配体与低密度脂蛋白受体相关蛋白1（LRP1）结合，通过Src家族激酶依赖性途径反式激活Trk受体。

Ligand binding to LRP1 transactivates Trk receptors by a Src family kinase-dependent pathway.

作者信息

Shi Yang, Mantuano Elisabetta, Inoue Gen, Campana W Marie, Gonias Steven L

机构信息

Department of Pathology, University of California San Diego, La Jolla, CA 92093-0612, USA.

出版信息

Sci Signal. 2009 Apr 28;2(68):ra18. doi: 10.1126/scisignal.2000188.

Low-density lipoprotein receptor-related protein 1 (LRP1) functions in endocytosis and intracellular signaling for a variety of structurally diverse ligands. Although LRP1 has been implicated in several aspects of neuronal function, molecular mechanisms underlying the activity of neuronal LRP1 remain unclear. Here, we describe a signaling pathway whereby LRP1 transactivates Trk receptors. Binding of tissue-type plasminogen activator or alpha(2)-macroglobulin (alpha(2)M) to LRP1 resulted in Src family kinase (SFK) activation and SFK-dependent Trk receptor transactivation in PC12 cells and neurons. Trk receptor transactivation was necessary for activation of Akt and extracellular signal-regulated kinase and for neurite outgrowth downstream of LRP1. Injection of the LRP1-binding domain of alpha(2)M into rat dorsal root ganglia induced Trk receptor phosphorylation, which was blocked by receptor-associated protein, an antagonist of ligand binding to LRP1. Trk receptor transactivation provides a mechanism by which diverse LRP1 ligands may show neurotrophic activity.

低密度脂蛋白受体相关蛋白1（LRP1）在多种结构各异的配体的内吞作用和细胞内信号传导中发挥作用。尽管LRP1已被认为与神经元功能的多个方面有关，但其在神经元中发挥作用的分子机制仍不清楚。在此，我们描述了一种信号通路，通过该通路LRP1可反式激活Trk受体。组织型纤溶酶原激活剂或α2巨球蛋白（α2M）与LRP1结合导致Src家族激酶（SFK）激活以及PC12细胞和神经元中依赖于SFK的Trk受体反式激活。Trk受体反式激活对于Akt和细胞外信号调节激酶的激活以及LRP1下游的神经突生长是必需的。将α2M的LRP1结合结构域注射到大鼠背根神经节中可诱导Trk受体磷酸化，而这被受体相关蛋白（一种配体与LRP1结合的拮抗剂）所阻断。Trk受体反式激活提供了一种机制，通过该机制多种LRP1配体可能表现出神经营养活性。