free the active growth factors, a process known as 'ectodomain shedding'. The 'sheddases' are members of the Adam family of metalloproteases. The mechanism of their activation is not well understood but a possible involvement of GPCR and/or protein kinase C has been reported. The ligands contain a consensus sequence known as the EGF motif; it harbors six cysteines forming three disulfide bonds and is essential for receptor binding. The four transmembrane glycoprotein receptors contain an extracellular ligand binding domain, a small intracellular juxtadomain followed by the tyrosine kinase domain and the C-terminal tail containing the docking sites for phosphotyrosine-binding proteins. The extracellular domain is composed of subdomains I through IV, of which I and III are leucine-rich repeats involved in ligand binding and II and IV are laminin-like, cysteine-rich domains. Of the four receptors, the prototypical Egfr and Erbb4 are autonomous in that they possess both ligand binding and tyrosine kinase activities. Erbb2 does not bind ligands and Erbb3 lacks kinase activity. Receptors form homo- or heterodimers; Erbb2 is a preferred partner. Among ligands, the prototypical Egf, along with Tgf-alpha, Areg and Epgn are Egfr-specific while Hbegf, Btc and Ereg bind both Egfr and Erbb4 receptors. Neuregulins (Nrg1 to 4) are another class of ligands that bind to Erbb4 and Erbb3 receptors; at least 20 isoforms are produced via alternative splicing. Ligand binding induces conformational changes leading to stabilization of the oligomeric structure, tyrosine kinase activation and transphosphorylation of receptors. The phosphorylated residues provide docking sites for various proteins with SH2 (src homology 2) and PTB (phosphotyrosine binding) domains. Phosphorylated Egfr and Erbb4 interact directly or via Shc1 with the adapter Grb2 to recruit Sos proteins followed by activation of Ras and the Raf/Mek/Erk cascade. Phopshorylated Erbb3 on the other hand recruits the regulatory p85 subunit of the PI3 lipid kinase leading to allosteric activation of the catalytic subunit and the enfolding of the PI3K-Akt pathway. Erbb2 (ligand defective) and Erbb3 (kinase defective) form a potent signaling heterodimer that activates both pathways. Egfr activity is attenuated and/or inhibited by dephosphorylation and ubiquitination; examples include Ptprj and Cbl. Egfr and Erbb2 are over-expressed and/or amplified in several cancers. To access the ontology report for annotations, GViewer and downloads, click here.
[Click to see the ontology report for related GO term - GO:0007173,  Kegg map - map04012  and entry at Reactome - REACT_9417.3]...(less)