Heregulin‐induced activation of ErbB3 by EGFR tyrosine kinase activity promotes tumor growth and metastasis in melanoma cells

Ueno, Yoshio; Sakurai, Hiroaki; Tsunoda, Satoshi; Choo, Min‐Kyung; Matsuo, Mitsuhiro; Koizumi, Keiichi; Saiki, Ikuo

doi:10.1002/ijc.23465

Cited by 70 publications

(55 citation statements)

References 31 publications

(51 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other results show that phosphorylated ErbB3 co-immunoprecipitated with EGFR after stimulation of HSG cells with either UTP or NRG1 but not with EGF (Fig. 9C), consistent with studies showing that EGFR/ErbB3 heterodimers are preferentially formed upon NRG binding to ErbB3 (58,59). To determine whether UTP-induced ErbB3 phosphorylation is dependent on metalloprotease activity, HSG cells were treated with TAPI-2, similar to FIGURE 6.…”

Section: P2y 2 R-mediated Egfr Phosphorylationsupporting

confidence: 86%

“…Once activated, EGFR/ErbB3 heterodimers couple to the phosphoinositide 3-kinase/Akt (serine/threonine-specific protein kinase) pathway (74). The physiological consequences of EGFR/ErbB3 heterodimer formation are still unclear; however, it appears to promote growth of pancreatic (75) and breast (76) cancers and melanoma (59). The HSG cells used for this study were derived from a malignant salivary gland tumor, suggesting that P2Y 2 Rs may contribute to salivary gland tumor growth.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

P2Y2 Nucleotide Receptors Mediate Metalloprotease-dependent Phosphorylation of Epidermal Growth Factor Receptor and ErbB3 in Human Salivary Gland Cells

Ratchford

Baker

Camden

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

The G protein-coupled receptor P2Y 2 nucleotide receptor (P2Y 2 R) has been shown to be up-regulated in a variety of tissues in response to stress or injury. Recent studies have suggested that P2Y 2 Rs may play a role in immune responses, wound healing, and tissue regeneration via their ability to activate multiple signaling pathways, including activation of growth factor receptors. Here, we demonstrate that in human salivary gland (HSG) cells, activation of the P2Y 2 R by its agonist induces phosphorylation of ERK1/2 via two distinct mechanisms, a rapid, protein kinase C-dependent pathway and a slower and prolonged, epidermal growth factor receptor (EGFR)-dependent pathway. The EGFR-dependent stimulation of UTP-induced ERK1/2 phosphorylation in HSG cells is inhibited by the adamalysin inhibitor tumor necrosis factor-␣ protease inhibitor or by small interfering RNA that selectively silences ADAM10 and ADAM17 expression, suggesting that ADAM metalloproteases are required for P2Y 2 R-mediated activation of the EGFR. G proteincoupled receptors have been shown to promote proteolytic release of EGFR ligands; however, neutralizing antibodies to known ligands of the EGFR did not inhibit UTP-induced EGFR phosphorylation. Immunoprecipitation experiments indicated that UTP causes association of the EGFR with another member of the EGF receptor family, ErbB3. Furthermore, stimulation of HSG cells with UTP induced phosphorylation of ErbB3, and silencing of ErbB3 expression inhibited UTP-induced phosphorylation of both ErbB3 and EGFR. UTP-induced phosphorylation of ErbB3 and EGFR was also inhibited by silencing the expression of the ErbB3 ligand neuregulin 1 (NRG1). These results suggest that P2Y 2 R activation in salivary gland cells promotes the formation of EGFR/ErbB3 heterodimers and metalloprotease-dependent neuregulin 1 release, resulting in the activation of both EGFR and ErbB3.G protein-coupled receptors (GPCRs), 3 the largest group of cell surface receptors, function not only as short term modulators of cell metabolism but also as regulators of cellular growth and differentiation via activation of the ERK/MAPK signaling cascade (1-5). The mechanisms whereby GPCRs activate the ERK/MAPK signaling pathway are complex and vary according to the type of GPCR and the tissue in which the receptor is expressed (1, 6, 7). During the past decade, numerous studies have demonstrated that GPCRs can couple to the ERK/MAPK signaling cascade directly through a G protein-dependent pathway or indirectly by activation of the epidermal growth factor receptor (EGFR, also known as ErbB1) (1, 8 -10). Mediators of GPCR-induced ERK/MAPK activation include Src tyrosine kinase (6,(11)(12)(13)(14)(15), protein kinase C (PKC) (6, 11, 12), prolinerich tyrosine kinase 2 (13, 14), increases in the intracellular calcium concentration ([Ca 2ϩ ] i ) (15, 16), reactive oxygen species (17-19), and metalloprotease-dependent shedding of an EGFR ligand (8, 20 -22). EGFR ligands promote homodimerization and autophosphorylation of the EGFR (23), resulting i...

show abstract

Section: P2y 2 R-mediated Egfr Phosphorylationsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

P2Y2 Nucleotide Receptors Mediate Metalloprotease-dependent Phosphorylation of Epidermal Growth Factor Receptor and ErbB3 in Human Salivary Gland Cells

Ratchford

Baker

Camden

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Thus, most studies linking EGFR activation to melanoma biology have relied on protein expression or activation studies (TopcuYilmaz et al 2010;Tworkoski et al 2011). An assortment of in vitro studies has suggested that ectopic EGFR expression may enhance melanoma cell growth (Diaz et al 2007;Ueno et al 2008) and that pharmacological blockade of EGFR using small-molecule inhibitors or monoclonal antibodies may suppress growth in melanoma cell lines (Boone et al 2011), either alone or in combination with other targeted agents (Ivanov and Hei 2005;Schicher et al 2009). Also, preliminary results raise the possibility that EGFR activation may contribute to uveal melanoma pathogenesis in some instances (Wu et al 2012).…”

Section: Epidermal Growth Factor Receptor (Egfr)mentioning

confidence: 99%

Melanoma: from mutations to medicine

et al. 2012

View full text Add to dashboard Cite

Melanoma is often considered one of the most aggressive and treatment-resistant human cancers. It is a disease that, due to the presence of melanin pigment, was accurately diagnosed earlier than most other malignancies and that has been subjected to countless therapeutic strategies. Aside from early surgical resection, no therapeutic modality has been found to afford a high likelihood of curative outcome. However, discoveries reported in recent years have revealed a near avalanche of breakthroughs in the melanoma field—breakthroughs that span fundamental understanding of the molecular basis of the disease all the way to new therapeutic strategies that produce unquestionable clinical benefit. These discoveries have been born from the successful fruits of numerous researchers working in many—sometimes-related, although also distinct—biomedical disciplines. Discoveries of frequent mutations involving BRAF(V600E), developmental and oncogenic roles for the microphthalmia-associated transcription factor (MITF) pathway, clinical efficacy of BRAF-targeted small molecules, and emerging mechanisms underlying resistance to targeted therapeutics represent just a sample of the findings that have created a striking inflection in the quest for clinically meaningful progress in the melanoma field.

show abstract

“…Traditionally, it was thought that ErbB3 played a moderator role in cellular proliferation acting as a simple scaffolding partner for the other signaling receptors, such as EGFR and ErbB2. 5 In prostate cancer, 27 lung cancer 28 and melanoma, 29 it has been speculated that the EGFR-ErbB3 heterodimer contributes to tumorigenesis, and here, utilizing pancreatic adenocarcinoma, we identified ErbB3 as the critical, rate-limiting component in EGFR-dependent cellular proliferation. We postulate that pancreatic cancer cellular proliferation is directly affected by the level of ErbB3 expression.…”

Section: Discussionmentioning

confidence: 78%