An Eph receptor regulates integrin activity through R-Ras.
An Eph receptor regulates integrin activity through R-Ras.
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DOI：
10.1073/pnas.96.24.13813
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发表时间：
1999-11
影响因子：
11.1
通讯作者：
June X. Zou;Bingcheng Wang;Bingcheng Wang;M. Kalo;A. Zisch;A. Zisch;Elena B. Pasquale;E. Ruoslahti
中科院分区：
文献类型：
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作者：
June X. Zou;Bingcheng Wang;Bingcheng Wang;M. Kalo;A. Zisch;A. Zisch;Elena B. Pasquale;E. Ruoslahti
整联蛋白介导细胞与细胞外基质和血液蛋白质附着的能力从细胞内部调节。整合素的配体结合活性增加对于凝血时的血小板聚集和白细胞外渗至发炎组织是关键的。粘附性降低被认为促进肿瘤细胞侵袭。R-Ras是一种小的细胞内GTP酶，调节整联蛋白与细胞外配体的结合。在这里，我们表明Eph受体酪氨酸激酶EphB 2可以通过R-Ras控制整合素活性。其中EphB 2被激活的细胞变得对包被有整联蛋白配体的底物粘附性差，并且R-Ras效应结构域中的酪氨酸残基被磷酸化。R-Ras磷酸化和细胞粘附的丧失是因果关系，因为在关键位点强制表达抗磷酸化的R-Ras变体使细胞对EphB 2的抗粘附作用没有反应。这是小GTP酶中一种不寻常的调节途径。通过Eph/R-Ras途径诱导的Eph减少可能解释Eph受体在轴突寻路中的排斥作用，并可能促进肿瘤细胞侵袭和血管生成。
The ability of integrins to mediate cell attachment to extracellular matrices and to blood proteins is regulated from inside the cell. Increased ligand-binding activity of integrins is critical for platelet aggregation upon blood clotting and for leukocyte extravasation to inflamed tissues. Decreased adhesion is thought to promote tumor cell invasion. R-Ras, a small intracellular GTPase, regulates the binding of integrins to their ligands outside the cell. Here we show that the Eph receptor tyrosine kinase, EphB2, can control integrin activity through R-Ras. Cells in which EphB2 is activated become poorly adherent to substrates coated with integrin ligands, and a tyrosine residue in the R-Ras effector domain is phosphorylated. The R-Ras phosphorylation and loss of cell adhesion are causally related, because forced expression of an R-Ras variant resistant to phosphorylation at the critical site made cells unresponsive to the anti-adhesive effect of EphB2. This is an unusual regulatory pathway among the small GTPases. Reduced adhesiveness induced through the Eph/R-Ras pathway may explain the repulsive effect of the Eph receptors in axonal pathfinding and may facilitate tumor cell invasion and angiogenesis.