Five carboxyl-terminal residues of neuregulin2 are critical for stimulation of signaling by the ErbB4 receptor tyrosine kinase

Hobbs, Stuart S.; Cameron, Elizabeth M.; Hammer, Robert P.; Le, Ann T. D.; Gallo, Richard M.; Blommel, Erika N.; Coffing, Stephanie L.; Han, Chang; Riese, David J.

doi:10.1038/sj.onc.1207250

Cited by 29 publications

(48 citation statements)

References 34 publications

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“…Glu42 of epiregulin corresponds to a Gln or Glu residue critical for the activity of efficacious ErbB4 ligands, including Gln43 of neuregulin-1beta, Gln43 of neuregulin-2beta, and Glu42 of betacellulin (Table 2) [5, 7, 12, 15, 21, 22, 24–26]. Thus, it appears that epiregulin and other high-affinity ErbB4 ligands share a common binding site on ErbB4 and that epiregulin and other efficacious ErbB4 ligands stimulate ErbB4 signaling in essentially the same manner.…”

Section: Cloning Of Epiregulin and Basic Epiregulin Pharmacologymentioning

confidence: 99%

Epiregulin: Roles in normal physiology and cancer

Riese

Cullum²

2014

Seminars in Cell & Developmental Biology

145

156

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Epiregulin is a 46-amino acid protein that belongs to the Epidermal Growth Factor (EGF) family of peptide hormones. Epiregulin binds to the EGF receptor (EGFR/ErbB1) and ErbB4 (HER4) and can stimulate signaling of ErbB2 (HER2/Neu) and ErbB3 (HER3) through ligand-induced heterodimerization with a cognate receptor. Epiregulin possesses a range of functions in both normal physiologic states as well as in pathologic conditions. Epiregulin contributes to inflammation, wound healing, tissue repair, and oocyte maturation by regulating angiogenesis and vascular remodeling and by stimulating cell proliferation. Deregulated epiregulin activity appears to contribute to the progression of a number of different malignancies, including cancers of the bladder, stomach, colon, breast, lung, head and neck, and liver. Therefore, epiregulin and the elements of the EGF/ErbB signaling network that lie downstream of epiregulin appear to be good targets for therapeutic intervention.

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Section: Cloning Of Epiregulin and Basic Epiregulin Pharmacologymentioning

confidence: 99%

Epiregulin: Roles in normal physiology and cancer

Riese

Cullum²

2014

Seminars in Cell & Developmental Biology

145

156

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“…The response in Western blotting in the inhibitor and siRNA studies was quantified as described previously (27). Briefly, varying amounts of uninhibited or NT siRNA-transfected TNF stimulation, corresponding to 100, 75, 50, 25, and 10% of the denatured lysate amount, were loaded onto SDS-polyacrylamide gels.…”

Section: Methodsmentioning

confidence: 99%

TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells

Hobbs¹,

Goettel

Liang³

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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TNF and epidermal growth factor (EGF) are well-known stimuli of cyclooxygenase (COX)-2 expression, and TNF stimulates transactivation of EGF receptor (EGFR) signaling to promote survival in colon epithelial cells. We hypothesized that COX-2 induction and cell survival signaling downstream of TNF are mediated by EGFR transactivation. TNF treatment was more cytotoxic to COX-2−/−mouse colon epithelial (MCE) cells than wild-type (WT) young adult mouse colon (YAMC) epithelial cells or COX-1−/−cells. TNF also induced COX-2 protein and mRNA expression in YAMC cells, but blockade of EGFR kinase activity or expression inhibited COX-2 upregulation. TNF-induced COX-2 expression was reduced and absent in EGFR−/−and TNF receptor-1 (TNFR1) knockout MCE cells, respectively, but was restored upon expression of the WT receptors. Inhibition of mediators of EGFR transactivation, Src family kinases and p38 MAPK, blocked TNF-induced COX-2 protein and mRNA expression. Finally, TNF injection increased COX-2 expression in colon epithelium of WT, but not kinase-defective EGFRwa2and EGFRwa5, mice. These data indicate that TNFR1-dependent transactivation of EGFR through a p38- and/or an Src-dependent mechanism stimulates COX-2 expression to promote cell survival. This highlights an EGFR-dependent cell signaling pathway and response that may be significant in colitis-associated carcinoma.

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“…NRG2β stimulates ErbB4 tyrosine phosphorylation and coupling to IL (interleukin)-3-independent proliferation in a heterologous BaF3 lymphoid cell model system. In contrast, NRG2α stimulates ErbB4 tyrosine phosphorylation, but does not stimulate ErbB4 coupling to IL-3-independent proliferation [5,11]. Exchanging amino acid residues between NRG2α and NRG2β identified those responsible for this difference.…”

Section: Introductionmentioning

confidence: 99%

The Q43L mutant of neuregulin 2β is a pan-ErbB receptor antagonist

Wilson

Mill

Gallo

et al. 2012

Biochemical Journal

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The ErbB4 receptor tyrosine kinase possesses both tumour suppressor and oncogenic activities. Thus pharmacological agents are needed to help elucidate ErbB4 functions. However, limitations of existing ErbB4 agonists and antagonists have led us to seek novel ErbB4 antagonists. The Q43L mutant of the ErbB4 agonist NRG2β (neuregulin 2β) stimulates ErbB4 tyrosine phosphorylation, yet fails to stimulate ErbB4 coupling to cell proliferation. Thus in the present paper we hypothesize that NRG2β/Q43L may be an ErbB4 antagonist. NRG2β/Q43L competitively antagonizes agonist stimulation of ErbB4 coupling to cell proliferation. NRG2β/Q43L stimulates less ErbB4 tyrosine phosphorylation than does NRG2β. In addition, NRG2β stimulation of cell proliferation requires PI3K (phosphoinositide 3-kinase) activity and NRG2β stimulates greater Akt phosphorylation than does NRG2β/Q43L. Moreover, EGFR [EGF (epidermal growth factor) receptor] kinase activity (but not that of ErbB4) is critical for coupling ErbB4 to proliferation. Experiments utilizing ErbB4 splicing isoforms and mutants suggest that NRG2β and NRG2β/Q43L may differentially stimulate ErbB4 coupling to the transcriptional co-regulator YAP (Yes-associated protein). Finally, NRG2β/Q43L competitively antagonizes agonist stimulation of EGFR and ErbB2/ErbB3, indicating that NRG2β/Q43L is a pan-ErbB antagonist. Thus we postulate that NRG2β/Q43L and other antagonistic ligands stimulate ErbB tyrosine phosphorylation on a set of residues distinct from that stimulated by agonists, thus suggesting a novel mechanism of ErbB receptor regulation. Moreover, NRG2β/Q43L and related ligand-based antagonists establish a paradigm for the discovery of anti-ErbB therapeutics.

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Five carboxyl-terminal residues of neuregulin2 are critical for stimulation of signaling by the ErbB4 receptor tyrosine kinase

Cited by 29 publications

References 34 publications

Epiregulin: Roles in normal physiology and cancer

Epiregulin: Roles in normal physiology and cancer

TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells

The Q43L mutant of neuregulin 2β is a pan-ErbB receptor antagonist

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