Lee Hyun-Shik, Nishanian Tagvor G, Mood Kathleen, Bong Yong-Sik, Daar Ira O
Laboratory of Cell and Developmental Signaling, National Cancer Institute-Frederick, Frederick, Maryland 21702, USA.
Nat Cell Biol. 2008 Aug;10(8):979-86. doi: 10.1038/ncb1758. Epub 2008 Jul 6.
A body of evidence is emerging that shows a requirement for ephrin ligands in the proper migration of cells, and the formation of cell and tissue boundaries. These processes are dependent on the cell-cell adhesion system, which plays a crucial role in normal morphogenetic processes during development, as well as in invasion and metastasis. Although ephrinB ligands are bi-directional signalling molecules, the precise mechanism by which ephrinB1 signals through its intracellular domain to regulate cell-cell adhesion in epithelial cells remains unclear. Here, we present evidence that ephrinB1 associates with the Par polarity complex protein Par-6 (a scaffold protein required for establishing tight junctions) and can compete with the small GTPase Cdc42 for association with Par-6. This competition causes inactivation of the Par complex, resulting in the loss of tight junctions. Moreover, the interaction between ephrinB1 and Par-6 is disrupted by tyrosine phosphorylation of the intracellular domain of ephrinB1. Thus, we have identified a mechanism by which ephrinB1 signalling regulates cell-cell junctions in epithelial cells, and this may influence how we devise therapeutic interventions regarding these molecules in metastatic disease.
越来越多的证据表明，在细胞的正常迁移以及细胞和组织边界的形成过程中，对 Ephrin 配体有需求。这些过程依赖于细胞 - 细胞黏附系统，该系统在发育过程中的正常形态发生过程以及侵袭和转移中起着至关重要的作用。尽管 EphrinB 配体是双向信号分子，但 EphrinB1 通过其细胞内结构域信号传导以调节上皮细胞中细胞 - 细胞黏附的确切机制仍不清楚。在这里，我们提供证据表明 EphrinB1 与 Par 极性复合体蛋白 Par - 6（一种建立紧密连接所需的支架蛋白）相关联，并且可以与小 GTP 酶 Cdc42 竞争与 Par - 6 的结合。这种竞争导致 Par 复合体失活，从而导致紧密连接的丧失。此外，EphrinB1 细胞内结构域的酪氨酸磷酸化会破坏 EphrinB1 与 Par - 6 之间的相互作用。因此，我们确定了一种 EphrinB1 信号传导调节上皮细胞中细胞 - 细胞连接的机制，这可能会影响我们如何设计针对转移性疾病中这些分子的治疗干预措施。
