Essential role of microfibrillar-associated protein 4 in human cutaneous homeostasis and in its photoprotection

Kasamatsu, Shinya; Hachiya, Akira; Fujimura, Tsutomu; Sriwiriyanont, Penkanok; Haketa, Keiichi; Visscher, Marty O.; Kitzmiller, W. John; Bello, Alexander; Kitahara, Takashi; Kobinger, Gary P.; Takema, Yoshinori

doi:10.1038/srep00164

Cited by 67 publications

(61 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, molecular interactions between tropoelastin and MFAP4 might positively affect the alignment and maturation of tropoelastin. Because we confirmed previously suggested interactions between MFAP4 and fibrillin-1 (26), it is also possible that MFAP4 together with fibrillin-1 cooperatively promote coacervation.…”

Section: Discussionsupporting

confidence: 75%

“…Together, these observations suggest that MFAP4 may contribute to the elastic fiber assembly and/or maintenance. Indeed, MFAP4 has been found to interact with fibrillin-1 and promote elastic fiber formation in in vitro dermal skin fibroblast cultures (26).In this study, we aimed to verify and further characterize the oligomerization pattern of MFAP4 and its molecular interactions with well established elastic fiber components such as tropoelastin, fibrillin-1 and -2, and LOX. We also used site- 3 The abbreviations used are: LOX, lysyl oxidase; COPD, chronic obstructive pulmonary disease; FReD, fibrinogen-related domain; MAGP, microfibrilassociated glycoprotein; Pn, postnatal day n; SPR, surface plasmon resonance; TBST, TBS with 0.05% Tween; TL5A, tachylectin 5A.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Characterization of Microfibrillar-associated Protein 4 (MFAP4) as a Tropoelastin- and Fibrillin-binding Protein Involved in Elastic Fiber Formation

Pilecki

Holm

Schlosser

et al. 2016

Journal of Biological Chemistry

116

View full text Add to dashboard Cite

MFAP4 (microfibrillar-associated protein 4) is an extracellular glycoprotein found in elastic fibers without a clearly defined role in elastic fiber assembly. In the present study, we characterized molecular interactions between MFAP4 and elastic fiber components. We established that MFAP4 primarily assembles into trimeric and hexameric structures of homodimers. Binding analysis revealed that MFAP4 specifically binds tropoelastin and fibrillin-1 and -2, as well as the elastin cross-linking amino acid desmosine, and that it co-localizes with fibrillin-1-positive fibers in vivo. Site-directed mutagenesis disclosed residues Phe 241 and Ser 203 in MFAP4 as being crucial for type I collagen, elastin, and tropoelastin binding. Furthermore, we found that MFAP4 actively promotes tropoelastin self-assembly. In conclusion, our data identify MFAP4 as a new ligand of microfibrils and tropoelastin involved in proper elastic fiber organization.Elastic fibers are key extracellular matrix structural elements of connective tissues that undergo repeated stretch, such as large arteries and the lung (1). The fibers consist of two major components: an amorphous elastin core surrounded by a sheath of fibrillin-rich microfibrils (2). Elastin is a highly hydrophobic polymer of the soluble precursor tropoelastin (3). Tropoelastin is known to undergo a self-assembly process known as coacervation (4), often believed to be a first step in the process of elastic fiber maturation. Because of the high content of lysine residues within the tropoelastin sequence, its assembly into a polymeric form is stabilized by formation of desmosine crosslinks, catalyzed by the lysyl oxidase (LOX) 3 enzyme family (5).Microfibrils, the other major component of elastic fibers, provide the structural scaffold for the deposition of elastin globules. They consist primarily of fibrillin-1 and fibrillin-2, large glycoproteins with a high degree of homology (6). Apart from fibrillins, numerous accessory proteins have been shown to associate with microfibrils or elastin and promote formation of mature fibers, including fibulins and microfibril-associated glycoproteins (MAGPs) (7-10). The importance of proper elastogenesis has been underscored by gene deficiency studies: mice lacking elastin, LOX, or fibrillin-1 die shortly after birth because of vascular abnormalities (11-13).MFAP4 (microfibrillar-associated protein 4) is an extracellular matrix protein belonging to the fibrinogen-related domain (FReD) family. The family includes several proteins engaged in tissue homeostasis and innate immunity, such as FIBCD1 (fibrinogen C domain-containing 1), ficolins, and angiopoietins (14 -16). The crystal structure of the FReD of several family members has been solved (17-19). The ligand-binding site, designated S1, is described in all the proteins and is located in close proximity to the calcium-binding site. MFAP4 has been reported to form homodimeric structures that further oligomerize, but its definite oligomerization pattern has not been established (20).MFAP4 is conside...

show abstract

Section: Discussionsupporting

confidence: 75%

mentioning

confidence: 99%

Characterization of Microfibrillar-associated Protein 4 (MFAP4) as a Tropoelastin- and Fibrillin-binding Protein Involved in Elastic Fiber Formation

Pilecki

Holm

Schlosser

et al. 2016

Journal of Biological Chemistry

116

View full text Add to dashboard Cite

show abstract

“…The molecular functions of these 3 genes have been defined in previous studies. [53][54][55][56][57] However, the role of these genes in tumorigenesis as well as in regulating cell differentiation has not been intensively explored previously-we are the first to identify their potential oncogenic functions in neuroblastoma by participating the cell differentiation process. More remarkably, we found that all the 3 differentiation-regulating targets of miR449a, MFAP4, PKP4 and TSEN15, are significantly correlated with neuroblastoma patient survival, with high mRNA expression levels of these genes in neuroblastoma tumor specimens correlated with poor patient survival.…”

