The Miami Project to Cure Paralysis, Department of Pharmacology, University of Miami, Miller School of Medicine, Miami, FL 33136-1060, USA.
Mol Syst Biol. 2010 Jul;6:391. doi: 10.1038/msb.2010.52.
Development and regeneration of the nervous system requires the precise formation of axons and dendrites. Kinases and phosphatases are pervasive regulators of cellular function and have been implicated in controlling axodendritic development and regeneration. We undertook a gain-of-function analysis to determine the functions of kinases and phosphatases in the regulation of neuron morphology. Over 300 kinases and 124 esterases and phosphatases were studied by high-content analysis of rat hippocampal neurons. Proteins previously implicated in neurite growth, such as ERK1, GSK3, EphA8, FGFR, PI3K, PKC, p38, and PP1a, were confirmed to have effects in our functional assays. We also identified novel positive and negative neurite growth regulators. These include neuronal-developmentally regulated kinases such as the activin receptor, interferon regulatory factor 6 (IRF6) and neural leucine-rich repeat 1 (LRRN1). The protein kinase N2 (PKN2) and choline kinase alpha (CHKA) kinases, and the phosphatases PPEF2 and SMPD1, have little or no established functions in neuronal function, but were sufficient to promote neurite growth. In addition, pathway analysis revealed that members of signaling pathways involved in cancer progression and axis formation enhanced neurite outgrowth, whereas cytokine-related pathways significantly inhibited neurite formation.
神经系统的发育和再生需要轴突和树突的精确形成。激酶和磷酸酶是细胞功能的普遍调节剂，它们在控制轴突和树突的发育和再生方面起着重要作用。我们进行了功能获得性分析，以确定激酶和磷酸酶在神经元形态调节中的作用。通过对大鼠海马神经元进行高内涵分析，研究了超过 300 种激酶和 124 种酯酶和磷酸酶。先前被认为与神经突生长有关的蛋白质，如 ERK1、GSK3、EphA8、FGFR、PI3K、PKC、p38 和 PP1a，在我们的功能测定中被证实具有作用。我们还鉴定了新的正、负向神经突生长调节剂。这些包括神经元发育调节激酶，如激活素受体、干扰素调节因子 6（IRF6）和神经亮氨酸重复 1（LRRN1）。蛋白激酶 N2（PKN2）和胆碱激酶α（CHKA）激酶，以及磷酸酶 PPEF2 和 SMPD1，在神经元功能中几乎没有或没有确定的作用，但足以促进神经突生长。此外，通路分析显示，参与癌症进展和轴形成的信号通路成员增强了神经突的生长，而细胞因子相关通路则显著抑制了神经突的形成。
