NGF activates the phosphorylation of MAP1B by GSK3β through the TrkA receptor and not the p75NTR receptor
NGF activates the phosphorylation of MAP1B by GSK3β through the TrkA receptor and not the p75NTR receptor
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DOI：
10.1046/j.1471-4159.2003.02062.x
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发表时间：
2003-11-01
影响因子：
4.7
通讯作者：
Gordon-Weeks, PR
中科院分区：
文献类型：
--
作者：
Goold, RG;Gordon-Weeks, PR
我们最近发现，神经生长因子(NGF)通过激活PC12细胞中与神经突起生长密切相关的丝氨酸/苏氨酸激酶糖原合成酶3β(GSK3β)而诱导微管相关蛋白1B(MAP1B)的磷酸化。PC12细胞表达两种类型的NGF膜受体：TrkA受体和p75(NTR)受体，从我们的研究中尚不清楚哪种受体起作用。我们在这里表明，脑源性神经营养因子激活p75(NTR)但不激活TrkA受体，并不刺激PC12细胞中MAP1B的GSK3β磷酸化。同样，在缺乏TrkA受体但表达p75(NTR)受体(PC12 NNR)的PC12细胞中，NGF未能激活MAP1B的GSK3β磷酸化。培养的鸡睫状神经节神经元缺乏TrkA受体，但表达p75(NTR)，也不显示NGF依赖的GSK3β对MAP1B的磷酸化；而在培养的大鼠颈上神经节神经元，NGF激活TrkA受体可诱导MAP1B的GSK3β磷酸化。最后，K252a抑制PC12细胞和颈上神经节细胞中TrkA受体酪氨酸激酶的活性，并呈剂量依赖性地抑制轴突的延长，同时阻断MAP1B的GSK3β磷酸化。这些结果表明，NGF激活GSK3β是通过TrkA酪氨酸激酶受体，而不是通过p75(NTR)受体。
We have recently shown that nerve growth factor (NGF) induces the phosphorylation of the microtubule-associated protein 1B (MAP1B) by activating the serine/threonine kinase glycogen synthase kinase 3beta (GSK3beta) in a spatio-temporal pattern in PC12 cells that correlates tightly with neurite growth. PC12 cells express two types of membrane receptor for NGF: TrkA receptors and p75(NTR) receptors, and it was not clear from our studies which receptor was responsible. We show here that brain-derived neurotrophic factor, which activates p75(NTR) but not TrkA receptors, does not stimulate GSK3beta phosphorylation of MAP1B in PC12 cells. Similarly, NGF fails to activate GSK3beta phosphorylation of MAP1B in PC12 cells that lack TrkA receptors but express p75(NTR) receptors (PC12 nnr). Chick ciliary ganglion neurons in culture lack TrkA receptors but express p75(NTR) and also fail to show NGF-dependent GSK3beta phosphorylation of MAP1B, whereas in rat superior cervical ganglion neurons in culture, NGF activation of TrkA receptors elicits GSK3beta phosphorylation of MAP1B. Finally, inhibition of TrkA receptor tyrosine kinase activity in PC12 cells and superior cervical ganglion neurons with K252a potently and dose-dependently inhibits neurite elongation while concomitantly blocking GSK3beta phosphorylation of MAP1B. These results suggest that the activation of GSK3beta by NGF is mediated through the TrkA tyrosine kinase receptor and not through p75(NTR) receptors.