Functional selectivity of EGF family peptide growth factors: Implications for cancer

Wilson, Kristy J.; Gilmore, Jennifer L.; Foley, John; Lemmon, Mark A.; Riese, David J.

doi:10.1016/j.pharmthera.2008.11.008

Cited by 235 publications

(276 citation statements)

References 77 publications

(95 reference statements)

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“…Recruitment Stimulated by Other EGF Receptor LigandsThe EGF receptor is activated by a family of homologous growth factors, including EGF TGF␣, BTC, HB-EGF, AREG, EPG, and EPR (17). To quantify the similarities and differences in the response of cells to stimulation by each of these ligands, the luciferase complementation assay was used to monitor the recruitment of the eight different signaling proteins to the EGF receptor in response to each of these agonist ligands.…”

Section: Generation and Characterization Of Stable Cell Lines-mentioning

confidence: 99%

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Different Epidermal Growth Factor Receptor (EGFR) Agonists Produce Unique Signatures for the Recruitment of Downstream Signaling Proteins

Ronan¹,

Macdonald-Obermann

Huelsmann

et al. 2016

Journal of Biological Chemistry

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The EGF receptor can bind seven different agonist ligands.Although each agonist appears to stimulate the same suite of downstream signaling proteins, different agonists are capable of inducing distinct responses in the same cell. To determine the basis for these differences, we used luciferase fragment complementation imaging to monitor the recruitment of Cbl, CrkL, Gab1, Grb2, PI3K, p52 Shc, p66 Shc, and Shp2 to the EGF receptor when stimulated by the seven EGF receptor ligands. Recruitment of all eight proteins was rapid, dose-dependent, and inhibited by erlotinib and lapatinib, although to differing extents. Comparison of the time course of recruitment of the eight proteins in response to a fixed concentration of each growth factor revealed differences among the growth factors that could contribute to their differing biological effects. Principal component analysis of the resulting data set confirmed that the recruitment of these proteins differed between agonists and also between different doses of the same agonist. Ensemble clustering of the overall response to the different growth factors suggests that these EGF receptor ligands fall into two major groups as follows: (i) EGF, amphiregulin, and EPR; and (ii) betacellulin, TGF␣, and epigen. Heparin-binding EGF is distantly related to both clusters. Our data identify differences in network utilization by different EGF receptor agonists and highlight the need to characterize network interactions under conditions other than high dose EGF.

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Section: Generation and Characterization Of Stable Cell Lines-mentioning

confidence: 99%

“…The EGF receptor binds seven different agonist ligands, including some of high affinity (EGF, TGF␣, BTC, 6 and HB-EGF) and some of low affinity (AREG, EPG, and EPR) (17). It has been reported that different EGF receptor ligands induce different responses when binding to the same cell line (18 -21).…”

mentioning

confidence: 99%

Different Epidermal Growth Factor Receptor (EGFR) Agonists Produce Unique Signatures for the Recruitment of Downstream Signaling Proteins

Ronan¹,

Macdonald-Obermann

Huelsmann

et al. 2016

Journal of Biological Chemistry

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“…All ErbB receptors contain an extracellular ligand-binding domain, a single pass transmembrane domain, an intracellular tyrosine kinase, and a C-terminal tail (3). The EGF receptor, ErbB3, and ErbB4 are activated through the binding of a family of homologous ligands (4). Unique among the ErbB receptors, ErbB2 has no known ligand (5,6).…”

mentioning

confidence: 99%

Mechanics of EGF Receptor/ErbB2 kinase activation revealed by luciferase fragment complementation imaging

Macdonald-Obermann

Piwnica‐Worms

Pike

2011

Proc. Natl. Acad. Sci. U.S.A.

