Rac1 GEF/GAP 调控复合物对兴奋性突触发育的动态调控。
Dynamic control of excitatory synapse development by a Rac1 GEF/GAP regulatory complex.
机构信息
Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
出版信息
Dev Cell. 2014 Jun 23;29(6):701-15. doi: 10.1016/j.devcel.2014.05.011.
The small GTPase Rac1 orchestrates actin-dependent remodeling essential for numerous cellular processes including synapse development. While precise spatiotemporal regulation of Rac1 is necessary for its function, little is known about the mechanisms that enable Rac1 activators (GEFs) and inhibitors (GAPs) to act in concert to regulate Rac1 signaling. Here, we identify a regulatory complex composed of a Rac-GEF (Tiam1) and a Rac-GAP (Bcr) that cooperate to control excitatory synapse development. Disruption of Bcr function within this complex increases Rac1 activity and dendritic spine remodeling, resulting in excessive synaptic growth that is rescued by Tiam1 inhibition. Notably, EphB receptors utilize the Tiam1-Bcr complex to control synaptogenesis. Following EphB activation, Tiam1 induces Rac1-dependent spine formation, whereas Bcr prevents Rac1-mediated receptor internalization, promoting spine growth over retraction. The finding that a Rac-specific GEF/GAP complex is required to maintain optimal levels of Rac1 signaling provides an important insight into the regulation of small GTPases.
小分子 GTP 酶 Rac1 协调肌动蛋白依赖性重塑，这对于包括突触发育在内的许多细胞过程至关重要。虽然 Rac1 的精确时空调节对于其功能是必要的，但对于能够使 Rac1 激活剂（GEF）和抑制剂（GAP）协同作用以调节 Rac1 信号的机制知之甚少。在这里，我们确定了一个由 Rac-GEF（Tiam1）和 Rac-GAP（Bcr）组成的调节复合物，该复合物协同控制兴奋性突触的发育。在该复合物中破坏 Bcr 的功能会增加 Rac1 的活性和树突棘重塑，导致过度的突触生长，这可以通过抑制 Tiam1 来挽救。值得注意的是，EphB 受体利用 Tiam1-Bcr 复合物来控制突触发生。EphB 激活后，Tiam1 诱导 Rac1 依赖性棘突形成，而 Bcr 阻止 Rac1 介导的受体内化，促进棘突生长而不是回缩。发现 Rac 特异性 GEF/GAP 复合物是维持 Rac1 信号最佳水平所必需的，这为小 GTP 酶的调节提供了重要的见解。
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