神经生长因子（NGF）通过TrkA受体而非p75（NTR）受体，激活糖原合成酶激酶3β（GSK3β）介导的微管相关蛋白1B（MAP1B）磷酸化。

NGF activates the phosphorylation of MAP1B by GSK3beta through the TrkA receptor and not the p75(NTR) receptor.

作者信息

Goold Robert G, Gordon-Weeks Phillip R

机构信息

The MRC Centre for Developmental Neurobiology, King's College London, London, UK.

出版信息

J Neurochem. 2003 Nov;87(4):935-46. doi: 10.1046/j.1471-4159.2003.02062.x.

DOI:10.1046/j.1471-4159.2003.02062.x

Abstract

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 p75NTR receptors, and it was not clear from our studies which receptor was responsible. We show here that brain-derived neurotrophic factor, which activates p75NTR 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 p75NTR receptors (PC12 nnr). Chick ciliary ganglion neurons in culture lack TrkA receptors but express p75NTR 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 p75NTR receptors.

摘要

我们最近发现，神经生长因子（NGF）通过激活丝氨酸/苏氨酸激酶糖原合酶激酶3β（GSK3β），以时空模式诱导微管相关蛋白1B（MAP1B）磷酸化，这与PC12细胞中的神经突生长密切相关。PC12细胞表达两种NGF膜受体：TrkA受体和p75NTR受体，而我们的研究尚不清楚哪种受体起作用。我们在此表明，激活p75NTR而不激活TrkA受体的脑源性神经营养因子不会刺激PC12细胞中MAP1B的GSK3β磷酸化。同样，在缺乏TrkA受体但表达p75NTR受体的PC12细胞（PC12 nnr）中，NGF也无法激活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p75NTR，也未显示出NGF依赖性的MAP1B的GSK3β磷酸化，而在培养的大鼠颈上神经节神经元中，TrkA受体的NGF激活会引发MAP1B的GSK3β磷酸化。最后，用K252a抑制PC12细胞和颈上神经节神经元中TrkA受体酪氨酸激酶活性，可有效且剂量依赖性地抑制神经突伸长，同时阻断MAP1B的GSK3β磷酸化。这些结果表明，NGF对GSK3β的激活是通过TrkA酪氨酸激酶受体介导的，而不是通过p75NTR受体。