Figure 8. Proposed Mechanism by which the msp1 Mutation Disrupts ERBB3 Function.

In the absence of ligand (left), ERBB3 acquires a “tethered” conformation that renders the receptor inactive [36]. Upon ligand binding, the receptor undergoes a conformational change to allow dimerization with its binding partner, ERBB2 (right). Heterodimerization leads to autophosphorylation of ERBB2 and transphosphorylation of the kinase-dead ERBB3 receptor [34]. Phosphorylated tyrosine residues activate downstream signaling pathways, which elicit diverse cell responses. Ligand-induced phosphorylation of ERBB3 is impaired in the msp1 (red Xs). The D313G mutation (red asterisk) may interfere with the receptors surface expression, ligand binding, and/or heterodimerization with ERBB2.