Specificity within the EGF family/ErbB receptor family signaling network

Abstract

Recent years have witnessed tremendous growth in the epidermal growth factor (EGF) family of peptide growth factors and the ErbB family of tyrosine kinases, the receptors for these factors. Accompanying this growth has been an increased appreciation for the roles these molecules play in tumorigenesis and in regulating cell proliferation and differentiation during development. Consequently, a significant question has been how diverse biological responses are specified by these hormones and receptors. Here we discuss several characteristics of hormone‐receptor interactions and receptor coupling that contribute to specificity: 1) a single EGF family hormone can bind multiple receptors; 2) a single ErbB family receptor can bind multiple hormones; 3) there are three distinct functional groups of EGF family hormones; 4) EGF family hormones can activate receptors in trans, and this heterodimerization diversifies biological responses; 5) ErbB3 requires a receptor partner for signaling; and 6) ErbB family receptors differentially couple to signaling pathways and biological responses. BioEssays 20:41–48, 1998. © 1998 John Wiley & Sons, Inc.

Synthetic Multivalent Ligands as Probes of Signal Transduction

“…Because different receptors often share common cytoplasmic components, information transfer must be constrained to prevent unwanted exchange between disparate pathways. [7,[10][11][12] To understand how signals are transmitted, how cells can respond distinctly to different stimuli using a set of common components must be unraveled. [7] Both chemists and biologists are poised to contribute.…”

Retinoids arrest breast cancer cell proliferation: retinoic acid selectively reduces the duration of receptor tyrosine kinase signaling

“…Epidermal growth factor (EGF)-related peptides are ligands for the ErbB family of receptor tyrosine kinases [24]. There are four known ErbB family receptors: EGFR (ErbB1), ErbB2 (also called Neu, HER-2), ErbB3 and ErbB4 [24].…”

Phenolic antioxidants trolox and caffeic acid modulate the oxidized LDL‐induced EGF‐receptor activation

“…In mammals, the EGFR family consists of four members, EGFR (or ErbB1), HER2 (or ErbB2/neu), HER3 (or ErbB3) and ErbB4 which are able to bind multiple peptide ligands (EGF, TGFa, amphiregulin, NDF, neuregulins, heregulins, HB-EGF, betacellulin and epiregulin) and, subsequently, to form homo-and heterodimeric complexes (Riese & Stern, 1998;Moghal & Sternberg, 1999;Hackel et al, 1999). Beside ligand-induced activation, EGFR can also be activated through ligandindependent mechanisms, for instance upon exposure of cells to ultraviolet radiations, oxidants, alkylating agents (Hackel et al, 1999) and oxidized lipids (Suc et al, 1998).…”

“…Activation of the EGFR pathway is characterized by the following sequence of events: (i) stimulation of its intrinsic tyrosine kinase and phosphorylation of its own tyrosine residues (of its cytoplasmic domain) and of intracellular substrate proteins; (ii) binding on phosphotyrosine of SH2-and PTB-domain containing proteins, such as enzymes (src, phospholipase C-g1, phosphatidylinositol 3-kinase, SHP2 phosphotyrosine phosphatase, ras-GAP) or adaptor molecules (Shc isoforms, Grb2, Grb7, Nck, Cbl) which mediate downstream signalling (reviewed in Riese & Stern, 1998;Moghal & Sternberg, 1999;Hackel et al, 1999).…”