ROBO 受体介导的信号传导
中文名称
通路描述
Roundabout（ROBO）家族编码调节轴突导向和细胞迁移的跨膜受体。Robo 受体的主要功能是介导导航生长锥的排斥作用。人类有四个 Robo 同源物：ROBO1、ROBO2、ROBO3 和 ROBO4。大多数 ROBO 具有与细胞粘附分子相似的细胞外结构域架构，即五个 Ig 结构域后跟三个 FN3 重复，除了 ROBO4。ROBO4 有两个 Ig 和两个 FN3 重复。ROBO 受体的胞质结构域通常缺乏保守性。然而，有四个短的保守胞质序列基序，命名为 CC0-3，作为配体结合蛋白的靶位点。人类 ROBO1 和 ROBO2 受体的配体是三种 SLIT 蛋白：SLIT1、SLIT2 和 SLIT3；所有 SLIT 蛋白在 N 端都有一个由四个 LRR（亮氨酸富集重复）组成的串联结构，称为 D1-D4，其后是六个 EGF（表皮生长因子）样结构域、一个类似 laminin G 的结构域（ALPS）、三个 EGF 样结构域和一个 C 端半胱氨酸环结构域。大多数 SLIT 蛋白在 EGF 样区域被未知的蛋白酶切割（见 Hohenster 2008, Ypsilanti and Chedotal 2014, Blockus and Chedotal 2016）。NELL2 是 ROBO3 的配体（Jaworski et al. 2015）。SLIT 蛋白结合调节 ROBO 与胞内适配子的相互作用。ROBO1 和 ROBO2 的胞质结构域决定了这些受体的排斥反应。基于无脊椎动物和脊椎动物的研究，可以推断 ROBO 通过控制细胞骨架动力学（通过 ABL 和 Ena，或 RAC1 活性）来诱导生长锥排斥（见 Hohenster 2008, Ypsilanti and Chedotal 2014, Blockus and Chedotal 2016）。虽然 ROBO 受体的功能存在冗余，但 ROBO1 被认为是腹侧束中轴突导向的主要受体，而 ROBO2 是背侧束中轴突导向的主要受体。ROBO2 还排斥来自板层（floor plate）的神经元细胞体（Kim et al. 2011）。除了调节轴突导向外，ROBO1 和 ROBO2 受体还参与初级神经元前体向中间神经元前体的增殖和转换，通过未充分表征的与 NOTCH 介导的 HES1 转录激活的交叉对话（Borrell et al. 2012）。丘脑皮层轴突延伸受神经活动依赖性 ROBO1 转录调控。较低的神经元活性与 ROBO1 转录增加相关，可能通过 NFKB 复合物介导（Mire et al. 2012）。建议核内同源框转录因子 NKX2.9 刺激 ROBO2 的转录，后者参与调节脊椎动物脊髓轴突从脊髓束的退出（Bravo-Ambrosio et al. 2012）。在四种 ROBO 蛋白中，ROBO4 不参与神经系统发育，而是参与血管生成。ROBO4 与 SLIT3 的相互作用涉及内皮细胞的增殖、运动性和趋化性，并加速血管形成（Zhang et al. 2009）。
英文描述
Signaling by ROBO receptors The Roundabout (ROBO) family encodes transmembrane receptors that regulate axonal guidance and cell migration. The major function of the Robo receptors is to mediate repulsion of the navigating growth cones. There are four human Robo homologues, ROBO1, ROBO2, ROBO3 and ROBO4. Most of the ROBOs have the similar ectodomain architecture as the cell adhesion molecules, with five Ig domains followed by three FN3 repeats, except for ROBO4. ROBO4 has two Ig and two FN3 repeats. The cytoplasmic domains of ROBO receptors are in general poorly conserved. However, there are four short conserved cytoplasmic sequence motifs, named CC0-3, that serve as binding sites for adaptor proteins. The ligands for the human ROBO1 and ROBO2 receptors are the three SLIT proteins SLIT1, SLIT2, and SLIT3; all of the SLIT proteins contain a tandem of four LRR (leucine rich repeat) domains at the N-terminus, termed D1-D4, followed by six EGF (epidermal growth factor)-like domains, a laminin G like domain (ALPS), three EGF-like domains, and a C-terminal cysteine knot domain. Most SLIT proteins are cleaved within the EGF-like region by unknown proteases (reviewed by Hohenster 2008, Ypsilanti and Chedotal 2014, Blockus and Chedotal 2016). NELL2 is a ligand for ROBO3 (Jaworski et al. 2015).
