NEUROTROPHIN SIGNAL-TRANSDUCTION BY THE TRK RECEPTOR

The initial event in the neuronal differentiation of PC12 cells is the binding of the neurotrophin nerve growth factor (NGF) to the Trk rece ptor. This interaction stimulates the intrinsic tyrosine kinase activi ty of Trk, initiating a signalling cascade involving the phosphorylati on of intracellular proteins on tyrosine, serine, and threonine residu es. These signals are then in turn propagated to other messengers, ult imately leading to differentiation, neurotrophin-dependent-survival, a nd the loss of proliferative capacity. To transmit NGF signals, NGF-ac tivated Trk rapidly associates with the cytoplasmic proteins, SHC, PI- 3 kinase, and PLC-gamma 1. These proteins are involved in stimulating the formation of various second messenger molecules and activating the Ras signal transduction pathway. Studies with Trk mutants indicate th at the activation of the Ras pathway is necessary for complete differe ntiation of PC12-derived cells and for the maintenance of the differen tiated phenotype. Trk also induces the tyrosine phosphorylation of SNT , a specific target of neurotrophic factor activity in neuronal cells. This review will discuss the potential roles of Trk and the proteins of the Trk signalling pathways in NGF function, and summarize our atte mpts to understand the mechanisms used by Trk to generate the many phe notypic responses of PC12 cells to NGF. (C) 1994 John Wiley & Sons, In c.