Sohn Sue J, Lewis Gavin M, Winoto Astar
Division of Immunology and Cancer Research Laboratory, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3200, USA.
EMBO J. 2008 Jul 9;27(13):1896-906. doi: 10.1038/emboj.2008.114. Epub 2008 Jun 12.
The mitogen-activated protein kinases (MAPKs) ERK1/2, p38, and JNK are thought to determine survival-versus-death fate in developing thymocytes. However, this view was challenged by studies using 'MEK1-ERK1/2-specific' pharmacological inhibitors, which block both positive and negative selection. Recently, these inhibitors were also shown to affect MEK5, an upstream activator of ERK5, another class of MAPK with homology to ERK1/2. To define the contribution of the MEK5-ERK5 pathway in T-cell development, we retrovirally expressed dominant-negative or constitutively activated form of MEK5 to inhibit or activate the MEK5-ERK5 pathway. We demonstrate that MEK5 regulates apoptosis of developing thymocytes but has no function in positive selection. ERK5 activity correlates with the levels of Nur77 family members but not that of Bim, two effector pathways of thymocyte apoptosis. These results illustrate the critical involvement of the MEK5-ERK5 pathway in thymocyte development distinct from that of ERK1/2 and highlight the importance of the MAPK network in mediating differential effects pertaining to T-cell differentiation and apoptosis.
丝裂原活化蛋白激酶（MAPKs）ERK1/2、p38和JNK被认为在发育中的胸腺细胞中决定生存与死亡的命运。然而，使用“MEK1-ERK1/2特异性”药理抑制剂的研究对这一观点提出了挑战，这些抑制剂会阻断阳性和阴性选择。最近，这些抑制剂还被证明会影响MEK5，MEK5是ERK5的上游激活剂，ERK5是另一类与ERK1/2具有同源性的MAPK。为了确定MEK5-ERK5通路在T细胞发育中的作用，我们通过逆转录病毒表达显性负性或组成型激活形式的MEK5来抑制或激活MEK5-ERK5通路。我们证明MEK5调节发育中胸腺细胞的凋亡，但在阳性选择中无功能。ERK5活性与Nur77家族成员的水平相关，但与Bim的水平无关，Bim是胸腺细胞凋亡的两条效应通路。这些结果说明了MEK5-ERK5通路在胸腺细胞发育中的关键作用，与ERK1/2不同，并强调了MAPK网络在介导与T细胞分化和凋亡相关的差异效应中的重要性。
