Wooten M W, Geetha T
Program in Cellular and Molecular Biosciences, Department of Biological Sciences, 331 Funchess Hall, Auburn University, Auburn, AL 36849, USA.
Biochem Soc Trans. 2006 Nov;34(Pt 5):757-60. doi: 10.1042/BST0340757.
NGF (nerve growth factor) binding to TrkA (tropomyosin receptor kinase A) induces dimerization, autophosphorylation and internalization of the receptor to signalling vesicles for delivery of differentiation signals. TrkA interacts with p75 receptor through the p62-TRAF-6 (tumour-necrosis-factor-receptor-associated factor 6) complex bridging the two receptors. The atypical protein kinase C is activated and recruited to the receptor complex as well. TrkA is Lys63-polyubiquitinated on Lys485 by the E3 (ubiquitin ligase), TRAF-6, and E2 (ubiquitin-conjugating enzyme), UbcH7. Inhibition of polyubiquitination has been observed to interrupt signalling and internalization. Furthermore, an absence of p62 prevents endosomal localization and signalling. Altogether, these findings reveal Lys63-linked polyubiquitin chains and the shuttling protein p62 co-ordinately regulate TrkA internalization, trafficking and sorting.
神经生长因子（NGF）与原肌球蛋白受体激酶A（TrkA）结合会诱导受体二聚化、自磷酸化并内化至信号小泡，以传递分化信号。TrkA通过连接两个受体的p62-肿瘤坏死因子受体相关因子6（TRAF-6）复合物与p75受体相互作用。非典型蛋白激酶C也会被激活并募集至受体复合物。E3泛素连接酶TRAF-6和E2泛素结合酶UbcH7使TrkA在赖氨酸485处发生赖氨酸63位多聚泛素化。已观察到多聚泛素化的抑制会中断信号传导和内化。此外，p62的缺失会阻止内体定位和信号传导。总之，这些发现揭示了赖氨酸63连接的多聚泛素链和穿梭蛋白p62协同调节TrkA的内化、运输和分选。
