Sprouty2 regulates growth and differentiation of human neuroblastoma cells through RET tyrosine kinase
Sprouty2 regulates growth and differentiation of human neuroblastoma cells through RET tyrosine kinase
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DOI：
10.1111/j.1349-7006.2007.00457.x
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发表时间：
2007-06-01
期刊：
影响因子：
5.7
通讯作者：
Takahashi, Masahide
中科院分区：
文献类型：
--
作者：
Ishida, Maki;Ichihara, Masatoshi;Takahashi, Masahide
Sprouty（SPRY）蛋白家族包括由受体酪氨酸激酶启动的下游信号传导的重要调节剂。在本研究中，我们研究了SPRY蛋白通过胶质细胞源性神经营养因子（GDNF）激活的RET受体酪氨酸激酶在细胞内信号传导中的作用。在用RET和GDNF受体家族α 1（GFR α 1）基因转染的HEK 293 T细胞中，SPRY 1、SPRY 2、SPRY 3和SPRY 4的表达显著降低了持续的ERK活化以及ELK-1活化。因为在表达RET和GFR α 1的TGW人神经母细胞瘤细胞中，GDNF有效地诱导SPRY 2的表达，我们进一步研究了SPRY 2在TGW细胞生长和分化中的作用。野生型SPRY 2（WT-SPRY 2）的表达降低了TGW细胞的生长。相反，SPRY 2的显性负性形式（MT-SPRY 2，具有突变的酪氨酸残基）的表达增强细胞增殖。此外，WT-SPRY 2的表达减少了GDNF依赖的TGW细胞的突起生长，而MT-SPRY 2的表达增强了它。综上所述，我们的结果表明，SPRY 2调节GDNF依赖的增殖和分化的TGW神经母细胞瘤细胞由RET酪氨酸激酶介导。
The Sprouty (SPRY) family of proteins includes important regulators of downstream signaling initiated by receptor tyrosine kinases. In the present study, we investigated the role of SPRY proteins in intracellular signaling via the RET receptor tyrosine kinase activated by glial cell line-derived neurotrophic factor (GDNF). Expression of SPRY1, SPRY2, SPRY3 and SPRY4 in HEK293T cells transfected with RET and GDNF receptor family alpha 1 (GFR alpha 1) genes significantly reduced sustained ERK activation as well as ELK-1 activation. Because expression of SPRY2 was efficiently induced by GDNF in TGW human neuroblastoma cells expressing RET and GFR alpha 1, we further investigated the role of SPRY2 in the growth and differentiation of TGW cells. Expression of wild-type SPRY2 (WT-SPRY2) decreased the growth of TGW cells. In contrast, expression of a dominant negative form of SPRY2 (MT-SPRY2, with a mutated tyrosine residue) enhanced cell proliferation. In addition, expression of WT-SPRY2 reduced GDNF-dependent neurite outgrowth of TGW cells, whereas expression of MT-SPRY2 enhanced it. Taken together, our results suggest that SPRY2 regulates GDNF-dependent proliferation and differentiation of TGW neuroblastoma cells mediated by RET tyrosine kinase.