Caron E, Self A J, Hall A
Medical Research Council Laboratory for Molecular Cell Biology, University College London, UK.
Curr Biol. 2000 Aug 24;10(16):974-8. doi: 10.1016/s0960-9822(00)00641-2.
beta2 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 beta2 integrins, but the signaling events that link membrane receptors to integrin activation are poorly understood.
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 alphaMbeta2, 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 alphaMbeta2 induced by phorbol esters, LPS, TNF-alpha or PAF. Finally, Rap1 activation specifically controls the binding properties of alphaMbeta2 towards its physiological ligand, namely the complement-opsonized phagocytic targets.
In macrophages, the Rap1 GTPase regulates activation of the alphaMbeta2 integrin in response to a wide variety of inflammatory mediators.
β2整合素介导炎症和免疫反应的多个方面，包括白细胞与内皮细胞的黏附、巨噬细胞和中性粒细胞中补体介导的吞噬作用，以及细胞毒性T细胞与其靶标之间抗原特异性共轭物的形成。多种炎症介质，如肿瘤坏死因子-α（TNF-α）、血小板活化因子（PAF）、脂多糖（LPS）和其他细菌产物可诱导β2整合素的功能活化，但将膜受体与整合素活化联系起来的信号事件仍知之甚少。
我们在此报告，组成型活性小GTP酶Rap1或R-ras的表达，而非Ras或RalA的表达，足以使巨噬细胞中的补体受体3（CR3）αMβ2功能活化，从而允许吞噬C3bi调理的靶标。抑制Rap1，而非其他Ras样或Rho样小GTP酶，可消除佛波酯、LPS、TNF-α或PAF诱导的αMβ2活化。最后，Rap1活化特异性控制αMβ2与其生理配体（即补体调理的吞噬靶标）的结合特性。
在巨噬细胞中，Rap1 GTP酶响应多种炎症介质调节αMβ2整合素的活化。
