Phosphoinositide 3-kinase regulates crosstalk between Trk A tyrosine kinase and p75NTR-dependent sphingolipid signaling pathways
Phosphoinositide 3-kinase regulates crosstalk between Trk A tyrosine kinase and p75NTR-dependent sphingolipid signaling pathways
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DOI：
10.1046/j.1471-4159.2001.00171.x
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发表时间：
2001-03-01
影响因子：
4.7
通讯作者：
Dobrowsky, RT
中科院分区：
文献类型：
--
作者：
Bilderback, TR;Gazula, VR;Dobrowsky, RT
研究了PC 12细胞中与Trk A和p75（NTR）神经营养因子受体偶联的信号通路之间的串扰机制。响应于神经生长因子（NGF），Trk A活化抑制p75（NTR）依赖性鞘磷脂（SM）水解。磷酸肌醇3-激酶（PI 3-激酶）抑制剂LY 294002逆转了这种抑制，表明PI 3-激酶的Trk A活化对于抑制p75（NTR）的鞘脂信号传导是必需的。与此相反，SM水解诱导的神经营养因子-3（NT-3），这并不激活PI-3激酶，是不受LY 294002。然而，瞬时表达的组成型活性PI 3-激酶抑制p75（NTR）依赖的SM水解的神经生长因子和NT-3。有趣的是，神经生长因子诱导的协会激活PI 3-激酶与酸性鞘磷脂酶（SMase）。这种相互作用定位于小窝相关结构域，并与免疫沉淀酸性SMase活性降低50%相关。神经生长因子刺激的PI 3-激酶活性是必要的抑制酸性SMase，但不需要配体诱导的协会的PI 3-激酶的p85亚基与磷脂酶。最后，这种相互作用是特异性的NGF，因为EGF没有诱导协会的PI 3-激酶与酸性SMase，总之，我们的数据表明，PI 3-激酶调节抑制性串扰之间的Trk A酪氨酸激酶和p75 NTR依赖的鞘脂信号通路，这种相互作用定位于小窝相关的结构域。
The mechanism of crosstalk between signaling pathways coupled to the Trk A and p75(NTR) neurotrophin receptors in PC12 cells was examined. In response to nerve growth factor (NGF), Trk A activation inhibited p75(NTR)-dependent sphingomyelin (SM) hydrolysis. The phosphoinositide 3-kinase (PI 3-kinase) inhibitor, LY294002, reversed this inhibition suggesting that Trk A activation of PI 3-kinase is necessary to inhibit sphingolipid signaling by p75(NTR). In contrast, SM hydrolysis induced by neurotrophin-3 (NT-3), which did not activate PI-3 kinase, was uneffected by LY294002. However, transient expression of a constituitively active PI 3-kinase inhibited p75(NTR)-dependent SM hydrolysis by both NGF and NT-3. Intriguingly, NGF induced an association of activated PI 3-kinase with acid sphingomyelinase (SMase). This interaction localized to caveolae-related domains and correlated with a 50% decrease in immunoprecipitated acid SMase activity. NGF-stimulated PI 3-kinase activity was necessary for inhibition of acid SMase but was not required for ligand-induced association of the p85 subunit of PI 3-kinase with the phospholipase. Finally, this interaction was specific for NGF since EGF did not induce an association of PI 3-kinase with acid SMase, In summary, our data suggest that PI 3-kinase regulates the inhibitory crosstalk between Trk A tyrosine kinase and p75NTR-dependent sphingolipid signaling pathways and that this interaction localizes to caveolae-related domains.