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Mark H Ginsberg - One of the best experts on this subject based on the ideXlab platform.
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Integrin modulation and signaling in leukocyte adhesion and migration
Immunological Reviews, 2007Co-Authors: David M Rose, Ronen Alon, Mark H GinsbergAbstract:: The movement of leukocytes from the blood into peripheral tissues plays a key role in immunity as well as chronic inflammatory and autoimmune diseases. The shear force of blood flow presents special challenges to leukocytes as they establish adhesion on the vascular endothelium and migrate into the underlying tissues. Integrins are a family of cell adhesion and signaling molecules, whose function can be regulated to meet these challenges. The affinity of Integrins for their vascular ligands can be stimulated in subseconds by chemoattractant signaling. This aids in inducing leukocyte adhesion under flow conditions. Further, linkage of these Integrins to the actin cytoskeleton also helps to establish adhesion to the endothelium under flow conditions. In the case of Alpha4beta1 Integrins, this linkage of the Integrin to the cytoskeleton is mediated in part by the binding of paxillin to the Alpha4 Integrin subunit and the subsequent binding of paxillin to the cytoskeleton molecule talin. The movement of leukocytes along the vascular endothelium and in between endothelial cells requires the temporal and spatial regulation of small guanosine triphosphatases, such as Rac1. We describe mechanisms through which Alpha4beta1 Integrin signaling regulates appropriate Rac activation to drive leukocyte migration.
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blocking the α4 Integrin paxillin interaction selectively impairs mononuclear leukocyte recruitment to an inflammatory site
Journal of Clinical Investigation, 2006Co-Authors: Chloe C Feral, Jaewon Han, David M Rose, Norma E Fox, Gregg J Silverman, Kenneth Kaushansky, Mark H GinsbergAbstract:Antagonists to Alpha4 Integrin show promise for several autoimmune and inflammatory diseases but may exhibit mechanism-based toxicities. We tested the capacity of blockade of Alpha4 Integrin signaling to perturb functions involved in inflammation, while limiting potential adverse effects. We generated and characterized mice bearing a Y991A mutation in Alpha4 Integrin [Alpha4(Y991A) mice], which blocks paxillin binding and inhibits Alpha4 Integrin signals that support leukocyte migration. In contrast to the embryonic-lethal phenotype of Alpha4 Integrin-null mice, mice bearing the Alpha4(Y991A) mutation were viable and fertile; however, they exhibited defective recruitment of mononuclear leukocytes into thioglycollate-induced peritonitis. Alpha4 Integrins are essential for definitive hematopoiesis; however, the Alpha4(Y991A) mice had intact lymphohematopoiesis and, with the exception of reduced Peyer's patches, normal architecture and cellularity of secondary lymphoid tissues. We conclude that interference with Alpha4 Integrin signaling can selectively impair mononuclear leukocyte recruitment to sites of inflammation while sparing vital functions of Alpha4 Integrins in development and hematopoiesis.
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blocking the alpha 4 Integrin paxillin interaction selectively impairs mononuclear leukocyte recruitment to an inflammatory site
Journal of Clinical Investigation, 2006Co-Authors: Chloe C Feral, Jaewon Han, David M Rose, Gregg J Silverman, Kenneth Kaushansky, Norma Fox, Mark H GinsbergAbstract:Antagonists to Alpha4 Integrin show promise for several autoimmune and inflammatory diseases but may exhibit mechanism-based toxicities. We tested the capacity of blockade of Alpha4 Integrin signaling to perturb functions involved in inflammation, while limiting potential adverse effects. We generated and characterized mice bearing a Y991A mutation in Alpha4 Integrin [Alpha4(Y991A) mice], which blocks paxillin binding and inhibits Alpha4 Integrin signals that support leukocyte migration. In contrast to the embryonic-lethal phenotype of Alpha4 Integrin-null mice, mice bearing the Alpha4(Y991A) mutation were viable and fertile; however, they exhibited defective recruitment of mononuclear leukocytes into thioglycollate-induced peritonitis. Alpha4 Integrins are essential for definitive hematopoiesis; however, the Alpha4(Y991A) mice had intact lymphohematopoiesis and, with the exception of reduced Peyer's patches, normal architecture and cellularity of secondary lymphoid tissues. We conclude that interference with Alpha4 Integrin signaling can selectively impair mononuclear leukocyte recruitment to sites of inflammation while sparing vital functions of Alpha4 Integrins in development and hematopoiesis.
