ARMS/Kidins220 and Synembryn-B levels regulate NGF-mediated secretion

Abstract

Proper development of the nervous system requires a temporally and spatially orchestrated set of events including differentiation, synapse formation and neurotransmission. NGF acting through the TrkA neurotrophin receptor regulates many of these events. However, the molecular mechanisms responsible for NGF-regulated secretion are not completely understood. Here, we describe a new signaling pathway involving TrkA, ARMS/Kidins220, Synembryn-B, and Rac1 in NGF-mediated secretion in PC12 cells. Whereas overexpression of ARMS/Kidins220 blocked NGF-mediated secretion, without affecting basal secretion, a decrease in ARMS/Kidins220 resulted in potentiation. Similar effects were observed with Synembryn-B, a protein that interacts directly with ARMS/Kidins220. Downstream of ARMS/Kidins220 and Synembryn-B are Gαq and Trio proteins, which modulate the activity of Rac1 in response to NGF. Expression of a dominant negative of Rac1 rescued the secretion defects of cells overexpressing ARMS/Kidins220 or Synembryn-B. Thus this neurotrophin pathway represents a new mechanism responsible for NGF-regulated secretion.