Yoong Li Foong, Wan Guoqiang, Too Heng-Phon
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Lower Kent Ridge Road, 119260, Singapore.
Mol Cell Neurosci. 2009 Aug;41(4):464-73. doi: 10.1016/j.mcn.2009.05.002. Epub 2009 May 20.
Glial cell line-derived neurotrophic factor (GDNF) transduces signal and promotes neurite outgrowths in diverse neurons through the interactions of GDNF family receptor alpha 1 (GFRalpha1) and other co-receptors including Ret receptor tyrosine kinase and NCAM. GFRalpha1 is alternatively spliced into two isoforms, GFRalpha1a and GFRalpha1b, with five amino acids difference. In this study, we found that both GFRalpha1a and GFRalpha1b were expressed in various human tissues. Interestingly, when stimulated with GDNF, GFRalpha1a but not GFRalpha1b promoted neurite outgrowth in neuroblastoma cells through the activations of ERK1/2, Rac1 and Cdc42. Remarkably, in cells co-expressing GFRalpha1a and GFRalpha1b, GDNF inhibited neurite outgrowths. The inhibitory activity of GFRalpha1b was dependent on RhoA and ROCK activation. Furthermore, GFRalpha1b but not GFRalpha1a activated Rho and various ROCK downstream effectors LIMK1/2, cofilin and MLC2. This study demonstrates the hitherto unrecognized roles of GFRalpha1 isoforms in the activation of distinct signaling pathways and in neurite outgrowths.
胶质细胞系源性神经营养因子（GDNF）通过胶质细胞系源性神经营养因子家族受体α1（GFRα1）与包括Ret受体酪氨酸激酶和NCAM在内的其他共受体的相互作用来转导信号并促进多种神经元的轴突生长。GFRα1可选择性剪接成两种异构体，即GFRα1a和GFRα1b，它们相差五个氨基酸。在本研究中，我们发现GFRα1a和GFRα1b均在多种人体组织中表达。有趣的是，在用GDNF刺激时，GFRα1a而非GFRα1b通过激活ERK1/2、Rac1和Cdc42促进神经母细胞瘤细胞的轴突生长。值得注意的是，在共表达GFRα1a和GFRα1b的细胞中，GDNF抑制轴突生长。GFRα1b的抑制活性依赖于RhoA和ROCK的激活。此外，GFRα1b而非GFRα1a激活Rho以及各种ROCK下游效应分子LIMK1/2、丝切蛋白和肌球蛋白轻链2。本研究证明了GFRα1异构体在激活不同信号通路和轴突生长中迄今未被认识到的作用。
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