Section: Discussionmentioning

confidence: 99%

microRNA-449a functions as a tumor suppressor in neuroblastoma through inducing cell differentiation and cell cycle arrest

Zhao

Sung³

et al. 2015

RNA Biology

View full text Add to dashboard Cite

(2015) microRNA-449a functions as a tumor suppressor in neuroblastoma through inducing cell differentiation and cell cycle arrest, RNA Biology, 12:5, 538-554, DOI: 10.1080/15476286.2015 Keywords: cell cycle arrest, differentiation, differentiation therapy, microRNA, neuroblastoma Abbreviations: Bio-control; biotinylated control oligonucleotides; Bio-miR-449a; biotinylated miR-449a mimic; CASP2; Caspase 2; CCNE2; Cyclin E2; CDC25A; cell division cycle 25A; CDK6; cyclin-dependent kinase 6; FDR; false discovery rate; FLOT2; Flotillin 2; GAP43; growth associated protein 43; GAPDH; glyceraldehyde-3-phosphate dehydrogenase; HDAC1; histone deacetylase 1; LEF1; lymphoid enhancer-binding factor 1; MFAP4; microfibril-associated protein 4; miR-449a; microRNA-449a; miRNA; micro-RNA; Oligo; oligonucleotides; PKP4; plakophilin 4; STMN1; stathmin 1; TSEN15; tRNA splicing endonuclease 15 homolog; RA;13-cis retinoic acid microRNA-449a (miR-449a) has been identified to function as a tumor suppressor in several types of cancers. However, the role of miR-449a in neuroblastoma has not been intensively investigated. We recently found that the overexpression of miR-449a significantly induces neuroblastoma cell differentiation, suggesting its potential tumor suppressor function in neuroblastoma. In this study, we further investigated the mechanisms underlying the tumor suppressive function of miR-449a in neuroblastoma. We observed that miR-449a inhibits neuroblastoma cell survival and growth through 2 mechanisms-inducing cell differentiation and cell cycle arrest. Our comprehensive investigations on the dissection of the target genes of miR-449a revealed that 3 novel targets-MFAP4, PKP4 and TSEN15 -play important roles in mediating its differentiation-inducing function. In addition, we further found that its function in inducing cell cycle arrest involves down-regulating its direct targets CDK6 and LEF1. To determine the clinical significance of the miR-449a-mediated tumor suppressive mechanism, we examined the correlation between the expression of these 5 target genes in neuroblastoma tumor specimens and the survival of neuroblastoma patients. Remarkably, we noted that high tumor expression levels of all the 3 miR-449a target genes involved in regulating cell differentiation, but not the target genes involved in regulating cell cycle, are significantly correlated with poor survival of neuroblastoma patients. These results suggest the critical role of the differentiation-inducing function of miR-449a in determining neuroblastoma progression. Overall, our study provides the first comprehensive characterization of the tumor-suppressive function of miR-449a in neuroblastoma, and reveals the potential clinical significance of the miR449a-mediated tumor suppressive pathway in neuroblastoma prognosis.

show abstract

“…A role for MFAP4 in the assembly of microfibrils has previously been proposed, 20 but the elastic laminae in the arteries had the appearance of smooth organized lamellar sheets in both Mfap4 +/+ and Mfap4 −/− mice when investigated by transmission electron microscopy ( Figure II mice presented with normal heart rate (HR), blood pressure, circulating cell number, and blood lipid levels (Tables I and II in …”

Section: Characterization Of the Vascular Phenotype In Mfap4-deficienmentioning

confidence: 99%

MFAP4 Promotes Vascular Smooth Muscle Migration, Proliferation and Accelerates Neointima Formation

Schlosser¹,

Pilecki²,

Hemstra³

et al. 2016

ATVB

101

View full text Add to dashboard Cite

V ascular smooth muscle cell (VSMC) activation and phenotypic switching are critical for remodeling processes in vascular proliferative disorders, including intimal hyperplasia. Both the migratory and proliferative activities of VSMCs, as well as the interplay between the extracellular matrix (ECM) and integrin receptors essentially, contribute to neointimal hyperplasia and restrictive remodeling processes in the vessels.1 Among integrins, the particular role of integrin α V β 3 in the induction of VSMC responses has been shown both in vivo and in vitro.

show abstract

Essential role of microfibrillar-associated protein 4 in human cutaneous homeostasis and in its photoprotection

Cited by 67 publications

References 58 publications

Characterization of Microfibrillar-associated Protein 4 (MFAP4) as a Tropoelastin- and Fibrillin-binding Protein Involved in Elastic Fiber Formation

Characterization of Microfibrillar-associated Protein 4 (MFAP4) as a Tropoelastin- and Fibrillin-binding Protein Involved in Elastic Fiber Formation

microRNA-449a functions as a tumor suppressor in neuroblastoma through inducing cell differentiation and cell cycle arrest

MFAP4 Promotes Vascular Smooth Muscle Migration, Proliferation and Accelerates Neointima Formation

Contact Info

Product

Resources

About