EGFR ligands exhibit functional differences in models of paracrine and autocrine signaling

Abstract

Epidermal growth factor (EGF) family peptides are ligands for the EGF receptor (EGFR). Here, we elucidate functional differences among EGFR ligands and mechanisms underlying these distinctions. In 32D/EGFR myeloid and MCF10A breast cells, soluble amphiregulin (AR), transforming growth factor alpha (TGFα), neuregulin 2 beta, and epigen stimulate greater EGFR coupling to cell proliferation and DNA synthesis than do EGF, betacellulin, heparin-binding EGF-like growth factor, and epiregulin. EGF competitively antagonizes AR, indicating that its functional differences reflect dissimilar intrinsic activity at EGFR. EGF stimulates much greater phosphorylation of EGFR Tyr1045 than does AR. Moreover, the EGFR Y1045F mutation and z-cbl dominant-negative mutant of the c-cbl ubiquitin ligase potentiate the effect of EGF but not of AR. Both EGF and AR stimulate phosphorylation of EGFR Tyr992. However, the EGFR Y992F mutation and phospholipase C gamma inhibitor U73122 reduce the effect of AR much more than that of EGF. Expression of TGFα in 32D/EGFR cells causes greater EGFR coupling to cell proliferation than does expression of EGF. Moreover, expression of EGF in 32D/EGFR cells causes these cells to be largely refractory to stimulation with soluble EGF. Thus, EGFR ligands are functionally distinct in models of paracrine and autocrine signaling and EGFR coupling to biological responses may be specified by competition among functionally distinct EGFR ligands.

GC1118, an Anti-EGFR Antibody with a Distinct Binding Epitope and Superior Inhibitory Activity against High-Affinity EGFR Ligands

“…EGF, b-cellulin (BTC), heparin-binding EGF-like growth factor (HB-EGF), and TGFa are high-affinity ligands with binding affinity (K D ) of 0.6 to 9.2 nmol/L, whereas amphiregulin (AREG), epiregulin (EREG), and epigen (EPI) are considered low-affinity ligands with K D of 350 nmol/L to 2.8 mmol/L (6, 7). EGFR ligands exhibit different signaling intensities, durations, and trafficking, resulting in differential EGFR signaling and physiologic consequences (8)(9)(10). AREG and EREG are EGFR ligands that are predominantly expressed in CRC cell lines (11).…”

Effect of the Leptin Receptor Q223R Polymorphism on the Host Transcriptome following Infection with Entamoeba histolytica

“…infected mice at 12 h demonstrated that the host transcriptional response at 12 h of infection was predominantly proinflammatory; for example, amphiregulin (AREG) (20)(21)(22), a potent activator of the epidermal growth factor receptor (EGFR) which is transactivated by LEPR, and CD47 (23) and CD38 (24) were induced (25). Ingenuity pathway analysis (IPA) indicated enrichment of gene functions involved in cell-to-cell signaling and interaction and in cellular function and maintenance, with immune cells being especially targeted (Table 3).…”

Activation of the EGF Receptor by Ligand Binding and Oncogenic Mutations: The “Rotation Model”

“…For example, TGFα and AREG stimulate proliferation of 32D cells more efficiently than do EGF and HB-EGF, and these efficiency differences have been correlated with differential phosphorylation of specific sites on the Cterminal tail of EGFR [90][91][92]. This is partly due to different binding affinities of the distinct ligands for EGFR [93,94].…”