TIAM1 AS A NOVEL SIGNALING MEDIATOR OF NGF-DEPENDENT NEURITE OUTGROWTH

SHIRAZI FARD; KELE, J1; VILAR, M; PARATCHA G; LEDDA F

Helsinki

Congreso; NGF 2010; 2010

Many evidence support a role of the Rac1-specific guanine exchange factor (GEF) Tiam1 in membrane ruffling, neuronal cell spreading, neurite formation, and dendritic spine morphogenesis. Recent studies have revealed that the Tiam1-Rac1 complex plays a critical role in NT-3 and BDNF-mediated signal transduction leading to actin cytoskeletal remodeling that is essential for Schwann cell migration and neurite outgrowth of cortical neurons, respectively. While Tiam1 appear to mediate NT-3 and BDNF-induced Rac1 activation, it is not clear whether activation of Rac1 by Tiam1 is critical for biological responses induced by NGF and TrkA. In this work, we identify Tiam1 as a novel mediator of NGF/TrkA-dependent neurite elongation. In particular, we show that knockdown of Tiam1 causes a significant reduction in Rac1 activity and neurite outgrowth induced by NGF. Physical interaction between Tiam1 and active Ras (Ras-GTP), but not tyrosine phosphorylation of Tiam1, plays a central role in Rac1 activation by NGF. In addition, our findings indicate that Ras is required to associate Tiam1 with Rac1 and promote Rac1 activation upon NGF stimulation. Taken together, these findings define a novel molecular mechanism through which Tiam1 mediates TrkA signaling and neurite outgrowth induced by NGF