].
• Reduction and alkylation of disulfide bonds in MAGP-1 did not destroy its type VI collagen-binding properties, indicating that the binding site was likely to be in the cysteine-free, N-terminal domain of MAGP-1 [10].

Anatomical context of MFAP2

• Microfibril-associated glycoprotein, MAGP (gene symbol MFAP2), is a component of connective tissue microfibrils and a candidate for involvement in the etiology of inherited connective tissue diseases [7].
• The elastic fiber consists of several components: a central core of alpha-elastin and a microfibrillar sheath containing three components: fibrillin, microfibril-associated glycoprotein, and a 35-kD protein with amine oxidase activity [11].
• Expression of microfibril-associated glycoprotein-1 (MAGP-1) in human epidermal keratinocytes [12].
• MAGP-1 produced by keratinocytes may play some functional role in the formation of dermal matrix organization in the dermis [12].
• The findings indicate that MAGP-1 may mediate a molecular interaction between type VI collagen microfibrils and fibrillin-containing microfibrils, structures which are often found in close proximity to each other in a wide range of extracellular matrices [10].

Associations of MFAP2 with chemical compounds

• MAGP-2 lacks the proline-, glutamine-, and tyrosine-rich sequences and a hydrophobic carboxyl terminus, characteristic of MAGP-1 [13].
• MAGP-1 mRNA levels in cultured keratinocytes during Ca(++)-induced differentiation were enhanced eightfold with a concomitant increase in involucrin (a marker of terminal differentiation) mRNA levels [12].
• Comparison with the previously characterized human MAGP-1 gene showed that structural similarity was largely confined to the exact size, sequence, and junction alignment of the two penultimate exons which encode the first six of the seven cysteine residues that are precisely spaced in both proteins [14].
• MAGP was extractable from tissue homogenates using NaCl, urea, or guanidine hydrochloride solutions, only if a strong reducing agent was present [15].
• MAGP is an acidic glycoprotein with a distinctive amino acid composition, being exceptionally rich in glutamic acid, rich in cystine, and low in glycine [15].

Physical interactions of MFAP2

• Refolding of the purified protein produced a soluble form of MAGP-1 that displayed saturable binding to tropoelastin [8].
• MAGP-1 bound to a region at the N terminus of fibrillin-1 in a calcium-dependent manner [8].

Regulatory relationships of MFAP2

• Decorin and biglycan were found not to inhibit the interaction of pepsin-treated type VI collagen with MAGP-1, indicating that its binding site on the collagen is not close to that for the proteoglycans [10].

Other interactions of MFAP2

• In addition, no evidence of an interaction was observed between MAGP-1 and a tropoelastin construct consisting of domains 17-27 that brackets the kallikrein cleavage site, suggesting a complex mechanism of interaction between the two molecules [8].
• Binding of MAGP-1 was also tested with overlapping recombinant fibrillin-1 fragments [8].
• MAGP and fibrillin were also substrates for transglutaminase, which may provide an important mechanism for stabilizing microfibrillar structure [16].
• Conditions have been defined that permit precise localization within the extracellular matrix of antibodies to MAGP and to elastin, singly and together [17].
• The exon structure of the human MAGP-2 gene. Similarity with the MAGP-1 gene is confined to two exons encoding a cysteine-rich region [14].

Analytical, diagnostic and therapeutic context of MFAP2

• Double immunofluorescence labeling of cultured keratinocytes demonstrated that both anti-MAGP-1 and anti-involucrin antibodies reacted with the identical cells [12].
• RT-PCR and Western blot assays demonstrated the presence of mRNA and the polypeptide of MAGP-1 in cultured keratinocytes [12].
• Immunoblotting with anti-MAGP antiserum identified two additional reactive species, of Mr = 60,000 and Mr approximately 300,000, in tissue extracts [15].
• MAGP did not react with antilysyl oxidase antiserum on immunoblots or by enzyme-linked immunosorbent assay [15].
• We observed the ultrastructural distribution of MAGP-36 by immunoelectron microscopy in human and bovine tissues [18].

References