CCN3 (NOV) is a novel angiogenic regulator of the CCN protein family
CCN3 (NOV) is a novel angiogenic regulator of the CCN protein family
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DOI：
10.1074/jbc.m302028200
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发表时间：
2003-06-27
影响因子：
4.8
通讯作者：
Lau, LF
中科院分区：
文献类型：
--
作者：
Lin, CG;Leu, SJ;Lau, LF
CCN3 (NOV) 是 CCN 家族的基质细胞蛋白，该家族还包括 CCN1 (CYR61)、CCN2 (CTGF)、CCN4 (WISP-1)、CCN5 (WISP-2) 和 CCN6 (WISP-3)。在发育过程中，CCN3 在所有三个胚层的衍生物中广泛表达，并且在动脉血管壁的平滑肌细胞中观察到高水平的表达。已在多种肿瘤中观察到 CCN3 表达的改变，包括肝细胞癌、肾母细胞瘤、尤文氏肉瘤、神经胶质瘤、横纹肌肉瘤和肾上腺皮质癌。为了了解其生物学功能，我们研究了纯化的重组 CCN3 的活性。我们发现，在内皮细胞中，CCN3 支持细胞粘附、诱导细胞定向迁移（趋化性）并促进细胞存活。从机制上讲，CCN3 通过多种细胞表面受体支持人脐静脉内皮细胞粘附，包括整合素 α(v)β(3)、α(5)β(1)、α(6)β(1) 和硫酸乙酰肝素蛋白聚糖。相反，CCN3诱导的细胞迁移依赖于整合素α(v)β(3)和α(5)β(1)，而α(6)β(1)在此过程中不起作用。尽管 CCN3 不包含 RGD 序列，但它直接与固定化整合素 α(v)β(3) 和 α(5)β(1) 结合，半最大结合分别发生在 10 nM 和 50 nM CCN3 时。此外，CCN3在植入大鼠角膜时诱导新生血管形成，表明它是一种新型的血管生成诱导剂。总之，这些发现表明CCN3是整合素α(v)β(3)和α(5)β(1)的配体，直接作用于内皮细胞以刺激促血管生成活性，并诱导体内血管生成。
CCN3 (NOV) is a matricellular protein of the CCN family, which also includes CCN1 (CYR61), CCN2 (CTGF), CCN4 (WISP-1), CCN5 (WISP-2), and CCN6 (WISP-3). During development, CCN3 is expressed widely in derivatives of all three germ layers, and high levels of expression are observed in smooth muscle cells of the arterial vessel wall. Altered expression of CCN3 has been observed in a variety of tumors, including hepatocellular carcinomas, Wilm's tumors, Ewing's sarcomas, gliomas, rhabdomyosarcomas, and adrenocortical carcinomas. To understand its biological functions, we have investigated the activities of purified recombinant CCN3. We show that in endothelial cells, CCN3 supports cell adhesion, induces directed cell migration (chemotaxis), and promotes cell survival. Mechanistically, CCN3 supports human umbilical vein endothelial cell adhesion through multiple cell surface receptors, including integrins alpha(v)beta(3), alpha(5)beta(1), alpha(6)beta(1), and heparan sulfate proteoglycans. In contrast, CCN3-induced cell migration is dependent on integrins alpha(v)beta(3) and alpha(5)beta(1), whereas alpha(6)beta(1) does not play a role in this process. Although CCN3 does not contain a RGD sequence, it binds directly to immobilized integrins alpha(v)beta(3) and alpha(5)beta(1), with half-maximal binding occurring at 10 nM and 50 nM CCN3, respectively. Furthermore, CCN3 induces neovascularization when implanted in rat cornea, demonstrating that it is a novel angiogenic inducer. Together, these findings show that CCN3 is a ligand of integrins alpha(v)beta(3) and alpha(5)beta(1), acts directly upon endothelial cells to stimulate pro-angiogenic activities, and induces angiogenesis in vivo.