Leukocyte Adhesion Molecules Deficiency: Its Structural Basis, Pathophysiology and Implications for Modulating the Inflammatory Response

Arnaout, M. Amin

doi:10.1111/j.1600-065x.1990.tb00564.x

Cited by 282 publications

(159 citation statements)

References 162 publications

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“…3 These observations suggest that site-specific modulation of N-glycans on integrin affects its biological functions. Therefore, a detailed mutagenesis study of N-glycans on integrins is indispensable for the elucidation of the complicated mechanisms that are involved in its functional regulation by glycosyltransferases, such as GnT-III, ␣2,6-sialyltransferase, and GnT-V (9,12,13,41).…”

Section: Discussionmentioning

confidence: 91%

“…The interaction between integrin and the extracellular matrix is essential to both physiologic and pathologic events, such as cell migration, development, cell viability, immune homeostasis, and tumorigenesis (2,3). Among the integrin superfamily, ␤1 integrin can combine with 12 distinct ␣ subunits (␣1-11, ␣v) to form heterodimers, thereby acquiring a wide variety of ligand specificity (1,4).…”

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confidence: 99%

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N-Glycosylation of the I-like Domain of β1 Integrin Is Essential for β1 Integrin Expression and Biological Function

Isaji

Sato

Fukuda

et al. 2009

Journal of Biological Chemistry

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N-Glycosylation of integrin ␣5␤1 plays a crucial role in cell spreading, cell migration, ligand binding, and dimer formation, but the detailed mechanisms by which N-glycosylation mediates these functions remain unclear. In a previous study, we showed that three potential N-glycosylation sites (␣5S3-5) on the ␤-propeller of the ␣5 subunit are essential to the functional expression of the subunit. In particular, site 5 (␣5S5) is the most important for its expression on the cell surface. In this study, the function of the N-glycans on the integrin ␤1 subunit was investigated using sequential site-directed mutagenesis to remove the combined putative N-glycosylation sites. Removal of the N-glycosylation sites on the I-like domain of the ␤1 subunit (i.e. the ⌬4-6 mutant) decreased both the level of expression and heterodimeric formation, resulting in inhibition of cell spreading. Interestingly, cell spreading was observed only when the ␤1 subunit possessed these three N-glycosylation sites (i.e. the S4-6 mutant). Furthermore, the S4-6 mutant could form heterodimers with either ␣5S3-5 or ␣5S5 mutant of the ␣5 subunit. Taken together, the results of the present study reveal for the first time that N-glycosylation of the I-like domain of the ␤1 subunit is essential to both the heterodimer formation and biological function of the subunit. Moreover, because the ␣5S3-5/ ␤1S4-6 mutant represents the minimal N-glycosylation required for functional expression of the ␤1 subunit, it might also be useful for the study of molecular structures.Integrin is a heterodimeric glycoprotein that consists of both an ␣ and a ␤ subunit (1). The interaction between integrin and the extracellular matrix is essential to both physiologic and pathologic events, such as cell migration, development, cell viability, immune homeostasis, and tumorigenesis (2, 3). Among the integrin superfamily, ␤1 integrin can combine with 12 distinct ␣ subunits (␣1-11, ␣v) to form heterodimers, thereby acquiring a wide variety of ligand specificity (1, 4). Integrins are thought to be regulated by inside-out signaling mechanisms that provoke conformational changes, which modulate the affinity of integrin for the ligand (5). However, an increasing body of evidence suggests that cell-surface carbohydrates mediate a variety of interactions between integrin and its extracellular environment, thereby affecting integrin activity and possibly tumor metastasis as well (6 -8).Guo et al. (9) reported that an increase in ␤1-6-GlcNAc sugar chains on the integrin ␤1 subunit stimulated cell migration. In addition, elevated sialylation of the ␤1 subunit, because of Ras-induced STGal-I transferase activity, also induced cell migration (10, 11). Conversely, cell migration and spreading were reduced by the addition of a bisecting GlcNAc, which is a product of N-acetylglucosaminyltransferase III (GnT-III), 2 to the ␣5␤1 and ␣3␤1 integrins (12, 13). Alterations of N-glycans on integrins might also regulate their cis interactions with membrane-associated proteins, including the epidermal ...