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Binding of EGF to its receptor induces dimerization of the normally monomeric receptor. Activation of its intracellular tyrosine kinase then occurs through the formation of an asymmetric kinase dimer in which one subunit, termed the "receiver" kinase, is activated by interaction with the other subunit, termed the "activator" kinase [Zhang, et al. (2006) Cell 125: 1137-1149. Although there is significant experimental support for this model, the relationship between ligand binding and the mechanics of kinase activation are not known. Here we use luciferase fragment complementation in EGF receptor (EGFR)/ErbB2 heterodimers to probe the mechanics of ErbB kinase activation. Our data support a model in which ligand binding causes the cis-kinase (the EGFR) to adopt the receiver position in the asymmetric dimer and to be activated first. If the EGF receptor is kinase active, this results in the phosphorylation of the trans-kinase (ErbB2). However, if the EGF receptor kinase is kinase dead, the ErbB2 kinase is never activated. Thus, activation of the kinases in the EGFR/ErbB2 asymmetric dimer occurs in a specific sequence and depends on the kinase activity of the EGF receptor.T he EGF receptor is a member of the ErbB family of receptor tyrosine kinases that also includes ErbB2, ErbB3, and ErbB4 (1, 2). All ErbB receptors contain an extracellular ligand-binding domain, a single pass transmembrane domain, an intracellular tyrosine kinase, and a C-terminal tail (3). The EGF receptor, ErbB3, and ErbB4 are activated through the binding of a family of homologous ligands (4). Unique among the ErbB receptors, ErbB2 has no known ligand (5, 6).Binding of an ErbB ligand to its receptor induces dimerization of the receptor through interaction of the extracellular domains. Essentially all combinations of ErbB receptors are possible. However, the ligandless ErbB2 appears to be the preferred heterodimerization partner among ErbB receptors (7,8).Ligand-induced dimerization of the extracellular domains leads to the activation of the intracellular tyrosine kinase through the formation of an asymmetric kinase dimer (9-11). In the asymmetric dimer, the C lobe of the activator kinase interacts with the N lobe of the receiver kinase in a manner similar to that in which cyclin A interacts with cyclin-dependent kinase (12). This interaction leads to the activation of the receiver kinase, which then phosphorylates the C-terminal tail of the activator kinase.Although a substantial body of evidence supports this model for EGF receptor kinase activation (9-11, 13), it is not clear how the binding of ligand to the extracellular domain directs the assembly of the intracellular asymmetric kinase dimer. In particular, if ligand binds to one subunit in an ErbB dimer, which kinase domain adopts the activator and which adopts the receiver position in the asymmetric dimer, or is the choice made randomly? Once formed, does the asymmetric kinase dimer readily shift from one configuration to the reciprocal one, activating each kinase in turn, or is this a con...

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“…Присоединение лиганда к субдоменам I и III индуцирует значительные конформационные перестройки во внекле-точном домене рецептора, который переходит в открытое состояние и димеризуется за счет межмолекулярного вза-имодействия одноименных субдоменов II / II и IV / IV [11].…”

Section: основные клеточные сигнальные пути вовлеченные в патогенез unclassified

“…Протяженная делеция внеклеточного домена EGFR vIII (del-7) ведет к независимой от лигандов активации рецептора. К увели-чению аффинности связывания с EGF и TGF и спонтанной димеризации ведут мутации, нарушающие контакт между субдоменами II и IV [11]. Активирующие мутации ERBB1 и ERBB2 в киназном домене вызывают лиганд-независи-мое увеличение сигнальной активности и резистентность к лечению тирозинкиназными ингибиторами [23].…”

Section: основные клеточные сигнальные пути вовлеченные в патогенез unclassified

Molecular Basis of Modern Targeted Therapy for Squamous Cell Carcinoma of the Tongue and Oral Mucosa With Monoclonal Antibodies

Льянова¹,

Владимирова²,

Франциянц³

et al. 2017

Zlokač. opuholi

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Functional selectivity of EGF family peptide growth factors: Implications for cancer

Cited by 235 publications

References 77 publications

Different Epidermal Growth Factor Receptor (EGFR) Agonists Produce Unique Signatures for the Recruitment of Downstream Signaling Proteins

Different Epidermal Growth Factor Receptor (EGFR) Agonists Produce Unique Signatures for the Recruitment of Downstream Signaling Proteins

Mechanics of EGF Receptor/ErbB2 kinase activation revealed by luciferase fragment complementation imaging

Molecular Basis of Modern Targeted Therapy for Squamous Cell Carcinoma of the Tongue and Oral Mucosa With Monoclonal Antibodies

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