NEURONAL DIFFERENTIATION SIGNALS ARE CONTROLLED BY NERVE GROWTH-FACTOR RECEPTOR TRK BINDING-SITES FOR SHC AND PLC-GAMMA/

Differentiation and survival of neuronal cell types requires the actio n of neurotrophic polypeptides such as nerve growth factor (NGF). In t he central and peripheral nervous system and the phaeochromocytoma cel l model PC12, NGF exerts its effects through the activation of the sig nalling capacity of Trk, a receptor tyrosine kinase (RTK) which upon i nteraction with NGF becomes phosphorylated on tyrosines and thereby ac quires the potential to interact with signal-transducing proteins such as phospholipase C-gamma (PLC gamma), phosphatidylinositol-3'-kinase (PI3'-K) and SHC. Mutagenesis of the specific binding sites forthese s rc homology 2 (SH2) domain-containing substrates within the Trk cytopl asmic domain suggests a non-essential function of PI3'-K and reveals a major role for the signal controlled by the SHC binding site at tyros ine 490 and a co-operative function of the PLC gamma-mediated pathway for neuronal differentiation of PC12 cells.