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Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 99%

N-Glycosylation of the I-like Domain of β1 Integrin Is Essential for β1 Integrin Expression and Biological Function

Isaji

Sato

Fukuda

et al. 2009

Journal of Biological Chemistry

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“…This results in the hereditary disease, leukocyte adhesion deficiency type I (LAD), which is a life-threatening condition. The affected patients usually die at a young age from repeated bacterial infections (Crowley et al, 1980;Arnaout et al, 1982;Springer, 1985;Arnaout, 1990b). This fact shows that other integrins or molecules cannot substitute for all (if any) p,-functions.…”

Section: The Leukocyte Pz-integrinsmentioning

confidence: 99%

Leukocyte Adhesion

Gahmberg

Tolvanen

Kotovuori

1997

European Journal of Biochemistry

207

191

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Leukocyte adhesion is of pivotal functional importance and this has resulted in extensive research and rapid develonient in the field. Leukocyte adhesion involves members of three molecular families: integrins, members of the immunoglobulin superfatnily and carbohydrate binding selectins and sialoadhesins. Recently, considerable structural information on leukocyte integrins and members of the immunoglobulin superfrtinily of adhesion molecules has been obtained. This fact. combined with the identification of several novel adhesion molecules. has increased our understanding o f how they function at the molecular level. Furthermore, the important issue of how integrins are activated to become adhesive is rapidly advancing,.. It is clearly evident that the knowledge accuniulated from basic research will increasingly be applied in clinical medicine. In this review we focus on two iinportant families of adhesion molecules. Norc. This Review will be reprinted in EJR Kei?cw.\ 1997 which will be av;iil;ible in April I99X.A number of different leukocytes are known and most probably more subgroups will be found concomitantly with the development in typing procedures. 111 addition, the cells rnay represent different stages of differentiation. An individual leukocyte m 11 s t be able to interact with a number of fundamentally different cells. often modified in various ways. and sometimes with the extracellular matrix or foreign microbes. These facts may partially be the reason that many different leukocyte adhesion systems and molecules exist. In addition i t is certainly useful for the organism to have a certain redundancy i n adhcsion molecule expression and function. which could seciire vital functions cven if some adhesion functions are lost or weakened.Cellular immunology used to be largely phenomenal and not inolecular. But with the development of monoclonal antibody and inolecular cloning techniques, combined with the rapid advance in structural elucidation. present day immunology is certainly ii molecular science, and in inany respects in the forefiont of modern biomedical research. In fact, a number of dcvelopinents in other fields of present day biomedical research originate from breakthroughs in iinmunology. and an excellent exaniple is leukocyte adhesion. Although much remains poorly understood, adhesion receptor-ligand interactions are now appreciated to such an extent that much can be applied t o several other areas of research.But research on leiikocytc adhesion is not rewarding only from a basic point of view. Undoubtedly. the large interest in this field steins from iiuinerous potential clinical applications. Many of the iniljor diseases affecting mankind. like cardiovnscular disease. stroke, chronic and iicute inflammations. cancer. malaria, and inany bacterial and viral infections directly involve leukocyte adhesion molecules. Therefore. it comes as no surprise

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“…It comprises three heterodimeric structures: CD11a/CD18 (LFA-1), CD11b/CD18 (Mac-1, CR3), and CD11c/CD18 (p150,95, CR4). Each of them is composed of different subunits (CD11abc) and a common 2 subunit (CD18) [8,9]. The function of these glycoproteins on granulocytes has been extensively investigated [8,10,11].…”

Section: Introductionmentioning

confidence: 99%

Chronic smoke exposure alters the phenotype pattern and the metabolic response in human alveolar macrophages

Sköld

Lundahl

Halldén

et al. 1996

Clinical and Experimental Immunology

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SUMMARYSmoking induces a chronic inflammatory process in the lower respiratory tract, where the alveolar macrophages (AM) are the main phagocytes. In the present study, the expressions of different membrane glycoproteins (CD11abc, CD71, CD54, CD14 and CD16) were determined by flow cytometry in AM from smokers and non-smokers after quenching of the intracellular autofluorescence. The metabolic activity of the AM was quantified as a functional test. The expressions of CD11a, CD54 and CD71 were higher in non-smokers' AM than in smokers'. The expressions of CD11b and CD16 were similar between the groups, while the CD11c was higher in smokers' AM compared with nonsmokers'. The expression of CD14 was weak in both groups, therefore there was no clear-cut difference between the background and positively labelled cell populations. The metabolic response after in vitro stimulation with the phorbol ester phorbol myristate acetate (PMA) was higher in non-smokers' than in smokers' AM. Our results indicate that chronic exposure to tobacco smoke influences both the expression of AM membrane antigens and the metabolic activity. AM from non-smokers express a phenotype more related to cell proliferation and an accessory function. In contrast, receptors reflecting adhesion and phagocytosis were unaltered or even increased in smokers' AM. The findings suggest a functional change in the AM population after chronic smoke exposure.

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Leukocyte Adhesion Molecules Deficiency: Its Structural Basis, Pathophysiology and Implications for Modulating the Inflammatory Response

Cited by 282 publications

References 162 publications

N-Glycosylation of the I-like Domain of β1 Integrin Is Essential for β1 Integrin Expression and Biological Function

N-Glycosylation of the I-like Domain of β1 Integrin Is Essential for β1 Integrin Expression and Biological Function

Leukocyte Adhesion

Chronic smoke exposure alters the phenotype pattern and the metabolic response in human alveolar macrophages

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