Cell Signaling and Developmental Biology Laboratory, Department of Biological Sciences, National University of Singapore, Singapore 117543, Republic of Singapore.
Mol Biol Cell. 2013 Jan;24(2):145-56. doi: 10.1091/mbc.E12-04-0300. Epub 2012 Nov 14.
BPGAP1 is a Rho GTPase-activating protein (RhoGAP) that regulates cell morphogenesis, cell migration, and ERK signaling by the concerted action of its proline-rich region (PRR), RhoGAP domain, and the BNIP-2 and Cdc42GAP homology (BCH) domain. Although multiple cellular targets for the PRR and RhoGAP have been identified, and their functions delineated, the mechanism by which the BCH domain regulates functions of BPGAP1 remains unclear. Here we show that its BCH domain induced robust ERK activation leading to PC12 cell differentiation by targeting specifically to K-Ras. Such stimulatory effect was inhibited, however, by both dominant-negative mutants of Mek2 (Mek2-K101A) and K-Ras (K-Ras-S17N) and also by the small G-protein GDP dissociation stimulator (SmgGDS). Consequently SmgGDS knockdown released this inhibition and resulted in a superinduction of K-Ras activation and PC12 differentiation mediated by BCH domain. These results demonstrate the versatility of the BCH domain of BPGAP1 in regulating ERK signaling by involving K-Ras and SmgGDS and support the unique role of BPGAP1 as a dual regulator for Ras and Rho signaling in cell morphogenesis and differentiation.
BPGAP1 是一种 Rho GTP 酶激活蛋白（RhoGAP），通过其富含脯氨酸的区域（PRR）、RhoGAP 结构域以及 BNIP-2 和 Cdc42GAP 同源（BCH）结构域的协同作用，调节细胞形态发生、细胞迁移和 ERK 信号转导。虽然已经确定了 PRR 和 RhoGAP 的多个细胞靶标，并对其功能进行了描述，但 BCH 结构域调节 BPGAP1 功能的机制尚不清楚。在这里，我们表明其 BCH 结构域通过特异性靶向 K-Ras 诱导强大的 ERK 激活，导致 PC12 细胞分化。然而，这种刺激作用被 Mek2（Mek2-K101A）和 K-Ras（K-Ras-S17N）的显性负突变体以及小 G 蛋白 GDP 解离刺激物（SmgGDS）抑制。因此，SmgGDS 的敲低释放了这种抑制作用，并导致 BCH 结构域介导的 K-Ras 激活和 PC12 分化的超诱导。这些结果表明 BPGAP1 的 BCH 结构域在通过涉及 K-Ras 和 SmgGDS 调节 ERK 信号转导方面的多功能性，并支持 BPGAP1 作为 Ras 和 Rho 信号在细胞形态发生和分化中的双重调节剂的独特作用。
