Abr and Bcr, two homologous Rac GTPase-activating proteins, control multiple cellular functions of murine macrophages
Abr and Bcr, two homologous Rac GTPase-activating proteins, control multiple cellular functions of murine macrophages
复制标题
DOI：
10.1128/mcb.00756-06
复制
发表时间：
2007-02-01
影响因子：
5.3
通讯作者：
Heisterkamp, Nora
中科院分区：
文献类型：
--
作者：
Cho, Young Jin;Cunnick, Jess M.;Heisterkamp, Nora
Rho家族的小GTP酶是吞噬白细胞功能的关键调节剂。Abr和Bcr是同源的多结构域蛋白。它们的C-末端结构域具有GTP酶激活蛋白（GAP）活性，在体外对Rac和Cdc 42具有特异性。为了解决这些完整蛋白质的体内相关性，其中知之甚少，目前的研究检查了小鼠巨噬细胞中Abr和Bcr基因消融的影响。Abr和Bcr的伴随损失诱导已知在Rae控制下的巨噬细胞行为的多种改变。缺乏Abr和Bcr的巨噬细胞表现出一种非典型的，细长的形态，这是由GAP结构域突变体Abr和Bcr在巨噬细胞系中的异位表达和组成型活性Rae在初级巨噬细胞中再现。一个强大的增加，集落刺激因子1（CSF-1）-定向运动中观察到的巨噬细胞缺乏这两种蛋白质，并在响应CSF-1的刺激，Abr和Bcr瞬时易位到质膜。在缺乏这两种蛋白质的巨噬细胞中，调理颗粒的吞噬作用也增加，并与持续的Rae激活相关。Bcr和Abr GAP突变体蛋白定位于吞噬体周围，并诱导明显的吞噬杯形成。这些结果将Abr和Bcr鉴定为迄今为止在原代巨噬细胞中体内特异性负调节Rae功能的唯一GAPS。
Small GTPases of the Rho family are key regulators of phagocytic leukocyte function. Abr and Bcr are homologous, multidomain proteins. Their C-terminal domain has GTPase-activating protein (GAP) activity that, in vitro, is specific for Rac and Cdc42. To address the in vivo relevance of these entire proteins, of which little is known, the current study examined the effect of the genetic ablation of Abr and Bcr in murine macrophages. The concomitant loss of Abr and Bcr induced multiple alterations of macrophage cellular behavior known to be under the control of Rae. Macrophages lacking both Abr and Bcr exhibited an atypical, elongated morphology that was reproduced by the ectopic expression of GAP domain mutant Abr and Bcr in a macrophage cell line and of constitutively active Rae in primary macrophages. A robust increase in colony-stimulating factor 1 (CSF-1)-directed motility was observed in macrophages deficient for both proteins and, in response to CSF-1 stimulation, Abr and Bcr transiently translocated to the plasma membrane. Phagocytosis of opsonized particles was also increased in macrophages lacking both proteins and correlated with sustained Rae activation. Bcr and Abr GAP mutant proteins localized around phagosomes and induced distinct phagocytic cup formation. These results identify Abr and Bcr as the only GAPS to date that specifically negatively regulate Rae function in vivo in primary macrophages.