Geetha Thangiah, Jiang Jianxiong, Wooten Marie W
Department of Biological Sciences, Program in Cellular and Molecular Biosciences, Auburn University, Auburn, Alabama 36849, USA.
Mol Cell. 2005 Oct 28;20(2):301-12. doi: 10.1016/j.molcel.2005.09.014.
Nerve growth factor (NGF) binding to p75(NTR) influences TrkA signaling, yet the molecular mechanism is unknown. We observe that NGF stimulates TrkA polyubiquitination, which was attenuated in p75(-/-) mouse brain. TrkA is a substrate of tumor necrosis factor receptor-associated factor 6 (TRAF6), and expression of K63R mutant ubiquitin or an absence of TRAF6 abrogated TrkA polyubiquitination and internalization. NGF stimulated formation of a TrkA/p75(NTR) complex through the p62 scaffold, recruiting the E3/TRAF6 and E2/UbcH7. Peptide targeted to the TRAF6 binding site present in p62 blocked interaction with TRAF6 and inhibited ubiquitination of TrkA, signaling, internalization, and NGF-dependent neurite outgrowth. Mutation of K485 to R blocked TRAF6 and NGF-dependent polyubiquitination of TrkA, resulting in retention of the receptor on the membrane and an absence in activation of specific signaling pathways. These findings reveal that polyubiquitination serves as a common platform for the control of receptor internalization and signaling.
神经生长因子（NGF）与p75神经营养因子受体（p75(NTR)）结合会影响酪氨酸激酶受体A（TrkA）信号传导，但其分子机制尚不清楚。我们观察到，NGF刺激TrkA多聚泛素化，而在p75基因敲除（p75(-/-)）小鼠大脑中这种多聚泛素化作用减弱。TrkA是肿瘤坏死因子受体相关因子6（TRAF6）的底物，K63R突变型泛素的表达或TRAF6的缺失消除了TrkA多聚泛素化和内化。NGF通过p62支架刺激形成TrkA/p75(NTR)复合物，募集E3/TRAF6和E2/UbcH7。靶向p62中TRAF6结合位点的肽阻断了与TRAF6的相互作用，并抑制了TrkA的泛素化、信号传导、内化以及NGF依赖性神经突生长。将K485突变为R阻断了TRAF6和NGF依赖性的TrkA多聚泛素化，导致受体保留在膜上且特定信号通路未被激活。这些发现表明，多聚泛素化是控制受体内化和信号传导的共同平台。