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an α 4 Integrin paxillin arf gap complex restricts rac activation to the leading edge of migrating cells
Nature Cell Biology, 2005Co-Authors: Naoyuki Nishiya, William B Kiosses, Jaewon Han, Mark H GinsbergAbstract:Formation of a stable lamellipodium at the front of migrating cells requires localization of Rac activation to the leading edge. Restriction of Alpha4 Integrin phosphorylation to the leading edge limits the interaction of Alpha4 with paxillin to the sides and rear of a migrating cell. The Alpha4-paxillin complex inhibits stable lamellipodia, thus confining lamellipod formation to the cell anterior. Here we report that binding of paxillin to the Alpha4 Integrin subunit inhibits adhesion-dependent lamellipodium formation by blocking Rac activation. The paxillin LD4 domain mediates this reduction in Rac activity by recruiting an ADP-ribosylation factor GTPase-activating protein (Arf-GAP) that decreases Arf activity, thereby inhibiting Rac. Finally, the localized formation of the Alpha4-paxillin-Arf-GAP complex mediates the polarization of Rac activity and promotes directional cell migration. These findings establish a mechanism for the spatial localization of Rac activity to enhance cell migration.
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an Alpha4 Integrin paxillin arf gap complex restricts rac activation to the leading edge of migrating cells
Nature Cell Biology, 2005Co-Authors: Naoyuki Nishiya, William B Kiosses, Jaewon Han, Mark H GinsbergAbstract:Formation of a stable lamellipodium at the front of migrating cells requires localization of Rac activation to the leading edge. Restriction of Alpha4 Integrin phosphorylation to the leading edge limits the interaction of Alpha4 with paxillin to the sides and rear of a migrating cell. The Alpha4-paxillin complex inhibits stable lamellipodia, thus confining lamellipod formation to the cell anterior. Here we report that binding of paxillin to the Alpha4 Integrin subunit inhibits adhesion-dependent lamellipodium formation by blocking Rac activation. The paxillin LD4 domain mediates this reduction in Rac activity by recruiting an ADP-ribosylation factor GTPase-activating protein (Arf-GAP) that decreases Arf activity, thereby inhibiting Rac. Finally, the localized formation of the Alpha4-paxillin-Arf-GAP complex mediates the polarization of Rac activity and promotes directional cell migration. These findings establish a mechanism for the spatial localization of Rac activity to enhance cell migration.
Jaewon Han - One of the best experts on this subject based on the ideXlab platform.
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blocking the α4 Integrin paxillin interaction selectively impairs mononuclear leukocyte recruitment to an inflammatory site
Journal of Clinical Investigation, 2006Co-Authors: Chloe C Feral, Jaewon Han, David M Rose, Norma E Fox, Gregg J Silverman, Kenneth Kaushansky, Mark H GinsbergAbstract:Antagonists to Alpha4 Integrin show promise for several autoimmune and inflammatory diseases but may exhibit mechanism-based toxicities. We tested the capacity of blockade of Alpha4 Integrin signaling to perturb functions involved in inflammation, while limiting potential adverse effects. We generated and characterized mice bearing a Y991A mutation in Alpha4 Integrin [Alpha4(Y991A) mice], which blocks paxillin binding and inhibits Alpha4 Integrin signals that support leukocyte migration. In contrast to the embryonic-lethal phenotype of Alpha4 Integrin-null mice, mice bearing the Alpha4(Y991A) mutation were viable and fertile; however, they exhibited defective recruitment of mononuclear leukocytes into thioglycollate-induced peritonitis. Alpha4 Integrins are essential for definitive hematopoiesis; however, the Alpha4(Y991A) mice had intact lymphohematopoiesis and, with the exception of reduced Peyer's patches, normal architecture and cellularity of secondary lymphoid tissues. We conclude that interference with Alpha4 Integrin signaling can selectively impair mononuclear leukocyte recruitment to sites of inflammation while sparing vital functions of Alpha4 Integrins in development and hematopoiesis.
