LEUKOCYTE ADHESION DEFICIENCY: An Inherited Defect in the Mac-1, LFA-1, and p150,95 Glycoproteins

Anderson, D. C.; Springer, Timothy A.

doi:10.1146/annurev.me.38.020187.001135

Cited by 1,062 publications

(387 citation statements)

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“…Two such mutations S116P and D209H exemplify the importance of the MIDAS and LIMBS, respectively, of the ␤ 2 I-like domain in ␣ L ␤ 2 ligand binding function (18,19). Many LAD-1 mutations disrupt ␤ 2 integrin biosynthesis or heterodimer formation or generate dysfunctional cell surface-expressed ␤ 2 integrins (17,42). Previously, we reported two LAD-1 mutations, C568R and R571C, in the ␤ 2 that generated ␣ L ␤ 2 variants with precocious ligand binding activity (32).…”

Section: Discussionmentioning

confidence: 99%

Mutation of a Conserved Asparagine in the I-like Domain Promotes Constitutively Active Integrins αLβ2 and αIIbβ3

Cheng

Foo

Shi

et al. 2007

Journal of Biological Chemistry

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The leukocyte ␤ 2 integrins are heterodimeric adhesion receptors required for a functional immune system. Many leukocyte adhesion deficiency-1 (LAD-1) mutations disrupt the expression and function of ␤ 2 integrins. Herein, we further characterized the LAD-1 mutation N329S in the ␤ 2 inserted (I)-like domain. This mutation converted ␣ L ␤ 2 from a resting into a high affinity conformer because ␣ L ␤ 2 N329S transfectants adhered avidly to ligand intercellular adhesion molecule (ICAM)-3 in the absence of additional activating agent. An extended open conformation is adopted by ␣ L ␤ 2 N329S because of its reactivity with the ␤ 2 activation reporter monoclonal antibodies MEM148 and KIM127. A corresponding mutation in ␤ 3 generated constitutively active ␣ IIb ␤ 3 that adhered to fibrinogen. This Asn is conserved in all human ␤ subunits, and it resides before the last helix of the I-like domain, which is known to be important in activation signal propagation. By mutagenesis studies and review of existing integrin structures, we conjectured that this conserved Asn may have a primary role in shaping the I-like domain by stabilizing the conformation of the ␣7 helix and the ␤6-␣7 loop in the I-like domain.The integrins are type I membrane cell adhesion molecules formed non-covalently by two subunits (␣/␤). Despite having no intrinsic enzymatic properties, integrins are bidirectional signal transducers brought about by the recruitment of cytosolic proteins, many of which are signaling proteins, to their relatively short cytoplasmic tails (1). Structural data reveal a composite of distinct domains and folds found in an integrin molecule (2, 3). Out of the 24 human integrins, nine contain in the ␣ subunit an additional inserted (I) domain that is the primary ligand-binding domain of these integrins (1). The I domain has a metal ion-dependent adhesion site (MIDAS) 3 that contains a divalent cation essential for ligand binding. Integrins that lack the I domain (henceforth referred to as I-less integrins) are found to bind ligand via the ␤ propeller of their ␣ subunit and the I-like domain of their ␤ subunit (2, 3). The I-like domain is found in all integrin ␤ subunits, and it is structurally similar to that of the I domain. However, it contains a specificity-determining loop, which was reported to contribute toward ligand binding specificity and integrin ␣␤ subunit association (4), and it has two additional divalent cation-binding sites. The MIDAS of the I-like domain is flanked by the adjacent to MIDAS (ADMIDAS) and the ligand-induced metal-binding site (LIMBS), which serve as negative and positive regulatory sites, respectively (5-7). The conserved coordinating residues that are involved in the three cation-binding sites of the I-like domain are highlighted (Fig. 1A).The leukocyte-restricted ␤ 2 integrins contain four members that differ in their ␣ subunits, the ␣ L ␤ 2 , ␣ M ␤ 2 , ␣ X ␤ 2 , and ␣ D ␤ 2 (1). These integrins maintain a functional immune system by their direct involvement in processes such as leukocyte adhe...

