Ligand depletion negatively controls the mitogenic activity of epidermal growth factor

Poll, Monique L.M. van de; Rotterdam, Walter van; Gadellaa, Mireille M.; Jacobs-Oomen, Saskia; Zoelen, E.J.J. van

doi:10.1016/j.yexcr.2004.12.011

Cited by 5 publications

(1 citation statement)

References 42 publications

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“…Differential ligand depletion has also been proposed as a mechanism that underlies functional distinctions among EGFR ligands (van de Poll et al 2005). We have partially addressed this issue by noting that a 1-h exposure to ErbB receptor ligands (and subsequent rinsing of the cells) is sufficient to elicit differential stimulation of ErbB receptor coupling to IL3 independence (data not shown).…”

Section: Resultsmentioning

confidence: 99%

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

Mill²,

et al. 2012

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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.

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Section: Resultsmentioning

confidence: 99%

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

Mill²,

et al. 2012

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ErbB2 and ErbB4 Cbl binding sites can functionally replace the ErbB1 Cbl binding site

Jansen

Sleumer

Damen

et al. 2009

Cellular Signalling

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Role of the C-terminal linear region of EGF-like growth factors in ErbB specificity

et al. 2009

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The epidermal growth factor (EGF)-like growth factors bind their ErbB receptors in a highly selective manner. Recently, we have shown that the sequence YYDLL in the C-terminal linear region is compatible with binding to all ligand-binding ErbB receptors. In the present study, we show that introduction of the YYDLL sequence into the ErbB1 specific ligands EGF and transforming growth factor-alpha (TGFalpha) broadened their receptor specificity towards ErbB4. Upon introduction of the YYDLL sequence into epiregulin, which by itself binds ErbB1 and ErbB4 but not ErbB3, its binding specificity was broadened to ErbB3, concomitant with enhanced affinity for ErbB4. Introduction of the YYDLL sequence into NRG1beta resulted in a 10-fold increase in affinity for ErbB3, without affecting its receptor specificity. Remarkably, the strongly enhanced affinity for ErbB3 negatively influenced their mitogenic activity towards cells coexpressing ErbB2 and ErbB3. These observations are discussed in terms of the optimised ErbB affinity, selectivity and mitogenic potential that have taken place during evolution.

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Ligand depletion negatively controls the mitogenic activity of epidermal growth factor

Cited by 5 publications

References 42 publications

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

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

ErbB2 and ErbB4 Cbl binding sites can functionally replace the ErbB1 Cbl binding site

Role of the C-terminal linear region of EGF-like growth factors in ErbB specificity

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