VE-cadherin regulates EphA2 in aggressive melanoma cells through a novel signaling pathway - Implications for vasculogenic mimicry
VE-cadherin regulates EphA2 in aggressive melanoma cells through a novel signaling pathway - Implications for vasculogenic mimicry
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DOI：
10.4161/cbt.5.2.2510
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发表时间：
2006-02-01
影响因子：
3.6
通讯作者：
Hendrix, MJC
中科院分区：
文献类型：
--
作者：
Hess, AR;Seftor, EA;Hendrix, MJC
富含基质的血管生成样网络的形成，被称为血管生成模仿（VM），是高度侵袭性黑色素瘤细胞的一个独特过程特征，该细胞表达的基因以前被认为只与内皮细胞和上皮细胞相关。本研究提供了新的观察结果，证明VE-cadherin可以通过与其膜结合配体ephrin-A1相互作用介导EphA2的磷酸化能力，从而调节EphA2在细胞膜上的表达。VE-cadherin和EphA2在体外和体内也被发现共定位于细胞-细胞粘附连接处。免疫沉淀研究显示EphA2和VE-cadherin在VM中可以直接和/或间接相互作用。此外，当EphA2在酪氨酸残基上被磷酸化时，EphA2和VE-cadherin在细胞-细胞粘附位点的共定位没有变化。虽然短暂敲除EphA2的表达不会改变VE-cadherin的定位，但短暂敲除VE-cadherin的表达会导致EphA2在细胞表面重组，在细胞质中积累，随后发生EphA2的去磷酸化。总之，这些结果表明VE-cadherin和EphA2作为黑色素瘤VM过程中的关键调控元件协同作用，并阐明了一种新的信号通路，可能被用于治疗干预。
The formation of matrix-rich, vasculogenic-like networks, termed vasculogenic mimicry (VM), is a unique process characteristic of highly aggressive melanoma cells found to express genes previously thought to be exclusively associated with endothelial and epithelial cells. This study contributes new observations demonstrating that VE-cadherin can regulate the expression of EphA2 at the cell membrane by mediating its ability to become phosphorylated through interactions with its membrane bound ligand, ephrin-A1. VE-cadherin and EphA2 were also found to be colocalized in cell-cell adhesion junctions, both in vitro and in vivo. Immunoprecipitation studies revealed that EphA2 and VE-cadherin could interact, directly and/or indirectly, during VM. Furthermore, there was no change in the colocalization of EphA2 and VE-cadherin at cell-cell adhesion sites when EphA2 was phosphorylated on tyrosine residues. Although transient knockout of EphA2 expression did not alter VE-cadherin localization, transient knockout of VE-cadherin expression resulted in the reorganization of EphA2 on the cells' surface, an accumulation of EphA2 in the cytoplasm, and subsequent dephosphorylation of EphA2. Collectively, these results suggest that VE-cadherin and EphA2 act in a coordinated manner as a key regulatory element in the process of melanoma VM and illuminate a novel signaling pathway that could be potentially exploited for therapeutic intervention.