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 ErbB2-ErbB3 Heterodimers

ErbB2 (HER2) and ErbB3 (HER3) along with ErbB1 (EGFR) and ErbB4 (HER4) are members of the EGF receptor family. ErbB3 binds members of the neuregulin (neu differentiation factor (NDF)) family, but lacks intrinsic tyrosine kinase activity. ErbB2 lacks a neuregulin binding domain, but has a potent tyrosine kinase activity and is the most oncopotent of the Erb receptors. Ligand bound ErbB3 dimerizes as part of its activation. Whenever ErbB2 is expressed on the cell surface together with ErbB3, it preferentially forms ErbB2:ErbB3 dimers that become activated via trans-phosphorylation. Phosphorylated ErbB2:ErbB3 dimers provide docking sites for factors involved in the initiation of cell signaling pathways, especially those involved in cell survival, cell growth and cell transformation. These include the Ras/Raf-1/MEK/ERK mitogenic; the phophoinositide 3-kinase (PI3K)/PDK1/Akt(PKB) anti-apoptotic; and JAK/STAT mitogenic pathways.

ErbB2 is the preferred heterodimerization partner of the other erb (HER) receptors, including erbB3. The expression of erbB2 on the cell surface of normal tissue is generally limited. Overexpression of erbB2 on the cell surface along with erbB3 increases the formation of erbB2:erbB3 heterodimers. ErbB2 containing heterodimers are potent signal mediators that promote prolonged survival and mitogenesis signaling because they release agonists slowly and are relatively resistant to down regulation. Prolonged overexpression of ErbB2 has been linked to a number of epithelial cancers, such as breast cancer. The anti-cancer drug Herceptin (trastuzumab) is believed to work by directing Cbl-dependent endocytosis and degradation of ErbB2 containing heterodimers.