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blocking the alpha 4 Integrin paxillin interaction selectively impairs mononuclear leukocyte recruitment to an inflammatory site
Journal of Clinical Investigation, 2006Co-Authors: Chloe C Feral, Jaewon Han, David M Rose, Gregg J Silverman, Kenneth Kaushansky, Norma Fox, Mark H GinsbergAbstract:Antagonists to Alpha4 Integrin show promise for several autoimmune and inflammatory diseases but may exhibit mechanism-based toxicities. We tested the capacity of blockade of Alpha4 Integrin signaling to perturb functions involved in inflammation, while limiting potential adverse effects. We generated and characterized mice bearing a Y991A mutation in Alpha4 Integrin [Alpha4(Y991A) mice], which blocks paxillin binding and inhibits Alpha4 Integrin signals that support leukocyte migration. In contrast to the embryonic-lethal phenotype of Alpha4 Integrin-null mice, mice bearing the Alpha4(Y991A) mutation were viable and fertile; however, they exhibited defective recruitment of mononuclear leukocytes into thioglycollate-induced peritonitis. Alpha4 Integrins are essential for definitive hematopoiesis; however, the Alpha4(Y991A) mice had intact lymphohematopoiesis and, with the exception of reduced Peyer's patches, normal architecture and cellularity of secondary lymphoid tissues. We conclude that interference with Alpha4 Integrin signaling can selectively impair mononuclear leukocyte recruitment to sites of inflammation while sparing vital functions of Alpha4 Integrins in development and hematopoiesis.
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an α 4 Integrin paxillin arf gap complex restricts rac activation to the leading edge of migrating cells
Nature Cell Biology, 2005Co-Authors: Naoyuki Nishiya, William B Kiosses, Jaewon Han, Mark H GinsbergAbstract:Formation of a stable lamellipodium at the front of migrating cells requires localization of Rac activation to the leading edge. Restriction of Alpha4 Integrin phosphorylation to the leading edge limits the interaction of Alpha4 with paxillin to the sides and rear of a migrating cell. The Alpha4-paxillin complex inhibits stable lamellipodia, thus confining lamellipod formation to the cell anterior. Here we report that binding of paxillin to the Alpha4 Integrin subunit inhibits adhesion-dependent lamellipodium formation by blocking Rac activation. The paxillin LD4 domain mediates this reduction in Rac activity by recruiting an ADP-ribosylation factor GTPase-activating protein (Arf-GAP) that decreases Arf activity, thereby inhibiting Rac. Finally, the localized formation of the Alpha4-paxillin-Arf-GAP complex mediates the polarization of Rac activity and promotes directional cell migration. These findings establish a mechanism for the spatial localization of Rac activity to enhance cell migration.
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an Alpha4 Integrin paxillin arf gap complex restricts rac activation to the leading edge of migrating cells
Nature Cell Biology, 2005Co-Authors: Naoyuki Nishiya, William B Kiosses, Jaewon Han, Mark H GinsbergAbstract:Formation of a stable lamellipodium at the front of migrating cells requires localization of Rac activation to the leading edge. Restriction of Alpha4 Integrin phosphorylation to the leading edge limits the interaction of Alpha4 with paxillin to the sides and rear of a migrating cell. The Alpha4-paxillin complex inhibits stable lamellipodia, thus confining lamellipod formation to the cell anterior. Here we report that binding of paxillin to the Alpha4 Integrin subunit inhibits adhesion-dependent lamellipodium formation by blocking Rac activation. The paxillin LD4 domain mediates this reduction in Rac activity by recruiting an ADP-ribosylation factor GTPase-activating protein (Arf-GAP) that decreases Arf activity, thereby inhibiting Rac. Finally, the localized formation of the Alpha4-paxillin-Arf-GAP complex mediates the polarization of Rac activity and promotes directional cell migration. These findings establish a mechanism for the spatial localization of Rac activity to enhance cell migration.
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phosphorylation of the Integrin α4 cytoplasmic domain regulates paxillin binding
Journal of Biological Chemistry, 2001Co-Authors: Jaewon Han, David M Rose, Shouchun Liu, David D Schlaepfer, Hayes Mcdonald, Mark H GinsbergAbstract:Alpha4 Integrins are essential for embryogenesis, hematopoiesis, inflammation, and immune response possibly because Alpha4 Integrins have distinct signaling properties from other Integrins. Specifically, the Alpha4 cytoplasmic domain binds tightly to paxillin, a signaling adaptor protein, leading to increased cell migration and an altered cytoskeletal organization that results in reduced cell spreading. The Alpha4 tail contains potential phosphorylation sites clustered in its core paxillin binding region. We now report that the Alpha4 tail is phosphorylated in vitro and in vivo. Furthermore, Ser(988) is a major phosphorylation site. Using antibodies specific for Ser(988)-phosphorylated Alpha4, we found the stoichiometry of Alpha4 phosphorylation varied in different cells. However, >60% of Alpha4 was phosphorylated in Jurkat T cells. Phosphorylation at Ser(988) blocked paxillin binding to the Alpha4 tail. A phosphorylation-mimicking mutant of Alpha4 (Alpha4S988D) blocked paxillin binding and reversed the inhibitory effect of Alpha4 on cell spreading. Consequently, Alpha4 phosphorylation is a biochemical mechanism to modulate paxillin binding to Alpha4 Integrins with consequent regulation of Alpha4 Integrin-dependent cellular functions.
