Hata Katsuhiko, Kaibuchi Kozo, Inagaki Shinobu, Yamashita Toshihide
Department of Molecular Neuroscience, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
J Cell Biol. 2009 Mar 9;184(5):737-50. doi: 10.1083/jcb.200807029.
Neuronal axons are guided by attractive and repulsive cues in their local environment. Because the repulsive guidance molecule A (RGMa) was originally identified as an axon repellent in the visual system, diverse functions in the developing and adult central nervous system have been ascribed to it. RGMa binding to its receptor neogenin induces RhoA activation, leading to inhibitory/repulsive behavior and collapse of the neuronal growth cone. However, the precise mechanisms that regulate RhoA activation are poorly understood. In this study, we show that Unc5B, a member of the netrin receptor family, interacts with neogenin as a coreceptor for RGMa. Moreover, leukemia-associated guanine nucleotide exchange factor (LARG) associates with Unc5B to transduce the RhoA signal. Focal adhesion kinase (FAK) is involved in RGMa-induced tyrosine phosphorylation of LARG as well as RhoA activation. These findings uncover the molecular basis for diverse functions mediated by RGMa.
神经元轴突在其局部环境中受到吸引和排斥线索的引导。由于排斥性导向分子A（RGMa）最初被鉴定为视觉系统中的轴突排斥因子，因此它在发育中和成年中枢神经系统中具有多种功能。RGMa与其受体新生蛋白结合会诱导RhoA激活，导致神经元生长锥出现抑制/排斥行为并塌陷。然而，调节RhoA激活的精确机制尚不清楚。在本研究中，我们表明，作为netrin受体家族成员的Unc5B与新生蛋白相互作用，作为RGMa的共受体。此外，白血病相关鸟嘌呤核苷酸交换因子（LARG）与Unc5B结合以转导RhoA信号。粘着斑激酶（FAK）参与RGMa诱导的LARG酪氨酸磷酸化以及RhoA激活。这些发现揭示了RGMa介导的多种功能的分子基础。
