Differential endocytic routing of homo- and hetero-dimeric ErbB tyrosine kinases confers signaling superiority to receptor heterodimers

Abstract

Both homo-and hetero-dimers of ErbB receptor tyrosine kinases mediate signaling by a large group of epidermal growth factor (EGF)-like ligands. However, some ligands are more potent than others, although they bind to the same direct receptor. In addition, signaling by receptor heterodimers is superior to homodimers. We addressed the mechanism underlying these two features of signal tuning by using three ligands: EGF; transforming growth factor α (TGFα); and their chimera, denoted E4T, which act on cells singly expressing ErbB-1 as a weak, a strong, and a very strong agonist, respectively. Co-expression of ErbB-2, a developmentally important co-receptor whose expression is frequently elevated in human cancers, specifically potentiated EGF signaling to the level achieved by TGFα, an effect that was partially mimicked by ErbB-3. Analysis of the mechanism underlying this trans-potentiation implied that EGF-driven homodimers of ErbB-1 are destined for intracellular degradation, whereas the corresponding heterodimers with ErbB-2 or with ErbB-3, dissociate in the early endosome. As a consequence, in the presence of either co-receptor, ErbB-1 is recycled to the cell surface and its signaling is enhanced. This latter route is followed by TGFα-driven homodimers of ErbB-1, and also by E4T-bound receptors, whose signaling is further enhanced by repeated cycles of binding and dissociation from the receptors. We conclude that alternative endocytic routes of homo-and hetero-dimeric receptor complexes may contribute to tuning and diversification of signal transduction. In addition, the ability of ErbB-2 to shunt ligand-activated receptors to recycling may explain, in part, its oncogenic potential.

The epidermal growth factor receptor family: Biology driving targeted therapeutics

“…Overexpression of ErbB2 promotes heterodimerization with EGFR [96,97]. Notably, EGFR-ErbB2 heterodimers evade lysosomal degradation in favor of endocytic recycling of EGFR-ErbB2 to the cell surface, leading to increased signal duration and potency [94,98]. Therefore, ErbB2 overexpression leads to increased EGFR density on the cell surface and prolongs activation of downstream MAPK and c-Jun [96,99,100].…”

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

“…The preferred ErbB2 dimer partner increases ligand-binding affinity (Karunagaran et al, 1996) and reduces EGF dissociation to prolong signal activation. Heterodimers containing ErbB2 are also more stable and endocytosed at lower rates than other ErbB dimers (Lenferink et al, 1998;Wang et al, 1999;Hommelgaard et al, 2004). Thus, signalling via ErbB1/2 heterodimers may be more powerful and sustained than that arising via ErbB1 homodimers.…”

Regulation of Epidermal Growth Factor Receptor Down-Regulation by UBPY-mediated Deubiquitination at Endosomes

“…Stimulation of cells with EGF induces the heterodimerization of EGFR with other family members (Alroy and Yarden, 1997). It has been shown that the heterodimerization of EGFR with ErbB2 and ErbB3 inhibits the down-regulation of EGFR (Lenferink et al, 1998;Wang et al, 1999;Worthylake et al, 1999). Therefore, it is possible that UBPY also indirectly regulates the down-regulation of EGFR by controlling the cellular levels of its heterodimerization partners, ErbB2 and/or ErbB3.…”