Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.
Department of Diagnosis and Surgery, School of Dentistry at Araraquara, UNESP-Univ Estadual Paulista, Araraquara, SP, Brazil.
J Dent Res. 2020 Jul;99(8):959-968. doi: 10.1177/0022034520917058. Epub 2020 May 13.
Cell-cell adhesion is a key mechanism to control tissue integrity and migration. In head and neck squamous cell carcinoma (HNSCC), cell migration facilitates distant metastases and is correlated with poor prognosis. RAP1, a ras-like protein, has an important role in the progression of HNSCC. RAC1 is an integrin-linked, ras-like protein that promotes cell migration. Here we show that loss of cell-cell adhesion is correlated with inactivation of RAP1 confirmed by 2 different biochemical approaches. RAP1 activation is required for cell-matrix adhesion confirmed by adhesion to fibronectin-coated plates with cells that have biochemically activated RAP1. This effect is reversed when RAP1 is inactivated. In addition, RAP1-mediated adhesion is only facilitated through α5β1 integrin complex and is not a function of either α5 or β1 integrin alone. Moreover, the inside-out signaling of RAP1 activation is coordinated with RAC1 activation. These findings show that RAP1 has a prominent role in cell-matrix adhesion via extracellular matrix molecule fibronectin-induced α5β1 integrin and supports a critical role for the RAP1/RAC1 signaling axis in HNSCC cell migration.
细胞间黏附是控制组织完整性和迁移的关键机制。在头颈部鳞状细胞癌（HNSCC）中，细胞迁移促进远处转移，并与预后不良相关。RAP1 是一种 Ras 样蛋白，在 HNSCC 的进展中起重要作用。RAC1 是一种整合素连接的 Ras 样蛋白，可促进细胞迁移。在这里，我们通过两种不同的生化方法证实，细胞间黏附的丧失与 RAP1 的失活相关。通过用生物化学方法激活 RAP1 的细胞黏附到纤维连接蛋白包被的平板上，证实了 RAP1 激活是细胞-基质黏附所必需的。当 RAP1 失活时，这种效应被逆转。此外，RAP1 介导的黏附仅通过α5β1 整合素复合物促进，而不是α5 或β1 整合素单独的功能。此外，RAP1 激活的内向外信号与 RAC1 激活协调。这些发现表明，RAP1 通过细胞外基质分子纤维连接蛋白诱导的α5β1 整合素在细胞-基质黏附中起重要作用，并支持 RAP1/RAC1 信号轴在 HNSCC 细胞迁移中的关键作用。
