Identification of a novel cell-adhesive protein spatiotemporally expressed in the basement membrane of mouse developing hair follicle

Kiyozumi, Daiji; Osada, Aki; Sugimoto, Nagisa; Weber, Charles N.; Ono, Yūichi; Imai, Toshio; Okada, Akiko; Sekiguchi, Kiyotoshi

doi:10.1016/j.yexcr.2005.01.020

Cited by 43 publications

(52 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to the RGD-containing proteins examined, ␣8␤1 integrin has been shown to bind to osteopontin, the latency-associated peptide of transforming growth factor-␤, tenascin-W, MAEG, and QBRICK/Frem1 in RGD-dependent manners (9,12,(31)(32)(33). Although the binding affinities for these ligand proteins remain to be determined, the following observations, together with our data, indicate that nephronectin is the most preferred ligand for ␣8␤1 integrin with the highest binding affinity.…”

Section: Discussionsupporting

confidence: 54%

Molecular Basis of the Recognition of Nephronectin by Integrin α8β1

Sato

Uemura

Morimitsu

et al. 2009

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Integrin ␣8␤1 interacts with a variety of Arg-Gly-Asp (RGD)-containing ligands in the extracellular matrix. Here, we examined the binding activities of ␣8␤1 integrin toward a panel of RGD-containing ligands. Integrin ␣8␤1 bound specifically to nephronectin with an apparent dissociation constant of 0.28 ؎ 0.01 nM, but showed only marginal affinities for fibronectin and other RGD-containing ligands. The high-affinity binding to ␣8␤1 integrin was fully reproduced with a recombinant nephronectin fragment derived from the RGD-containing central "linker" segment. A series of deletion mutants of the recombinant fragment identified the LFEIFEIER sequence on the C-terminal side of the RGD motif as an auxiliary site required for high-affinity binding to ␣8␤1 integrin. Alanine scanning mutagenesis within the LFEIFEIER sequence defined the EIE sequence as a critical motif ensuring the high-affinity integrinligand interaction. Although a synthetic LFEIFEIER peptide failed to inhibit the binding of ␣8␤1 integrin to nephronectin, a longer peptide containing both the RGD motif and the LFEIF-EIER sequence was strongly inhibitory, and was ϳ2,000-fold more potent than a peptide containing only the RGD motif. Furthermore, trans-complementation assays using recombinant fragments containing either the RGD motif or LFEIFEIER sequence revealed a clear synergism in the binding to ␣8␤1 integrin. Taken together, these results indicate that the specific high-affinity binding of nephronectin to ␣8␤1 integrin is achieved by bipartite interaction of the integrin with the RGD motif and LFEIFEIER sequence, with the latter serving as a synergy site that greatly potentiates the RGD-driven integrin-ligand interaction but has only marginal activity to secure the interaction by itself.Integrins are a family of adhesion receptors that interact with a variety of extracellular ligands, typically cell-adhesive proteins in the extracellular matrix (ECM).2 They play mandatory roles in embryonic development and the maintenance of tissue architectures by providing essential links between cells and the ECM (1). Integrins are composed of two non-covalently associated subunits, termed ␣ and ␤. In mammals, 18 ␣ and 8 ␤ subunits have been identified, and combinations of these subunits give rise to at least 24 distinct integrin heterodimers.Based on their ligand-binding specificities, ECM-binding integrins are classified into three groups, namely laminin-, collagen-and RGD-binding integrins (2, 3), of which the RGD-binding integrins have been most extensively investigated. The RGD-binding integrins include ␣5␤1, ␣8␤1, ␣IIb␤3, and ␣V-containing integrins, and have been shown to interact with a variety of ECM ligands, such as fibronectin and vitronectin, with distinct binding specificities. The ␣8 integrin subunit was originally identified in chick nerves (4). Integrin ␣8␤1 is expressed in the metanephric mesenchyme and plays a crucial role in epithelial-mesenchymal interactions during the early stages of kidney morphogenesis.

show abstract

Section: Discussionsupporting

confidence: 54%

Molecular Basis of the Recognition of Nephronectin by Integrin α8β1

Sato

Uemura

Morimitsu

et al. 2009

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…For example, interaction between Fras1 and the mesenchymally expressed protein Frem1 is vital to Fras1 localization and function (Kiyozumi et al, 2006). Previous studies in mammalian cell culture have suggested Itga8 as another mesenchymally expressed partner of the Fraser complex (Kiyozumi et al, 2005); indeed, mammalian Itga8 [eMAGE (Richardson et al, 2010)] and zebrafish itga8 (J.C.T., unpublished observations) are expressed in pharyngeal arch mesenchyme. Many other studies have linked endodermal pouching to skeletal morphology (reviewed by Knight and Schilling, 2006).…”

