DIFFERENTIAL ENDOCYTIC ROUTING OF HOMO-DIMERIC AND HETERO-DIMERIC ERBB TYROSINE KINASES CONFERS SIGNALING SUPERIORITY TO RECEPTOR HETERODIMERS

Both homo- and hetero-dimers of ErbB receptor tyrosine kinases mediate signaling by a large group of epidermal growth factor (EGF)-like liga nds. However, some ligands are more potent than others, although they bind to the same direct receptor. In addition, signaling by receptor h eterodimers is superior to homodimers, We addressed the mechanism unde rlying these two features of signal tuning by using three ligands: EGF ; transforming growth factor alpha (TGF alpha); and their chimera, den oted E4T, which act on cells singly expressing ErbB-1 as a weak, a str ong, and a very strong agonist, respectively, Co-expression of ErbB-2, a developmentally important co-receptor whose expression is frequentl y elevated in human cancers, specifically potentiated EGF signaling to the level achieved by TGF alpha, an effect that was partially mimicke d by ErbB-3, Analysis of the mechanism underlying this trans-potentiat ion implied that EGF-driven homodimers of ErbB-1 are destined for intr acellular degradation, whereas the corresponding heterodimers with Erb B-2 or,vith ErbB-3, dissociate in the early endosome, As a consequence , in the presence of either co-receptor, ErbB-1 is recycled to the cel l surface and its signaling is enhanced, This latter route is followed by TGF alpha-driven homodimers of ErbB-1, and also by E4T-bound recep tors, whose signaling is further enhanced by repeated cycles of bindin g and dissociation from the receptors. We conclude that alternative en docytic routes of homo- and hetero-dimeric receptor complexes may cont ribute to tuning and diversification of signal transduction. In additi on, the ability of ErbB-2 to shunt ligand-activated receptors to recyc ling may explain, in part, its oncogenic potential.