Roles of ErbB-3 and ErbB-4 in the Physiology and Pathology of the Mammary Gland

ErbB-3 and ErbB-4 are the most recently discovered and least characterized of the class I tyrosine kinase receptors. ErbB-3 is noteworthy for its low tyrosine kinase activity, suggesting that it may function more as an adaptor in signaling than as a kinase. Heregulin serves as a ligand for both receptors. A primary mechanism of heregulin action involves heterodimerization of its targeted receptors with other members of the class I family to promote cross-phosphorylation and cellular responses. Betacellulin also acts as a ligand for ErbB-4 to stimulate its kinase activity in both homo- and hetero-dimers. A new ligand (ASGP-2) for ErbB-2 has been discovered which operates by an intramembrane mechanism and may be able to modulate external ligand-dependent ErbB-3 or ErbB-4 heterodimeric interactions with ErbB-2. Heterodimerization stimulated by the ligands is a key feature of mitogenic signaling in mammary epithelial cells and tumors. Characterization of the signaling pathways for these receptors is still incomplete, but phosphatidylinositol 3-kinase and SHC have been implicated. Heregulin synthesized by the mesenchyme has been implicated in mammary development, modulated by systemic hormones. Observations on cultured mammary cells and mammary tumors have suggested linkages of ErbB-3 and ErbB-4 to proliferation and differentiation, respectively, but further work is needed to establish their definitive roles.