ErbB family members, and ErbB3 is the preferred partner of ErbB2. This heterodimer conformation allows the signaling complex to activate multiple pathways including the MAPK, PI3K/Akt, and PLCγ. There is also evidence that the ErbB2-ErbB3 heterodimer can bind and be activated by EGF-like ligands. Activation of the PI3K/Akt pathway The intracellular domain of ErbB3 contains 6 recognition sites for the SH2 domain of the p85 subunit of PI3K. ErbB3 binding causes the allosteric activation of p110α, the lipid kinase subunit of PI3K, a function not found in either EGFR or ErbB2. Role in cancer While no evidence has been found that ErbB3 overexpression, constitutive activation, or mutation alone is oncogenic, the protein as a heterodimerization partner, most critically with ErbB2, is implicated in growth, proliferation, chemotherapeutic resistance, and the promotion of invasion and metastasis. ErbB3 is associated with targeted therapeutic resistance in numerous cancers including resistance to: HER2 inhibitors in HER2+ breast cancers anti-estrogen therapy in ER+ breast cancers EGFR inhibitors in lung and head and neck cancers hormones in prostate cancers IGF1R inhibitors in hepatomas BRAF inhibitors in melanoma ErbB2 overexpression may promote the formation of active heterodimers with ErbB3 and other ErbB family members without the need for ligand binding, resulting in weak but constitutive signaling activity. Role in normal development ERBB3 is expressed in the mesenchyme of the endocardial cushion, which will later develop into the valves of the heart. ErbB3 null mouse embryos show severely underdeveloped atrioventricular valves, leading to death at embryonic day 13.5. Although this function of ErbB3 depends on neuregulin, it does not seem to require ErbB2, which is not expressed in the tissue. ErbB3 also seems to be required for neural crest differentiation and the development of the sympathetic nervous system and neural crest derivatives such as Schwann cells. See also Epidermal growth factor receptor family Epidermal growth factor receptor Receptor tyrosine-kinases References Further reading Tyrosine kinase receptors