Naoyuki Nishiya - One of the best experts on this subject based on the ideXlab platform.
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an α 4 Integrin paxillin arf gap complex restricts rac activation to the leading edge of migrating cells
Nature Cell Biology, 2005Co-Authors: Naoyuki Nishiya, William B Kiosses, Jaewon Han, Mark H GinsbergAbstract:Formation of a stable lamellipodium at the front of migrating cells requires localization of Rac activation to the leading edge. Restriction of Alpha4 Integrin phosphorylation to the leading edge limits the interaction of Alpha4 with paxillin to the sides and rear of a migrating cell. The Alpha4-paxillin complex inhibits stable lamellipodia, thus confining lamellipod formation to the cell anterior. Here we report that binding of paxillin to the Alpha4 Integrin subunit inhibits adhesion-dependent lamellipodium formation by blocking Rac activation. The paxillin LD4 domain mediates this reduction in Rac activity by recruiting an ADP-ribosylation factor GTPase-activating protein (Arf-GAP) that decreases Arf activity, thereby inhibiting Rac. Finally, the localized formation of the Alpha4-paxillin-Arf-GAP complex mediates the polarization of Rac activity and promotes directional cell migration. These findings establish a mechanism for the spatial localization of Rac activity to enhance cell migration.
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an Alpha4 Integrin paxillin arf gap complex restricts rac activation to the leading edge of migrating cells
Nature Cell Biology, 2005Co-Authors: Naoyuki Nishiya, William B Kiosses, Jaewon Han, Mark H GinsbergAbstract:Formation of a stable lamellipodium at the front of migrating cells requires localization of Rac activation to the leading edge. Restriction of Alpha4 Integrin phosphorylation to the leading edge limits the interaction of Alpha4 with paxillin to the sides and rear of a migrating cell. The Alpha4-paxillin complex inhibits stable lamellipodia, thus confining lamellipod formation to the cell anterior. Here we report that binding of paxillin to the Alpha4 Integrin subunit inhibits adhesion-dependent lamellipodium formation by blocking Rac activation. The paxillin LD4 domain mediates this reduction in Rac activity by recruiting an ADP-ribosylation factor GTPase-activating protein (Arf-GAP) that decreases Arf activity, thereby inhibiting Rac. Finally, the localized formation of the Alpha4-paxillin-Arf-GAP complex mediates the polarization of Rac activity and promotes directional cell migration. These findings establish a mechanism for the spatial localization of Rac activity to enhance cell migration.
William B Kiosses - One of the best experts on this subject based on the ideXlab platform.
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an α 4 Integrin paxillin arf gap complex restricts rac activation to the leading edge of migrating cells
Nature Cell Biology, 2005Co-Authors: Naoyuki Nishiya, William B Kiosses, Jaewon Han, Mark H GinsbergAbstract:Formation of a stable lamellipodium at the front of migrating cells requires localization of Rac activation to the leading edge. Restriction of Alpha4 Integrin phosphorylation to the leading edge limits the interaction of Alpha4 with paxillin to the sides and rear of a migrating cell. The Alpha4-paxillin complex inhibits stable lamellipodia, thus confining lamellipod formation to the cell anterior. Here we report that binding of paxillin to the Alpha4 Integrin subunit inhibits adhesion-dependent lamellipodium formation by blocking Rac activation. The paxillin LD4 domain mediates this reduction in Rac activity by recruiting an ADP-ribosylation factor GTPase-activating protein (Arf-GAP) that decreases Arf activity, thereby inhibiting Rac. Finally, the localized formation of the Alpha4-paxillin-Arf-GAP complex mediates the polarization of Rac activity and promotes directional cell migration. These findings establish a mechanism for the spatial localization of Rac activity to enhance cell migration.
