Neuregulin Signaling

Neuregulins play important roles in the development, maintenance, and repair of the nervous system. They are members of the epidermal growth factor (EGF) family of growth factors and are ligands for the ErbB receptors. Deregulated expression of these receptors, in particular ErbB1 and ErbB2, has been implicated in the development and malignancy of numerous types of human cancers.Neuregulins binding to the extracellular domain of ErbB1 (EGF, TGFα, AR), ErbB3 (NRG-1, NRG-2) or ErbB4 (NRG-1, NRG-2, NRG-3, NRG-4, BTC, HB-EGF, EPR) induces the formation of receptor homodimers and ErbB2-containing heterodimers. ErbB3 homodimers do not signal, since the receptor has impaired kinase activity, whereas ErbB2 seems to have no direct ligand, but is the preferred dimerization partner for the other ErbB receptors.Dimerization consequently stimulates the intrinsic tyrosine kinase activity of the ErbB receptors followed by autophosphorylation of specific tyrosine residues within the cytoplasmic domain. These phosphorylated tyrosines provide docking sites for proteins containing Src homology 2 (SH2) or phosphotyrosine binding (PTB) domains, including adaptor proteins such as Shc, Crk, Grb2, Grb7; kinases such as Src, Chk, phosphatidylinositol 3-kinase (PI3K); and the protein tyrosine phosphatase SHP2. The recruitment of these adaptor proteins and enzymes leads to the activation of intracellular signaling cascades. The major pathways involved in signal transduction include the Ras- and Shc-activated MAPK pathway, the PI3K-activated AKT pathway, the JAK/STAT pathway and the PLC-γ pathway, which ultimately affect cell proliferation and migration (both associated with tumorigenesis), adhesion, differentiation and apoptosis.