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Section: Discussionmentioning

confidence: 99%

Mutation of a Conserved Asparagine in the I-like Domain Promotes Constitutively Active Integrins αLβ2 and αIIbβ3

Cheng

Foo

Shi

et al. 2007

Journal of Biological Chemistry

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“…Furthermore, c~-(1,3)-fucosylation at the D-GlcpNAc residue ~f 3'-SLN gives sialyl-Lewis x, identified as a functional ligand "or E-, P-and L-selectin. It mediates trafficking and recruitnent of blood-borne leukocytes to endothelial cells during aormal and pathological inflammatory responses to injury md infection [6,7]. The multi-step chemical synthesis of this ~iologically important trisaccharide has been described [8], 9ut it is very laborious.…”

Section: Introductionmentioning

confidence: 99%

Complete synthesis of 3′‐sialyl‐N‐acetyllactosamine by regioselective transglycosylation

Vetere

Paoletti

1996

FEBS Letters

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“…Neutrophils utilize a variety of adhesion molecules (14), but studies employing either genetically manipulated mice (15), antibody blocking studies (16), and studies with adhesion molecule-deficient patients (17) have shown that integrins, in particular ␤ 2 and ␤ 3 , are fundamentally important in adhesive events (16,18). Integrin ligation in neutrophils results in reorganization of the cytoskeleton, cell spreading across an adhesive surface, and release of O 2 Ϫ and granule constituents.…”

mentioning

confidence: 99%

Tumor Necrosis Factor-α Activation of the c-Jun N-terminal Kinase Pathway in Human Neutrophils

Avdi¹,

Nick²,

Whitlock³

et al. 2001

Journal of Biological Chemistry

104

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The intensity and duration of an inflammatory response depends on the balance of factors that favor perpetuation versus resolution. At sites of inflammation, neutrophils adherent to other cells or matrix components are exposed to tumor necrosis factor-␣ (TNF␣). Although TNF␣ has been implicated in induction of pro-inflammatory responses, it may also inhibit the intensity of neutrophilic inflammation by promoting apoptosis. Since TNF␣ is not only an important activator of the stress-induced pathways leading to p38 MAPk and c-Jun N-terminal kinase (JNK) but also a potent effector of apoptosis, we investigated the effects of TNF␣ on the JNK pathway in adherent human neutrophils and the potential involvement of this pathway in neutrophil apoptosis. Stimulation with TNF␣ was found to result in ␤ 2 integrin-mediated activation of the cytoplasmic tyrosine kinases Pyk2 and Syk, and activation of a three-part MAPk module composed of MEKK1, MKK7, and/or MKK4 and JNK1. JNK activation was attenuated by blocking antibodies to ␤ 2 integrins, the tyrosine kinase inhibitors, genistein, and tyrphostin A9, a Pyk2-specific inhibitor, and piceatannol, a Syk-specific inhibitor. Exposure of adherent neutrophils to TNF␣ led to the rapid onset of apoptosis that was demonstrated by augmented annexin V binding and caspase-3 cleavage. TNF␣؊induced increases in annexin V binding to neutrophils were attenuated by blocking antibodies to ␤ 2 integrins, and the caspase-3 cleavage was attenuated by tyrphostin A9. Hence, exposure of adherent neutrophils to TNF␣ leads to utilization of the JNK-signaling pathways that may contribute to diverse functional responses including induction of apoptosis and subsequent resolution of the inflammatory response.The rapid influx of polymorphonuclear leukocytes (neutrophils) into sites of injury is an important component of the acute inflammatory response in humans (1). The resulting adherence and chemotaxis of leukocytes in the appropriate cytokine milieu are not only necessary for efficient clearance of microorganisms (2) but may also participate in appropriate resolution of the inflammatory response through the subsequent induction of cell death by apoptosis.Tumor necrosis factor-␣ (TNF␣), 1 a pluripotent cytokine, is produced by a variety of leukocytes in response to stimulation by lipopolysaccharide (3). In turn, exposure to TNF␣ induces wide ranging biological effects including cell differentiation, proliferation, apoptosis, and multiple pro-inflammatory effects. TNF␣ exerts potent effects on neutrophils that have been suggested to contribute to the inflammatory response in sepsis (4, 5) and the adult respiratory distress syndrome (6). However, TNF␣ also exerts anti-inflammatory effects as demonstrated by an enhanced inflammatory response in TNF␣ Ϫ/Ϫ mice after infection (7), an effect that has been ascribed to the ability of TNF␣ to induce apoptosis in neutrophils (8).Whereas TNF␣ can prime neutrophils in suspension (9, 10), many TNF␣-induced cellular responses, including oxidant release, have been repo...

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LEUKOCYTE ADHESION DEFICIENCY: An Inherited Defect in the Mac-1, LFA-1, and p150,95 Glycoproteins

Cited by 1,062 publications

References 28 publications

Mutation of a Conserved Asparagine in the I-like Domain Promotes Constitutively Active Integrins αLβ2 and αIIbβ3

Mutation of a Conserved Asparagine in the I-like Domain Promotes Constitutively Active Integrins αLβ2 and αIIbβ3

Complete synthesis of 3′‐sialyl‐N‐acetyllactosamine by regioselective transglycosylation

Tumor Necrosis Factor-α Activation of the c-Jun N-terminal Kinase Pathway in Human Neutrophils

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