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an Alpha4 Integrin paxillin arf gap complex restricts rac activation to the leading edge of migrating cells
Nature Cell Biology, 2005Co-Authors: Naoyuki Nishiya, William B Kiosses, Jaewon Han, Mark H GinsbergAbstract:Formation of a stable lamellipodium at the front of migrating cells requires localization of Rac activation to the leading edge. Restriction of Alpha4 Integrin phosphorylation to the leading edge limits the interaction of Alpha4 with paxillin to the sides and rear of a migrating cell. The Alpha4-paxillin complex inhibits stable lamellipodia, thus confining lamellipod formation to the cell anterior. Here we report that binding of paxillin to the Alpha4 Integrin subunit inhibits adhesion-dependent lamellipodium formation by blocking Rac activation. The paxillin LD4 domain mediates this reduction in Rac activity by recruiting an ADP-ribosylation factor GTPase-activating protein (Arf-GAP) that decreases Arf activity, thereby inhibiting Rac. Finally, the localized formation of the Alpha4-paxillin-Arf-GAP complex mediates the polarization of Rac activity and promotes directional cell migration. These findings establish a mechanism for the spatial localization of Rac activity to enhance cell migration.
R Swingler - One of the best experts on this subject based on the ideXlab platform.
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the effect of anti α4 Integrin antibody on brain lesion activity in ms
Neurology, 1999Co-Authors: Niall Tubridy, Peter O Behan, R Capildeo, Abhijit Chaudhuri, R Forbes, C P Hawkins, J Palace, Basil Sharrack, R A C Hughes, R SwinglerAbstract:OBJECTIVE: To determine the effect of humanized monoclonal antibody against Alpha4 Integrin (reactive with Alpha4beta1 Integrin or very-late antigen-4) on MRI lesion activity in MS. METHODS: A randomized, double-blind, placebo-controlled trial in 72 patients with active relapsing-remitting and secondary progressive MS was performed. Each patient received two IV infusions of anti-Alpha4 Integrin antibody (natalizumab; Antegren) or placebo 4 weeks apart and was followed up for 24 weeks with serial MRI and clinical assessment. RESULTS: The treated group exhibited significantly fewer new active lesions (mean 1.8 versus 3.6 per patient) and new enhancing lesions (mean 1.6 versus 3.3 per patient) than the placebo group over the first 12 weeks. There was no significant difference in the number of new active or new enhancing lesions in the second 12 weeks of the study. The number of baseline-enhancing lesions (i.e., lesions that enhanced on the baseline scan) that continued to enhance 4 weeks following the first treatment was not significantly different between the two groups. The number of patients with acute MS exacerbations was not significantly different in the two groups during the first 12 weeks (9 in the treated group versus 10 in placebo) but was higher in the treatment group in the second 12 weeks (14 versus 3; p = 0.005). The study was not, however, designed to look definitively at the effect of treatment on relapse rate. Treatment was well tolerated. CONCLUSIONS: Short-term treatment with monoclonal antibody against Alpha4 Integrin results in a significant reduction in the number of new active lesions on MRI. Further studies will be required to determine the longer term effect of this treatment on MRI and clinical outcomes.
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the effect of anti Alpha4 Integrin antibody on brain lesion activity in ms the uk antegren study group
Neurology, 1999Co-Authors: Niall Tubridy, Peter O Behan, R Capildeo, Abhijit Chaudhuri, C P Hawkins, J Palace, Basil Sharrack, R A C Hughes, Raeburn B Forbes, R SwinglerAbstract:Objective: To determine the effect of humanized monoclonal antibody against α4 Integrin (reactive with α4β1 Integrin or very-late antigen–4) on MRI lesion activity in MS. Methods: A randomized, double-blind, placebo-controlled trial in 72 patients with active relapsing-remitting and secondary progressive MS was performed. Each patient received two IV infusions of anti-α4 Integrin antibody (natalizumab; Antegren) or placebo 4 weeks apart and was followed up for 24 weeks with serial MRI and clinical assessment. Results: The treated group exhibited significantly fewer new active lesions (mean 1.8 versus 3.6 per patient) and new enhancing lesions (mean 1.6 versus 3.3 per patient) than the placebo group over the first 12 weeks. There was no significant difference in the number of new active or new enhancing lesions in the second 12 weeks of the study. The number of baseline-enhancing lesions (i.e., lesions that enhanced on the baseline scan) that continued to enhance 4 weeks following the first treatment was not significantly different between the two groups. The number of patients with acute MS exacerbations was not significantly different in the two groups during the first 12 weeks (9 in the treated group versus 10 in placebo) but was higher in the treatment group in the second 12 weeks (14 versus 3; p = 0.005). The study was not, however, designed to look definitively at the effect of treatment on relapse rate. Treatment was well tolerated. Conclusions: Short-term treatment with monoclonal antibody against α4 Integrin results in a significant reduction in the number of new active lesions on MRI. Further studies will be required to determine the longer term effect of this treatment on MRI and clinical outcomes.