ErbB4 Signaling

ErbB4 is a 180-kDa transmembrane RTK that regulates cell proliferation and differentiation. The ErbB4 gene has been isolated as the fourth member of the human EGFR subfamily of tyrosine kinases. Four structurally different ErbB4 isoforms have been identified. Ligands that bind to ErbB4 with high affinity and specificity and which provoke receptor activation and signaling are divided into two groups, the Neuregulin family (NRG, also termed Heregulins), and certain members of the EGF family of ligands. There are four NRG genes - 1, 2, 3, and 4, and the product of each is capable of recognizing ErbB4 in a biologically productive manner.Binding of each ligand to ErbB4 is followed by a metalloprotease mediated cleavage of the receptor by TACE. This produces a membrane-associated 80-kDa fragment (m80) which is then a substrate for subsequent γ-secretase cleavage. The second cleavage releases the cytoplasmic domain (s80) from the membrane and allows nuclear translocation of this fragment where it is involved in transcriptional regulation of genes.Ligand binding to ErbB4 also triggers a process common to other ErbB receptors, i.e., dimerization and autophosphorylation. Heterodimerization of ErbB4 with ErbB2 forms a higher affinity binding site, enhances the level of autophosphorylation, and can significantly modify the biological response to ErbB4 ligands. ErbB4 homodimerization occurs in the presence of its ligand. This is followed by the activation of downstream signaling pathways such as PI3K/AKTwhich protects cells from apoptosis by a mechanism that requires activation of cell survival pathways. The Ras/Raf/MEK/ERK pathway is also activated. ErbB4 is expressed in several tissues, mainly heart, neural tissue and various epithelia. ErbB4 and its ligands have important roles in normal cardiovascular and neural development, differentiation of the mammary gland and in pathological conditions such as heart diseases and cancer.