ABSTRACT

Neuroblastoma is a highly metastatic tumor that emerges from neural crest cell progenitors. Focal Adhesion Kinase (FAK) is a regulator of cell migration that binds to the receptor Neogenin-1 and is upregulated in neuroblastoma. Here, we show that Netrin-1 ligand binding to Neogenin-1 leads to FAK autophosphorylation and integrin β1 activation in a FAK dependent manner, thus promoting neuroblastoma cell migration. Moreover, Neogenin-1, which was detected in all tumor stages and was required for neuroblastoma cell migration, was found in a complex with integrin β1, FAK, and Netrin-1. Importantly, Neogenin-1 promoted neuroblastoma metastases in an immunodeficient mouse model. Taken together, these data show that Neogenin-1 is a metastasis-promoting protein that associates with FAK, activates integrin β1 and promotes neuroblastoma cell migration.

摘要

神经母细胞瘤是一种从神经嵴细胞祖细胞中出现的高度转移性肿瘤。粘着斑激酶 (FAK) 是一种细胞迁移调节剂，可与受体 Neogenin-1 结合，并在神经母细胞瘤中上调。在这里，我们展示了与 Neogenin-1 结合的 Netrin-1 配体以 FAK 依赖性方式导致 FAK 自磷酸化和整合素 β1 活化，从而促进神经母细胞瘤细胞迁移。此外，在与整合素 β1、FAK 和 Netrin-1 的复合物中发现了在所有肿瘤阶段都检测到并且是神经母细胞瘤细胞迁移所需的 Neogenin-1。重要的是，Neogenin-1 在免疫缺陷小鼠模型中促进了神经母细胞瘤的转移。总之，这些数据表明，Neogenin-1 是一种与 FAK 结合的促进转移蛋白，可激活整合素 β1 并促进神经母细胞瘤细胞迁移。