ALTERNATIVE INTRACELLULAR ROUTING OF ERBB RECEPTORS MAY DETERMINE SIGNALING POTENCY

The ErbB signaling module consists of four receptor tyrosine kinases a nd several dozen ligands that activate specific homo-and heterodimeric complexes of ErbB proteins. Combinatorial ligand/receptor/effector in teractions allow large potential for signal diversification. Here we a ddressed the possibility that turn-off mechanisms enhance the diversif ication potential. Concentrating on ErbB-1 and two of its ligands, epi dermal growth factor (EGF) and transforming growth factor alpha (TGF-a lpha), and the Neu differentiation factor (NDF/neuregulin) and one of its receptors, ErbB-3, we show that ligand binding variably accelerate s endocytosis of the respective ligand-receptor complex. However, unli ke the EGF-activated ErbB-1, which is destined primarily to degradatio n in lysosomes, NDF and TGF-alpha direct their receptors to recycling, probably because these ligands dissociate from their receptors earlie r along the endocytic pathway. In the case of NDF, structural, as well as biochemical, analyses imply that ligand degradation occurs at a re latively late endosomal stage. Attenuation of receptor down-regulation by this mechanism apparently confers to both NDF and TGF-alpha more p otent and prolonged signaling activity. In conclusion, alternative end ocytic trafficking of ligand-ErbB complexes may tune and diversify sig nal transduction by EGF family ligands.