Activated epidermal growth factor receptor in ovarian cancer.

Abstract

Growth factor receptors direct numerous cellular functions and behavior including cell proliferation and survival, apoptosis, differentiation, and migration. The receptor tyrosine kinase (RTK) family of growth factor receptors includes the epidermal growth factor (EGF) receptor subfamily (also known as the ErbB or type I RTKs). The ErbB family includes four ErbB proteins: ErbB-1 (EGF receptor), ErbB2, ErbB3, and ErbB4. These structurally related, single membrane spanning receptors consist of an extracellular ligand-binding domain, a transmembrane domain, a juxtamembrane domain, the catalytic tyrosine kinase domain, and a C-terminal tail containing multiple tyrosine residues (Fig. 10.1). Ligand binding promotes EGF receptor homoand heterodimerization with ErbB family members, activation of the intracellular tyrosine kinase domain, and phosphorylation of specific tyrosine residues of the receptor cytoplasmic domain. This leads to assembly of signaling complexes and stimulation of numerous downstream signaling cascades associated with cell growth and survival, increased angiogenesis, and metastasis in tumors. Numerous ligands interact with the ErbB receptor family. EGF, transforming growth factor-a (TGF-a), and amphiregulin only bind to the EGF receptor. The ligands heparin-binding EGF-like growth factor (HBEGF), betacellulin, epiregulin, and epigen bind both the EGF receptor and ErbB4. These EGF receptor ligands are synthesized as membrane-bound precursors then cleaved to release the mature form of the ligand. EGF receptor ligands can activate receptors on the cell of origin, on nearby cells, or on cells at more distant sites after systemic distribution. In some instances, receptor activation by the precursor (membrane-bound ligand) may occur as a consequence