The GTPase Rap1 controls functional activation of macrophage integrin αMβ2 by LPS and other inflammatory mediators

被引:217
作者
Caron, E
Self, AJ
Hall, A
机构
[1] UCL, MRC, Mol Cell Biol Lab, London WC1E 6BT, England
[2] UCL, Dept Biochem & Mol Biol, London WC1E 6BT, England
基金
英国惠康基金;
关键词
D O I
10.1016/S0960-9822(00)00641-2
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Background: beta 2 integrins mediate many aspects of the inflammatory and immune responses, including adhesion of leukocytes to the endothelium, complement-mediated phagocytosis in macrophages and neutrophils, and antigen-specific conjugate formation between cytotoxic T cells and their targets. A variety of inflammatory mediators, such as tumor necrosis factor-alpha (TNF-alpha), platelet-activating factor (PAF), and lipopolysaccharide (LPS) and other bacterial products induce the functional activation of beta 2 integrins, but the signaling events that link membrane receptors to integrin activation are poorly understood. Results: We report here that expression of the constitutively active small GTPases Rap1 or R-ras, but not Ras or RalA, is sufficient for functional activation of alpha M beta 2, the complement receptor 3 (CR3), in macrophages, allowing phagocytosis of C3bi-opsonized targets. Inhibition of Rap1, but not other Ras-like or Rho-like small GTPases, abolishes activation of alpha M beta 2 induced by phorbol esters, LPS, TNF-alpha or PAF. Finally, Rap1 activation specifically controls the binding properties of alpha M beta 2 towards its physiological ligand, namely the complement-opsonized phagocytic targets. Conclusions: In macrophages, the Rap1 GTPase regulates activation of the alpha M beta 2 integrin in response to a wide variety of inflammatory mediators.
引用
收藏
页码:974 / 978
页数:5
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