Nakagawa Yoshimi, Yamada Noriaki, Shimizu Hidehisa, Shiota Masayuki, Tamura Mariko, Kim-Mitsuyama Shokei, Miyazaki Hitoshi
Gene Research Center, University of Tsukuba, Ibaraki 305-8572, Japan.
Biochem Biophys Res Commun. 2004 Dec 3;325(1):314-9. doi: 10.1016/j.bbrc.2004.10.029.
The cell growth, survival, and migration of vascular endothelial cells (ECs) are positively regulated by several protein tyrosine kinase receptors. Therefore, protein tyrosine phosphatases (PTPs) must also be important for these processes. The present study found that transmembranal PTPepsilonM, but not cytoplasmic PTPepsilonC, is expressed in porcine ECs and in rat smooth muscle cells, both of which were prepared from the aorta. The overexpression of wild-type PTPepsilonM promoted cell survival and migration in porcine aortic ECs even in medium without and with 1% serum, respectively. A catalytically inactive, substrate-trapping mutant of PTPepsilonM, respectively, did not affect and conversely suppressed cell survival and migration. Interestingly, the forced expression of wild-type PTPepsilonC reduced cell viability in contrast to PTPepsilonM in ECs lacking endogenous PTPepsilonC, indicating the biological significance of selective expression of PTPepsilon isoforms in the vasculature. PTPepsilonM activated c-Src kinase probably by directly dephosphorylating phospho-Tyr527, a negative regulatory site of c-Src. The increases in cell survival and migration induced by overexpressed PTPepsilonM were suppressed by the c-Src inhibitor SU6656. Considering the behaviors of vascular ECs in the pathogenesis of atherosclerosis, these data suggest that PTPepsilonM negatively regulates the development of this disease by activating c-Src.
几种蛋白酪氨酸激酶受体对血管内皮细胞（ECs）的细胞生长、存活和迁移具有正向调节作用。因此，蛋白酪氨酸磷酸酶（PTPs）对这些过程也必定很重要。本研究发现，跨膜型PTPepsilonM而非胞质型PTPepsilonC在猪ECs和大鼠平滑肌细胞中表达，这两种细胞均取自主动脉。野生型PTPepsilonM的过表达分别在不含血清和含1%血清的培养基中促进了猪主动脉ECs的细胞存活和迁移。PTPepsilonM的一种催化失活的底物捕获突变体分别未影响且相反地抑制了细胞存活和迁移。有趣的是，与缺乏内源性PTPepsilonC的ECs中的PTPepsilonM相反，野生型PTPepsilonC的强制表达降低了细胞活力，这表明PTPepsilon异构体在脉管系统中选择性表达具有生物学意义。PTPepsilonM可能通过直接使c-Src的负调控位点磷酸化酪氨酸527去磷酸化来激活c-Src激酶。过表达的PTPepsilonM诱导的细胞存活和迁移增加被c-Src抑制剂SU6656抑制。考虑到血管ECs在动脉粥样硬化发病机制中的行为，这些数据表明PTPepsilonM通过激活c-Src对该疾病的发展起负调控作用。
