The Rac-GAP Bcr is a novel regulator of the Par complex that controls cell polarity.
The Rac-GAP Bcr is a novel regulator of the Par complex that controls cell polarity.
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DOI：
10.1091/mbc.e13-06-0333
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发表时间：
2013-12
影响因子：
3.3
通讯作者：
Tolias KF
中科院分区：
文献类型：
--
作者：
Narayanan AS;Reyes SB;Um K;McCarty JH;Tolias KF
Par 复合物（Par3、Par6 和 PKCζ）控制细胞极性，这对于许多生物过程至关重要。在这里，我们将 Rac1 GTPase 激活蛋白 Bcr 确定为 Par 复合物的一个组成部分，该复合物通过局部限制 Rac1 和 PKC z 功能来调节极化细胞迁移。细胞极化对于许多生物过程至关重要，包括定向细胞迁移，极性的丧失会导致癌症等病理状况。 Par 复合体（Par3、Par6 和 PKCζ）部分通过将 Rac 特异性鸟嘌呤核苷酸交换因子 T 淋巴瘤侵袭和转移 1 (Tiam1) 招募到专门的细胞位点来控制细胞极性，其中 Tiam1 促进局部 Rac1 激活和细胞骨架重塑。然而，将 Par-Tiam1 复合物活性限制在前缘以在迁移过程中维持细胞极性的机制仍不清楚。我们将 Rac 特异性 GTP 酶激活蛋白 (GAP) 断点簇区域蛋白 (Bcr) 确定为 Par-Tiam1 复合物的新型调节因子。我们发现 Bcr 与 Par 复合体的成员相互作用并抑制 Rac1 和 PKCζ 信号传导。 Bcr 缺失会导致星形胶质细胞迁移更快、更随机，并出现显着的极性缺陷。这些极性缺陷可以通过降低 PKC z 活性或通过表达全长 Bcr 来挽救，但不能通过表达 N 端缺失突变体或同源 Rac-GAP、Abr 来挽救，这两种突变体都无法与 Par 复合物结合。这些结果表明，Bcr 是 Par-Tiam1 复合体的重要成员，通过局部限制 Rac1 和 PKC z 功能来控制极化细胞迁移。
The Par complex (Par3, Par6, and PKCζ) controls cell polarity, which is essential for many biological processes. Here we identify the Rac1 GTPase-activating protein Bcr as an integral member of the Par complex that regulates polarized cell migration by locally restricting both Rac1 and PKCζ function. Cell polarization is essential for many biological processes, including directed cell migration, and loss of polarity contributes to pathological conditions such as cancer. The Par complex (Par3, Par6, and PKCζ) controls cell polarity in part by recruiting the Rac-specific guanine nucleotide exchange factor T-lymphoma invasion and metastasis 1 (Tiam1) to specialized cellular sites, where Tiam1 promotes local Rac1 activation and cytoskeletal remodeling. However, the mechanisms that restrict Par-Tiam1 complex activity to the leading edge to maintain cell polarity during migration remain unclear. We identify the Rac-specific GTPase-activating protein (GAP) breakpoint cluster region protein (Bcr) as a novel regulator of the Par-Tiam1 complex. We show that Bcr interacts with members of the Par complex and inhibits both Rac1 and PKCζ signaling. Loss of Bcr results in faster, more random migration and striking polarity defects in astrocytes. These polarity defects are rescued by reducing PKCζ activity or by expressing full-length Bcr, but not an N-terminal deletion mutant or the homologous Rac-GAP, Abr, both of which fail to associate with the Par complex. These results demonstrate that Bcr is an integral member of the Par-Tiam1 complex that controls polarized cell migration by locally restricting both Rac1 and PKCζ function.