Sprouty4 Is an Endogenous Negative Modulator of TrkA Signaling and Neuronal Differentiation Induced by NGF

被引:25
作者
Alsina, Fernando C. [1 ]
Irala, Dolores [1 ]
Fontanet, Paula A. [1 ]
Hita, Francisco J. [1 ]
Ledda, Fernanda [1 ,2 ]
Paratcha, Gustavo [1 ,2 ]
机构
[1] Univ Buenos Aires, Div Mol & Cellular Neurosci, Inst Cellular Biol & Neurosci Prof Dr E De Robert, CONICET,Sch Med, Buenos Aires, DF, Argentina
[2] Karolinska Inst, Dept Neurosci, Lab Mol & Cellular Neurosci, Stockholm, Sweden
来源
PLOS ONE | 2012年 / 7卷 / 02期
基金
英国医学研究理事会;
关键词
TYROSINE KINASE; ERK ACTIVATION; PROTEIN-KINASE; GROWTH; ANTAGONIST; PATHWAYS; CELLS; TRANSDUCTION; DOWNSTREAM; INHIBITION;
D O I
10.1371/journal.pone.0032087
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The Sprouty (Spry) family of proteins represents endogenous regulators of downstream signaling pathways induced by receptor tyrosine kinases (RTKs). Using real time PCR, we detect a significant increase in the expression of Spry4 mRNA in response to NGF, indicating that Spry4 could modulate intracellular signaling pathways and biological processes induced by NGF and its receptor TrkA. In this work, we demonstrate that overexpression of wild-type Spry4 causes a significant reduction in MAPK and Rac1 activation and neurite outgrowth induced by NGF. At molecular level, our findings indicate that ectopic expression of a mutated form of Spry4 (Y53A), in which a conserved tyrosine residue was replaced, fail to block both TrkA-mediated Erk/MAPK activation and neurite outgrowth induced by NGF, suggesting that an intact tyrosine 53 site is required for the inhibitory effect of Spry4 on NGF signaling. Downregulation of Spry4 using small interference RNA knockdown experiments potentiates PC12 cell differentiation and MAPK activation in response to NGF. Together, these findings establish a new physiological mechanism through which Spry4 regulates neurite outgrowth reducing not only the MAPK pathway but also restricting Rac1 activation in response to NGF.
引用
收藏
页数:12
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