Ligand Induced Activation ofEGFR

EGFR, along with the other ErbB family members, is activated by a diverse array of extracellular growth factor ligands, such as EGF, transforming growth factor a (TGFa) and amphiregulin (AR) (1,2) as well as betacellulin, epiregulin, heparin binding-EGF, and the neuregulins (8). Upon ligation, ErbB proteins form homo- or hetero-dimers resulting in activation of their tyrosine kinase functionality and subsequent transphos-phorylation of the receptors on multiple tyrosine residues in the cytoplasmic tail (Fig. 1), facilitating the recruitment of docking partners (9).

No known ligand for ErbB2 has thus far been identified. It has been proposed that ErbB2 must form heterodimers with other ErbBs in order to undergo ligand-dependent activation. ErbB2 is also the preferred dimerization partner for all ErbB proteins (10). In a similar vein, ErbB3 lacks kinase activity and thus requires heterodimerization with and transphosphorylation by another ErbB member in order to become activated (11). EGFR, in contrast, can become activated by cognate ligands in homodimer form.

The biochemical basis for EGFR activation upon ligand binding and dimerization has recently been elucidated (12). Recent crystallographic studies have shown that EGFR can adopt one of two conformations, an auto-inhibited (inactive) state, or an activated state. Upon ligand binding, an asymmetric homodimer forms between these two states, such that the C-terminal lobe of the "active" EGFR monomer causes relief of the autoinhibition in the "inactive" EGFR monomer. This mechanism is reminiscent of cyclin-mediated activation of cyclin-dependent kinases (CDKs) (13) and results in potent activation of EGFR's kinase activity followed by autophosphorylation of C-terminal tyrosine residues. This mode of activation suggests that EGFR does not require prior tyrosine phosphorylation, but does require dimerization, in order to become activated, and that it may activate other ErbB family members in asymmetric heterodimers, independently of its own intrinsic kinase activity.

Upon ligation, EGFR is rapidly endocytosed into clathrin-coated vesicles, along with bound ligand (14). In early endosomes, c-Cbl, an E3 ubiquitin ligase is recruited to EGFR, resulting in ubiquitination of the receptor (15). Ubiquitinated EGFR, localized within early endosomes, maintains mitogenic signaling capacity (16). Activated EGFR in endosomes is then sorted towards the lysosomal degradation pathway, resulting in signal attenuation or, in rare circumstances, is recycled to the cell surface following vesicular fusion with the plasma membrane.

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