SLIT protein binding modulates ROBO interactions with the cytosolic adaptors. The cytoplasmic domain of ROBO1 and ROBO2 determines the repulsive responses of these receptors. Based on the studies from both invertebrate and vertebrate organisms it has been inferred that ROBO induces growth cone repulsion by controlling cytoskeletal dynamics via either Abelson kinase (ABL) and Enabled (Ena), or RAC1 activity (reviewed by Hohenster 2008, Ypsilanti and Chedotal 2014, Blockus and Chedotal 2016). While there is some redundancy in the function of ROBO receptors, ROBO1 is implicated as the predominant receptor for axon guidance in ventral tracts, and ROBO2 is the predominant receptor for axon guidance in dorsal tracts. ROBO2 also repels neuron cell bodies from the floor plate (Kim et al. 2011).In addition to regulating axon guidance, ROBO1 and ROBO2 receptors are also implicated in regulation of proliferation and transition of primary to intermediate neuronal progenitors through a poorly characterized cross-talk with NOTCH-mediated activation of HES1 transcription (Borrell et al. 2012).Thalamocortical axon extension is regulated by neuronal activity-dependent transcriptional regulation of ROBO1 transcription. Lower neuronal activity correlates with increased ROBO1 transcription, possibly mediated by the NFKB complex (Mire et al. 2012).It is suggested that the homeodomain transcription factor NKX2.9 stimulates transcription of ROBO2, which is involved in regulation of motor axon exit from the vertebrate spinal code (Bravo-Ambrosio et al. 2012).Of the four ROBO proteins, ROBO4 is not involved in neuronal system development but is, instead, involved in angiogenesis. The interaction of ROBO4 with SLIT3 is involved in proliferation, motility and chemotaxis of endothelial cells, and accelerates formation of blood vessels (Zhang et al. 2009).
SLIT protein binding modulates ROBO interactions with the cytosolic adaptors. The cytoplasmic domain of ROBO1 and ROBO2 determines the repulsive responses of these receptors. Based on the studies from both invertebrate and vertebrate organisms it has been inferred that ROBO induces growth cone repulsion by controlling cytoskeletal dynamics via either Abelson kinase (ABL) and Enabled (Ena), or RAC1 activity (reviewed by Hohenster 2008, Ypsilanti and Chedotal 2014, Blockus and Chedotal 2016). While there is some redundancy in the function of ROBO receptors, ROBO1 is implicated as the predominant receptor for axon guidance in ventral tracts, and ROBO2 is the predominant receptor for axon guidance in dorsal tracts. ROBO2 also repels neuron cell bodies from the floor plate (Kim et al. 2011).In addition to regulating axon guidance, ROBO1 and ROBO2 receptors are also implicated in regulation of proliferation and transition of primary to intermediate neuronal progenitors through a poorly characterized cross-talk with NOTCH-mediated activation of HES1 transcription (Borrell et al. 2012).Thalamocortical axon extension is regulated by neuronal activity-dependent transcriptional regulation of ROBO1 transcription. Lower neuronal activity correlates with increased ROBO1 transcription, possibly mediated by the NFKB complex (Mire et al. 2012).It is suggested that the homeodomain transcription factor NKX2.9 stimulates transcription of ROBO2, which is involved in regulation of motor axon exit from the vertebrate spinal code (Bravo-Ambrosio et al. 2012).Of the four ROBO proteins, ROBO4 is not involved in neuronal system development but is, instead, involved in angiogenesis. The interaction of ROBO4 with SLIT3 is involved in proliferation, motility and chemotaxis of endothelial cells, and accelerates formation of blood vessels (Zhang et al. 2009).
所含基因
15 个基因