Vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments.
Vascular endothelial cadherin controls VEGFR-2 internalization and signaling from intracellular compartments.
复制标题
血管内皮钙粘蛋白控制着细胞内室的VEGFR-2内在化和信号传导。
DOI：
10.1083/jcb.200602080
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发表时间：
2006-08-14
影响因子：
7.8
通讯作者：
Dejana, Elisabetta
中科院分区：
文献类型：
--
作者：
Lampugnani, Maria Grazia;Orsenigo, Fabrizio;Gagliani, Maria Cristina;Tacchetti, Carlo;Dejana, Elisabetta
受体内吞作用是控制细胞信号传导事件的幅度、持续时间和性质的基本步骤。融合的内皮细胞生长受到接触抑制，对血管内皮生长因子（VEGF）的增殖信号反应较差。在先前的研究中，我们发现血管内皮钙粘蛋白（VEC）与VEGF受体（VEGFR）2型的结合有助于密度依赖性生长抑制（Lampugnani，G.M.，A. Zanetti，M. Corada，T. Takahashi，G. Balconi，F. Breviario，F.奥尔塞尼戈，A.卡特利诺河Kemler，T.O.丹尼尔和E.黛佳娜2003. 161：793-804）。在本研究中，我们描述了VEC减少VEGFR-2信号传导的机制。我们发现VEGF诱导VEGFR-2的网格蛋白依赖性内化。当VEC不存在或在连接处不接合时，VEGFR-2更快地内化并在内体隔室中保留更长时间。内化不会终止其信号传导;相反，内化的受体被磷酸化，与活性磷脂酶C-γ共分布，并激活p44/42丝裂原活化蛋白激酶磷酸化和细胞增殖。抑制VEGFR-2内化重建细胞生长的接触抑制，而沉默连接相关密度增强磷酸酶-1/CD148磷酸酶恢复VEGFR-2内化和信号传导。因此，VEC通过将VEGFR-2保留在膜上并阻止其内化到信号区室中来限制细胞增殖。
Receptor endocytosis is a fundamental step in controlling the magnitude, duration, and nature of cell signaling events. Confluent endothelial cells are contact inhibited in their growth and respond poorly to the proliferative signals of vascular endothelial growth factor (VEGF). In a previous study, we found that the association of vascular endothelial cadherin (VEC) with VEGF receptor (VEGFR) type 2 contributes to density-dependent growth inhibition (Lampugnani, G.M., A. Zanetti, M. Corada, T. Takahashi, G. Balconi, F. Breviario, F. Orsenigo, A. Cattelino, R. Kemler, T.O. Daniel, and E. Dejana. 2003. J. Cell Biol. 161:793–804). In the present study, we describe the mechanism through which VEC reduces VEGFR-2 signaling. We found that VEGF induces the clathrin-dependent internalization of VEGFR-2. When VEC is absent or not engaged at junctions, VEGFR-2 is internalized more rapidly and remains in endosomal compartments for a longer time. Internalization does not terminate its signaling; instead, the internalized receptor is phosphorylated, codistributes with active phospholipase C–γ, and activates p44/42 mitogen-activated protein kinase phosphorylation and cell proliferation. Inhibition of VEGFR-2 internalization reestablishes the contact inhibition of cell growth, whereas silencing the junction-associated density-enhanced phosphatase-1/CD148 phosphatase restores VEGFR-2 internalization and signaling. Thus, VEC limits cell proliferation by retaining VEGFR-2 at the membrane and preventing its internalization into signaling compartments.