Section: Discussionmentioning

confidence: 96%

fras1shapes endodermal pouch 1 and stabilizes zebrafish pharyngeal skeletal development

et al. 2012

View full text Add to dashboard Cite

SUMMARYLesions in the epithelially expressed human gene FRAS1 cause Fraser syndrome, a complex disease with variable symptoms, including facial deformities and conductive hearing loss. The developmental basis of facial defects in Fraser syndrome has not been elucidated. Here we show that zebrafish fras1 mutants exhibit defects in facial epithelia and facial skeleton. Specifically, fras1 mutants fail to generate a late-forming portion of pharyngeal pouch 1 (termed late-p1) and skeletal elements adjacent to late-p1 are disrupted. Transplantation studies indicate that fras1 acts in endoderm to ensure normal morphology of both skeleton and endoderm, consistent with well-established epithelial expression of fras1. Late-p1 formation is concurrent with facial skeletal morphogenesis, and some skeletal defects in fras1 mutants arise during late-p1 morphogenesis, indicating a temporal connection between late-p1 and skeletal morphogenesis. Furthermore, fras1 mutants often show prominent second arch skeletal fusions through space occupied by late-p1 in wild type. Whereas every fras1 mutant shows defects in late-p1 formation, skeletal defects are less penetrant and often vary in severity, even between the left and right sides of the same individual. We interpret the fluctuating asymmetry in fras1 mutant skeleton and the changes in fras1 mutant skeletal defects through time as indicators that skeletal formation is destabilized. We propose a model wherein fras1 prompts late-p1 formation and thereby stabilizes skeletal formation during zebrafish facial development. Similar mechanisms of stochastic developmental instability might also account for the high phenotypic variation observed in human FRAS1 patients.

show abstract

“…As an extracellular matrix protein, it is in a relevant location with respect to the early stages of HIV-1 exposure through heterosexual sex. With two RGD (arginine-glycine-aspartic acid) and 12 CSPG (chondroitin sulfate proteoglycan) domains, FREM1 variants can potentially exert different functions by differentially interacting with integrin, collagen, and fibronectin through variations in functional domains (26). These are important components of the genital mucosal barrier and play an important role in HIV-1 infection (4,6,7,10,13,14,33,43,51).…”

Section: Discussionmentioning

confidence: 99%

A Genetic Polymorphism of FREM1 Is Associated with Resistance against HIV Infection in the Pumwani Sex Worker Cohort

Luo

Sainsbury

Tuff

et al. 2012

J Virol

View full text Add to dashboard Cite

A subgroup of women enrolled in the Pumwani sex worker cohort remain seronegative and PCR negative for human immunodeficiency virus type 1 despite repeated exposure through high-risk sex work. Studies have shown that polymorphisms of genes involved in antigen presentation and viral restriction factors are associated with resistance to HIV infection. To discover other possible genetic factors underlying this HIV-resistant phenotype, we conducted an exploratory nonbiased, low-resolution, genome-wide single-nucleotide polymorphism (SNP) analysis comparing 60 HIV-resistant women to 48 HIV-infected controls. The SNP minor allele rs1552896, in an intron of FREM1, was significantly associated with the resistant phenotype (P ‫؍‬ 1.68 ؋ 10 ؊5 ; adjusted P ‫؍‬ 2.37 ؋ 10 ؊4 ; odds ratio [OR], 9.51; 95% confidence interval [CI], 2.82 to 32.05). We expanded the sample size by genotyping rs1552896 in the Pumwani cohort and comparing 114 HIV-resistant women to 609 HIV-infected controls and confirmed the association (P ‫؍‬ 1.7 ؋ 10 ؊4 ; OR, 2.67; 95% CI, 1.47 to 4.84). To validate the association in a second cohort, we genotyped 783 women enrolled in a mother-child health study and observed the minor allele of rs1552896 enriched in HIV-uninfected women (n ‫؍‬ 488) compared to HIV-infected enrollees (n ‫؍‬ 295) (P ‫؍‬ 0.036; OR, 1.69; 95% CI, 0.98 to 2.93). Quantitative reverse transcription-PCR showed that FREM1 mRNA was highly expressed in tissues relevant for HIV-1 infection, and immunohistochemical analysis revealed that FREM1 protein is expressed in the ectocervical mucosa of HIV-resistant women. The significant association of rs1552896 with an HIV-resistant phenotype, together with the expression profile of FREM1 in tissues relevant to HIV infection, suggests that FREM1 is a potentially novel candidate gene for resistance to HIV infection.

show abstract

Identification of a novel cell-adhesive protein spatiotemporally expressed in the basement membrane of mouse developing hair follicle

Cited by 43 publications

References 51 publications

Molecular Basis of the Recognition of Nephronectin by Integrin α8β1

Molecular Basis of the Recognition of Nephronectin by Integrin α8β1

fras1shapes endodermal pouch 1 and stabilizes zebrafish pharyngeal skeletal development

A Genetic Polymorphism of FREM1 Is Associated with Resistance against HIV Infection in the Pumwani Sex Worker Cohort

Contact Info

Product

Resources

About