Department of Biosynthesis of Nucleic Acids, Institute of Molecular Biology and Genetics, 150 Zabolotnogo street, Kyiv 03680, Ukraine.
Int J Biol Sci. 2012;8(1):39-48. doi: 10.7150/ijbs.8.39. Epub 2011 Nov 16.
The activation of extracellular signal-regulated kinases (ERK1/2) has been associated with specific outcomes. Sustained activation of ERK1/2 by nerve growth factor (NGF) is associated with translocation of ERKs to the nucleus of PC12 cells and precedes their differentiation into sympathetic-like neurons whereas transient activation by epidermal growth factor (EGF) leads to cell proliferation. It was demonstrated that different growth factors initiating the same cellular signaling pathways may lead to the different cell destiny, either to proliferation or to the inhibition of mitogenesis and apoptosis. Thus, further investigation on kinetic differences in activation of certain signal cascades in different cell types by biologically different agents are necessary for understanding the mechanisms as to how cells make a choice between proliferation and differentiation.It was reported that chitinase 3-like 1 (CHI3L1) protein promotes the growth of human synovial cells as well as skin and fetal lung fibroblasts similarly to insulin-like growth factor 1 (IGF1). Both are involved in mediating the mitogenic response through the signal-regulated kinases ERK1/2. In addition, CHI3L1 which is highly expressed in different tumors including glioblastomas possesses oncogenic properties. As we found earlier, chitinase 3-like 2 (CHI3L2) most closely related to human CHI3L1 also showed increased expression in glial tumors at both the RNA and protein levels and stimulated the activation of the MAPK pathway through phosphorylation of ERK1/2 in 293 and U87 MG cells. The work described here demonstrates the influence of CHI3L2 and CHI3L1 on the duration of MAPK cellular signaling and phosphorylated ERK1/2 translocation to the nucleus. In contrast to the activation of ERK1/2 phosphorylation by CHI3L1 that leads to a proliferative signal (similar to the EGF effect in PC12 cells), activation of ERK1/2 phosphorylation by CHI3L2 (similar to NGF) inhibits cell mitogenesis and proliferation.
细胞外信号调节激酶（ERK1/2）的激活与特定的结果有关。神经生长因子（NGF）持续激活 ERK1/2 与 ERKs 向 PC12 细胞核的易位有关，并先于它们分化为交感神经元，而表皮生长因子（EGF）的短暂激活导致细胞增殖。研究表明，启动相同细胞信号通路的不同生长因子可能导致不同的细胞命运，无论是增殖还是抑制有丝分裂和细胞凋亡。因此，需要进一步研究不同生物活性物质在不同细胞类型中激活特定信号级联的动力学差异，以了解细胞在增殖和分化之间做出选择的机制。有报道称，几丁质酶 3 样 1（CHI3L1）蛋白与胰岛素样生长因子 1（IGF1）相似，促进人滑膜细胞以及皮肤和胎儿肺成纤维细胞的生长。两者都参与通过信号调节激酶 ERK1/2 介导有丝分裂反应。此外，CHI3L1 在包括神经胶质瘤在内的不同肿瘤中高度表达，具有致癌特性。正如我们之前发现的，与人类 CHI3L1 最密切相关的几丁质酶 3 样 2（CHI3L2）在神经胶质瘤中也表现出 RNA 和蛋白质水平的表达增加，并通过在 293 和 U87 MG 细胞中磷酸化 ERK1/2 刺激 MAPK 途径的激活。这里描述的工作表明了 CHI3L2 和 CHI3L1 对 MAPK 细胞信号持续时间和磷酸化 ERK1/2 向核易位的影响。与 CHI3L1 激活 ERK1/2 磷酸化导致增殖信号（类似于 PC12 细胞中的 EGF 效应）相反，CHI3L2（类似于 NGF）激活 ERK1/2 磷酸化抑制细胞有丝分裂和增殖。
