Bivalence of EGF-like ligands drives the ErbB signaling network

Abstract

Although ligand-induced dimerization was first reported 6 Corresponding author for the epidermal growth factor (EGF) receptor (Yarden and Schlessinger, 1987a,b), the exact mechanism by which E.Tzahar and R.Pinkas-Kramarski contributed equally to this work the monomeric EGF molecule promotes dimerization is still unknown. This is particularly important because the Signaling by epidermal growth factor (EGF)-like three-loop structure of the EGF domain is a common ligands is mediated by an interactive network of four protein motif found in a variety of extracellular proteins, ErbB receptor tyrosine kinases, whose mechanism of including not only growth factors but also adhesion ligand-induced dimerization is unknown. We conmolecules and coagulation factors (Groenen et al., 1994). trasted two existing models: a conformation-driven Moreover, the receptor for EGF (also called ErbB-1) activation of a receptor-intrinsic dimerization site and undergoes extensive heterodimerization with three related a ligand bivalence model. Analysis of a Neu differentimembrane proteins of its subfamily: the orphan receptor ation factor (NDF)-induced heterodimer between ErbB-2 (Goldman et al., 1990;Wada et al., 1990) and the ErbB-3 and ErbB-2 favors a bivalence model; the ligand simultaneously binds both ErbB-3 and ErbB-2, two receptors of the Neu differentiation factor (NDF/ but, due to low-affinity of the second binding event, neuregulin), ErbB-3 and ErbB-4 (Tzahar et al., 1994). ligand bivalence drives dimerization only when the NDF itself contains an EGF-like motif that is sufficient receptors are membrane anchored. Results obtained for receptor binding, and it exists in several alternatively with a chimera and isoforms of NDF/neuregulin predict spliced isoforms (Peles and Yarden, 1993). Although no that each terminus of the ligand molecule contains a known ligand binds directly to ErbB-2, this receptor distinct binding site. The C-terminal low-affinity site appears to serve as a preferred heterodimerizing partner has broad specificity, but it prefers interaction with of the other ErbB molecules (Tzahar et al., 1996), and ErbB-2, an oncogenic protein acting as a promiscuous the resulting complexes are characterized by relatively low-affinity subunit of the three primary receptors.high ligand affinity (Peles et al., 1993;Sliwkowski et al.,

The relation between survival and expression of HER1 and HER2 depends on the expression of HER3 and HER4: a study in bladder cancer patients

“…Epidermal growth factor receptors are commonly active in a dimeric form and interaction between different EGF receptor pairs represents a mechanism for signal diversification and amplification (Olayioye et al, 2000;Yarden and Sliwkowski, 2001). Various dimeric pairs depend on the concentration of receptors, the concentration of particular ligands and the affinity of the receptors towards each other (Pinkas-Kramarski et al, 1996;Tzahar et al, 1997). Ligands binding the EGF family receptors induce receptor homo-or heterodimerisation, which involves an array of a number of homodimeric and heterodimeric combinations (Burden and Yarden, 1997).…”

The efficacy of Herceptin therapies is influenced by the expression of other erbB receptors, their ligands and the activation of downstream signalling proteins

“…As these ligands activate different erbB receptors, it is possible that multiple erbB receptor combinations might be active in a tumor, a characteristic that could influence its response to an erbB-targeted therapeutic (Karunagaran et al, 1996). The ligands present may select the dimerization partners, and may also influence the time course of membrane translocation, activation and internalization of the receptor (Peles et al, 1993;Tzahar et al, 1994;Pinkas-Kramarski et al, 1996). Downstream signalling may be determined by the set of docking proteins that may bind to the activated receptors.…”

Replacement of N‐terminal portions of TGF‐α with corresponding heregulin sequences affects ligand‐induced receptor signaling and intoxication of tumor cells by chimeric growth‐factor toxins

“…13,16 Here we have extended these studies and have constructed two novel ligand hybrids. The H181T8 and H194T20 molecules are based on human TGF-␣ but instead of N-terminal TGF-␣ amino acid residues 1-7 or 1-19 carry the corresponding residues 177-181 or 177-194 of human HRG-␤1, respectively.…”

“…11 Bivalency of the ligands facilitates high-affinity binding to these primary receptors while also enabling low-affinity interaction with a second receptor protein. 12,13 Thereby ErbB2 for which no high-affinity ligand has been described is the preferred heterodimerization partner for all other ErbB family members. 14,15 Dependent on the ligands available and the particular receptor types expressed by a certain tissue or cell, a complex network of homo-and heterodimeric receptors can be formed, which increases the diversity of the signals generated.…”

“…Thereby H181T8 resembles "biregulin," a chimeric ligand consisting of HRG-␤1 amino acid residues 1-7 fused to EGF. 13,16 For bacterial expression and subsequent analysis of cell binding specificities, the chimeric growth factors were genetically fused to truncated Pseudomonas exotoxin A (ETA). ETA is a well-characterized, intracellularly active bacterial toxin that harbors different activities required for cell binding, uptake into cells and toxic activity in distinct functional domains.…”