Esteban Pedro F, Yoon Hye-Young, Becker Jodi, Dorsey Susan G, Caprari Paola, Palko Mary Ellen, Coppola Vincenzo, Saragovi H Uri, Randazzo Paul A, Tessarollo Lino
Neural Development Group, Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD 21702, USA.
J Cell Biol. 2006 Apr 24;173(2):291-9. doi: 10.1083/jcb.200512013.
Neurotrophins play an essential role in mammalian development. Most of their functions have been attributed to activation of the kinase-active Trk receptors and the p75 neurotrophin receptor. Truncated Trk receptor isoforms lacking the kinase domain are abundantly expressed during development and in the adult; however, their function and signaling capacity is largely unknown. We show that the neurotrophin-3 (NT3) TrkCT1-truncated receptor binds to the scaffold protein tamalin in a ligand-dependent manner. Moreover, NT3 initiation of this complex leads to activation of the Rac1 GTPase through adenosine diphosphate-ribosylation factor 6 (Arf6). At the cellular level, NT3 binding to TrkCT1-tamalin induces Arf6 translocation to the membrane, which in turn causes membrane ruffling and the formation of cellular protrusions. Thus, our data identify a new signaling pathway elicited by the kinase-deficient TrkCT1 receptor. Moreover, we establish NT3 as an upstream regulator of Arf6.
神经营养因子在哺乳动物发育过程中发挥着至关重要的作用。它们的大多数功能都归因于激酶活性的Trk受体和p75神经营养因子受体的激活。在发育过程中和成年期，缺乏激酶结构域的截短型Trk受体亚型大量表达；然而，它们的功能和信号传导能力在很大程度上尚不清楚。我们发现神经营养因子-3（NT3）截短型TrkCT1受体以配体依赖的方式与支架蛋白talin结合。此外，NT3引发的这种复合物通过二磷酸腺苷核糖基化因子6（Arf6）导致Rac1 GTP酶激活。在细胞水平上，NT3与TrkCT1-talin的结合诱导Arf6转位至细胞膜，进而导致细胞膜褶皱和细胞突起的形成。因此，我们的数据确定了由激酶缺陷型TrkCT1受体引发的一条新的信号通路。此外，我们确立了NT3作为Arf6的上游调节因子的地位。
