Lrig1 is an endogenous inhibitor of ret receptor tyrosine kinase activation, downstream signaling, and biological responses to GDNF
Lrig1 is an endogenous inhibitor of ret receptor tyrosine kinase activation, downstream signaling, and biological responses to GDNF
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DOI：
10.1523/jneurosci.2196-07.2008
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发表时间：
2008-01-02
影响因子：
5.3
通讯作者：
Paratcha, Gustavo
中科院分区：
文献类型：
--
作者：
Ledda, Fernanda;Bieraugel, Oliver;Paratcha, Gustavo
胶质细胞源性神经营养因子（GDNF）/Ret信号转导对腹侧中脑多巴胺能、运动、感觉和交感神经元具有强有力的营养作用。限制Ret受体酪氨酸激酶激活的分子机制还不清楚。在这里，我们表明，Lrig 1，一个跨膜蛋白含有富含亮氨酸的重复序列和Ig样结构域在其胞外区，在负反馈回路中的行为，以调节Ret受体酪氨酸激酶的活性。特别是，我们证明，Lrig 1是能够与Ret的物理相互作用，Lrig 1/Ret协会抑制GDNF结合，招聘的Ret脂筏，受体自磷酸化，和丝裂原活化蛋白激酶（MAPK）激活响应GDNF。在神经元细胞中，Lrig 1过表达也以细胞自主的方式抑制GDNF/Ret诱导的神经突生长。使用小干扰RNA敲低实验下调Lrig 1增强了GDNF对神经元分化和MAPK激活的响应。总之，这些结果提供了对Lrig 1功能的深入了解，并建立了一种新的生理机制来限制GDNF和Ret在神经元细胞中诱导的信号传导和生物反应。
Glial cell line-derived neurotrophic factor (GDNF)/Ret signaling has potent trophic effects on ventral midbrain dopaminergic, motor, sensory, and sympathetic neurons. The molecular mechanisms that restrict Ret receptor tyrosine kinase activation are not well understood. Here, we show that Lrig1, a transmembrane protein containing leucine-rich repeats and Ig-like domains in its extracellular region, acts in a negative feedback loop to regulate the activity of Ret receptor tyrosine kinase. In particular, we demonstrate that Lrig1 is capable of physically interacting with Ret and that Lrig1/Ret association inhibits GDNF binding, recruitment of Ret to lipid rafts, receptor autophosphorylation, and mitogen-activated protein kinase (MAPK) activation in response to GDNF. In neuronal cells, Lrig1 overexpression also inhibits GDNF/Ret-induced neurite outgrowth in a cell-autonomous manner. Downregulation of Lrig1 using small interference RNA knock-down experiments potentiates both neuronal differentiation and MAPK activation in response to GDNF. Together, these results provide an insight into Lrig1 function and establish a new physiological mechanism to restrict signaling and biological responses induced by GDNF and Ret in neuronal cells.