HER4-mediated Biological and Biochemical Properties in NIH 3T3 Cells

Cohen, Bruce D.; Green, Janell M.; Foy, Linda; Fell, H P

doi:10.1074/jbc.271.9.4813

Cited by 78 publications

(19 citation statements)

References 54 publications

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“…Moreover, phosphorylation of ErbB4 at Tyr 1056 creates a canonical binding site for the PI3K regulatory subunit [35,36]. Thus it is plausible to postulate that the PI3K pathway is required for ErbB4 coupling to IL-3-independent proliferation in BaF3/EGFR + ErbB4 cells, and that differential ErbB4 coupling to the PI3K pathway may underlie the functional differences between ErbB4 agonists and antagonists.…”

Section: Resultsmentioning

confidence: 99%

“…ErbB4 phosphorylation on Tyr 1056 creates a binding site for the PI3K regulatory subunit [30,35–37]. Because we had demonstrated that the PI3K/Akt signalling pathway appears to be critical in specifying the effects of stimulation with ErbB4 agonists and antagonists, we postulated that Tyr 1056 is critical for NRG2β stimulation of IL-3 independence in BaF3/EGFR + ErbB4 cells.…”

Section: Resultsmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

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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“…Interestingly, the mechanisms by which HRGβ1 overcame fulvestrant action were subtly different in the HER2 low-expressing and HER2-overexpressing cell lines. In the MCF-7 and T47D cells, fulvestrant selectively enhanced the ability of HRGβ1 to phosphorylate ErbB4 at Y1056, a PI3K-p85 recruitment site [56], and promote AKT signalling activity, whereas in the BT474 and MDAMB361 cells, it was the HRGβ1-induced ErbB4 Y1284 SHC recruitment site [56] and ERK1/2 phosphorylation that were selectively augmented by antihormonal treatment. The differential ErbB4 phosphorylation and downstream pathway recruitment may reflect the expression of alternative ErbB4 isoforms in these cells, with the CYT-2 isoform, which lacks the Y1056 PI3K binding consensus site, potentially being preferentially expressed in the ErbB2-overexpressing cell lines [57].…”

Section: Discussionmentioning

confidence: 99%

Fulvestrant-induced expression of ErbB3 and ErbB4 receptors sensitizes oestrogen receptor-positive breast cancer cells to heregulin β1

et al. 2011

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IntroductionWe have previously reported that induction of epidermal growth factor receptor and ErbB2 in response to antihormonal agents may provide an early mechanism to allow breast cancer cells to evade the growth-inhibitory action of such therapies and ultimately drive resistant cell growth. More recently, the other two members of the ErbB receptor family, ErbB3 and ErbB4, have been implicated in antihormone resistance in breast cancer. In the present study, we have investigated whether induction of ErbB3 and/or ErbB4 may provide an alternative resistance mechanism to antihormonal action in a panel of four oestrogen receptor (ER)-positive breast cancer cell lines.MethodsMCF-7, T47D, BT474 and MDAMB361 cell lines were exposed to fulvestrant (100 nM) for seven days, and effects on ErbB3/4 expression and signalling, as well as on cell growth, were assessed. Effects of heregulin β1 (HRGβ1) were also examined in the absence and presence of fulvestrant to determine the impact of ER blockade on the capacity of this ErbB3/4 ligand to promote signalling and cell proliferation.ResultsFulvestrant potently reduced ER expression and transcriptional activity and significantly inhibited growth in MCF-7, T47D, BT474 and MDAMB361 cells. However, alongside this inhibitory activity, fulvestrant also consistently induced protein expression and activity of ErbB3 in MCF-7 and T47D cells and ErbB4 in BT474 and MDAMB361 cell lines. Consequently, fulvestrant treatment sensitised all cell lines to the actions of the ErbB3/4 ligand HRGβ1 with enhanced ErbB3/4-driven signalling activity, reexpression of cyclin D1 and significant increases in cell proliferation being observed when compared to untreated cells. Indeed, in T47D and MDAMB361 HRGβ1 was converted from a ligand having negligible or suppressive growth activity into one that potently promoted cell proliferation. Consequently, fulvestrant-mediated growth inhibition was completely overridden by HRGβ1 in all four cell lines.ConclusionsThese findings suggest that although antihormones such as fulvestrant may have potent acute growth-inhibitory activity in ER-positive breast cancer cells, their ability to induce and sensitise cells to growth factors may serve to reduce and ultimately limit their inhibitory activity.

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“…Nevertheless, the oncogenic transformation capacity is not identical among members of the EGFR family. Cohen et al [39] demonstrated that any combination of EGFRs was able to induce in vitro transformation of NIH:3T3 cells. In spite of this, EGFR/c-erbB-2 was the only heterodimer capable of inducing in vivo transformation into a tumor phenotype.…”

Section: Discussionmentioning

confidence: 99%

Negative Prognostic Impact of the Coexpression of Epidermal Growth Factor Receptor and c-erbB-2 in Locally Advanced Cervical Cancer

et al. 2009

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Objective: The objective was to determine the impact of the coexpression of epidermal growth factor receptor (EGFR) and tumor marker c-erbB-2 on disease-free survival (DFS) and pelvic relapse-free survival (PRFS) in patients with locally advanced cervical cancer (LACC) receiving concurrent chemoradiotherapy. Methods: The expression of EGFR and c-erbB-2 was assessed by immunohistochemistry, which was centralized and blinded to outcome. Univariate and multivariate analyses were used to evaluate the impact of EGFR and c-erbB-2 on DFS and PRFS. Results: 170 patients with LACC were included and received concurrent chemoradiotherapy. 25 (15%) biopsies were considered EGFR and c-erbB-2 positive; 100 (59%) were either EGFR or c-erbB-2 positive, and 45 (26%) were EGFR and c-erbB-2 negative. The 3- and 5-year DFS was 39% each for EGFR- and c-erbB-2-positive patients, 54 and 49%, respectively, for EGFR- or c-erbB-2-positive patients, and 76 and 72%, respectively, for EGFR- and c-erbB-2-negative patients (p = 0.006). EGFR- and c-erbB-2-positive tumors were significantly associated with a decrease in PRFS (hazard ratio, HR, 3.99; 95% confidence interval, CI, 1.44–11.05, p = 0.007), and DFS (HR 2.9; 95% CI, 1.26–6.66, p = 0.01). Conclusion: Patients with LACC coexpressing EGFR and c-erbB-2, and treated with concurrent chemoradiotherapy, had a worse clinical prognosis with shorter DFS and PRFS.

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HER4-mediated Biological and Biochemical Properties in NIH 3T3 Cells

Cited by 78 publications

References 54 publications

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

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

Fulvestrant-induced expression of ErbB3 and ErbB4 receptors sensitizes oestrogen receptor-positive breast cancer cells to heregulin β1

Negative Prognostic Impact of the Coexpression of Epidermal Growth Factor Receptor and c-erbB-2 in Locally Advanced Cervical Cancer

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