Ramos J W, Kojima T K, Hughes P E, Fenczik C A, Ginsberg M H
Department of Vascular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
J Biol Chem. 1998 Dec 18;273(51):33897-900. doi: 10.1074/jbc.273.51.33897.
Increased integrin ligand binding affinity (activation) is triggered by intracellular signaling events. A Ras-initiated mitogen-activated protein kinase pathway suppresses integrin activation in fibroblasts. We used expression cloning to isolate cDNAs that prevent Ras suppression of integrin activation. Here, we report that PEA-15, a small death effector domain (DED)-containing protein, blocks Ras suppression. PEA-15 does not block the capacity of Ras to activate the ERK mitogen-activated protein kinase pathway. Instead, it inhibits suppression via a pathway blocked by a dominant-negative form of the distinct small GTPase, R-Ras. Heretofore, all known DEDs functioned in the regulation of apoptosis. In contrast, the DED of PEA-15 is essential for its capacity to reverse suppression of integrin activation. Thus, certain DED-containing proteins can regulate integrin activation as opposed to apoptotic protease cascades.
整合素配体结合亲和力（激活）的增加是由细胞内信号事件触发的。一条由Ras启动的丝裂原活化蛋白激酶途径抑制成纤维细胞中的整合素激活。我们利用表达克隆技术分离出可阻止Ras对整合素激活进行抑制的cDNA。在此，我们报告，PEA-15，一种含有小死亡效应结构域（DED）的蛋白，可阻断Ras的抑制作用。PEA-15并不阻断Ras激活ERK丝裂原活化蛋白激酶途径的能力。相反，它通过一条被显性负性形式的独特小GTP酶R-Ras所阻断的途径来抑制这种抑制作用。在此之前，所有已知的DED都在细胞凋亡调控中发挥作用。相比之下，PEA-15的DED对于其逆转整合素激活抑制作用的能力至关重要。因此，某些含DED的蛋白可调节整合素激活，而非凋亡蛋白酶级联反应。
