Transactivation of the Receptor-tyrosine Kinase Ephrin Receptor A2 Is Required for the Low Molecular Weight Hyaluronan-mediated Angiogenesis That Is implicated in Tumor Progression
Transactivation of the Receptor-tyrosine Kinase Ephrin Receptor A2 Is Required for the Low Molecular Weight Hyaluronan-mediated Angiogenesis That Is implicated in Tumor Progression
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DOI：
10.1074/jbc.m114.554766
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发表时间：
2014-08-29
影响因子：
4.8
通讯作者：
Singleton, Patrick A.
中科院分区：
文献类型：
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作者：
Lennon, Frances E.;Mirzapoiazova, Tamara;Singleton, Patrick A.
背景：透明质酸（HA）介导的血管生成与肿瘤进展有关。结果如下：LMW-HA介导的EphA 2的反式激活是PATJ和Dbs膜募集所需的，随后是血管生成所需的RhoA激活。结论：EphA 2在HA介导的血管生成中起重要作用。重要性：靶向LMW-HA的下游效应物可能是血管生成相关疾病包括各种恶性肿瘤的有用的治疗干预。血管生成或新血管的形成在各种癌症的生长和转移潜力中是重要的。因此，了解血管生成发生的机制在许多恶性肿瘤中具有重要的治疗意义。我们和其他人已经证明，低分子量透明质酸（LMW-HA，约2500 Da）促进内皮细胞（EC）屏障破坏和血管生成。然而，发生这种情况的机制定义不清。我们的数据表明，用LMW-HA处理人EC诱导CD 44 v10与受体酪氨酸激酶EphA 2、EphA 2的反式激活（酪氨酸磷酸化）和PDZ结构域支架蛋白PATJ向细胞外周的募集的关联。沉默（siRNA）CD 44、EphA 2、PATJ或Dbs（RhoGEF）表达阻断了LMW-HA介导的血管生成（EC增殖、迁移和小管形成）。此外，沉默EphA 2、PATJ、Src或Dbs表达阻断LMW-HA介导的RhoA活化。为了转化我们的体外发现，我们利用了一种新的anginex/脂质体靶向鼠血管生成内皮细胞与CD 44或EphA 2 siRNA，并观察到抑制LMW-HA诱导的血管生成植入基质胶塞。总之，这些结果表明，PATJ和Dbs膜募集需要LMW-HA介导的EphA 2反式激活，随后血管生成需要RhoA激活。这些结果表明，靶向LMW-HA的下游效应物可能是血管生成相关疾病（包括肿瘤进展）的有用治疗干预。
Background: Hyaluronan (HA)-mediated angiogenesis has been implicated in tumor progression. Results: LMW-HA-mediated transactivation of EphA2 is required for PATJ and Dbs membrane recruitment and subsequent RhoA activation required for angiogenesis. Conclusion: EphA2 plays a crucial role in HA-mediated angiogenesis. Significance: Targeting downstream effectors of LMW-HA could be a useful therapeutic intervention for angiogenesis-associated diseases including various malignancies.Angiogenesis or the formation of new blood vessels is important in the growth and metastatic potential of various cancers. Therefore, understanding the mechanism(s) by which angiogenesis occurs can have important therapeutic implications in numerous malignancies. We and others have demonstrated that low molecular weight hyaluronan (LMW-HA, approximate to 2500 Da) promotes endothelial cell (EC) barrier disruption and angiogenesis. However, the mechanism(s) by which this occurs is poorly defined. Our data indicate that treatment of human EC with LMW-HA induced CD44v10 association with the receptor-tyrosine kinase, EphA2, transactivation (tyrosine phosphorylation) of EphA2, and recruitment of the PDZ domain scaffolding protein, PATJ, to the cell periphery. Silencing (siRNA) CD44, EphA2, PATJ, or Dbs (RhoGEF) expression blocked LMW-HA-mediated angiogenesis (EC proliferation, migration, and tubule formation). In addition, silencing EphA2, PATJ, Src, or Dbs expression blocked LMW-HA-mediated RhoA activation. To translate our in vitro findings, we utilized a novel anginex/liposomal targeting of murine angiogenic endothelium with either CD44 or EphA2 siRNA and observed inhibition of LMW-HA-induced angiogenesis in implanted Matrigel plugs. Taken together, these results indicate LMW-HA-mediated transactivation of EphA2 is required for PATJ and Dbs membrane recruitment and subsequent RhoA activation required for angiogenesis. These results suggest that targeting downstream effectors of LMW-HA could be a useful therapeutic intervention for angiogenesis-associated diseases including tumor progression.