Autocrine Extracellular Signal-regulated Kinase (ERK) Activation in Normal Human Keratinocytes: Metalloproteinase-mediated Release of Amphiregulin Triggers Signaling from ErbB1 to ERK

Kansra, Sanjay; Stoll, Stefan; Johnson, Jessica L.; Elder, James T.

doi:10.1091/mbc.e04-03-0233

Cited by 47 publications

(64 citation statements)

References 72 publications

(96 reference statements)

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“…4). The autocrine activation of EGFR-ERK1/2 signaling by amphiregulin upon serum withdrawal has also been described in normal keratinocytes (20 (12). Our present study demonstrating that down-regulation of HSulf-1 augments amphiregulin-EGFR autocrine signaling without affecting the ligand levels provides a novel mechanism of acquired autocrine signaling in breast cancer.…”

Section: Discussionsupporting

confidence: 75%

Loss of HSulf-1 Expression Enhances Autocrine Signaling Mediated by Amphiregulin in Breast Cancer

Narita

Chien

Mullany

et al. 2007

Journal of Biological Chemistry

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Heparan sulfate (HS) glycosaminoglycans are the oligosaccharide chains of heparan sulfate proteoglycans. The sulfation of HS glycosaminoglycan residues is required for its interaction with various heparin-binding growth factors to promote their biological activities to activate their high affinity receptor tyrosine kinases. We have identified HS glycosaminoglycan-6-O-endosulfatase HSulf-1 as a down-regulated gene in ovarian, breast, and several other cancer cell lines. Here we have shown that HSulf-1 inhibits autocrine activation of the EGFR-ERK (epidermal growth factor receptor-extracellular signal-regulated kinase) pathway induced by serum withdrawal in MDA-MB-468 breast cancer cells. Short hairpin RNA-mediated down-regulation of HSulf-1 in HSulf-1 clonal lines of MDA-MB-468 led to a significant increase in autocrine activation of ERK compared with vector only control. The autocrine signaling was also inhibited with neutralization antibodies against amphiregulin and HB-EGF, the heparin-binding growth factor family of the EGF superfamily. Furthermore, HSulf-1-mediated inhibition of autocrine signaling was associated with reduced cyclin D1 levels, leading to decreased S phase fraction and increased G 2 -M fraction, as well as increased cell death. Finally, evaluation of HSulf-1 expression levels in primary invasive breast tumors by RNA in situ hybridization indicated that HSulf-1 is down-regulated in the majority (60%) of tumors, with a predominant association with lobular histology. These data suggest a potential role of HSulf-1 down-regulation in mammary carcinogenesis.Breast cancer is the most common type of cancer among women in the United States. Despite the advances in early detection and therapeutic treatment options, an estimated 215,000 new cases and 41,000 deaths were reported in 2006 (1). One of the molecular signatures known to be associated with poor prognosis is the epidermal growth factor receptor (EGFR).2 The EGFR expression in breast cancer is often associated with resistance to endocrine hormone therapy (2, 3). Recent studies also indicate that hormone-induced estrogen receptor (ER) activation leads to activation of EGFR, suggesting that cross-talk between the two signaling pathways may be a crucial drug-resistant mechanism in ER-positive breast tumors (4). In addition, gene expression profiling studies identified the basal-like tumor as one of the breast tumor subtypes characterized with EGFR expression and poor prognosis (5, 6). EGFR signaling is induced by various EGF-like growth factor family ligands, such as EGF, amphiregulin, heparin-binding EGF-like growth factor (HB-EGF), betacellulin, epiregulin, and transforming growth factor-␣ (7). Amphiregulin is one of the most investigated EGFR ligands in relation to breast cancer. Amphiregulin is a heparin-binding growth factor that requires heparan sulfate (HS) glycosaminoglycans as a low affinity coreceptor (8) and is overexpressed in the majority of primary breast tumors (9). Expression of amphiregulin and EGFR are seen both in breast tumors a...

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Section: Discussionsupporting

confidence: 75%

Loss of HSulf-1 Expression Enhances Autocrine Signaling Mediated by Amphiregulin in Breast Cancer

Narita

Chien

Mullany

et al. 2007

Journal of Biological Chemistry

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“…1Ae, lane 1). This was probably due to previously reported epidermal growth factor secretion and autocrine signaling in these cells (Kansra et al, 2004). However, in contrast to dermal cells, TGFb3 stimulation induced a transient and dose-dependent decrease in ERK1/2 phosphorylation in these cells (Fig.…”

Section: Resultsmentioning

confidence: 60%

TβRI/Alk5-independent TβRII signaling to ERK1/2 in human skin cells according to distinct levels of TβRII expression

Bandyopadhyay

Han

Dai

et al. 2011

Journal of Cell Science

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TGFβ binding to the TGFβ receptor (TβR) activates R-Smad-dependent pathways, such as Smad2/3, and R-Smad-independent pathways, such as ERK1/2. The mechanism of the TGFβ–TβRII–TβRI–Smad2/3 pathway is established; however, it is not known how TGFβ activates ERK1/2. We show here that although TGFβ equally activated Smad2/3 in all cells, it selectively activated ERK1/2 in dermal cells and inhibited ERK1/2 in epidermal cells. These opposite effects correlated with the distinct expression levels of TβRII, which are 7- to 18-fold higher in dermal cells than in epidermal cells. Reduction of TβRII expression in dermal cells abolished TGFβ-stimulated ERK1/2 activation. Upregulation of TβRII expression in epidermal cells to a similar level as that in dermal cells switched TGFβ-induced ERK1/2 inhibition to ERK1/2 activation. More intriguingly, in contrast to the equal importance of TβRII in mediating TGFβ signaling to both Smad2/3 and ERK1/2, knockdown of TβRI/Alk5 blocked activation of only Smad2/3, not ERK1/2, in dermal cells. Similarly, expression of the constitutively activated TβRI-TD kinase activated only Smad2/3 and not ERK1/2 in epidermal cells. This study provides an explanation for why TGFβ selectively activates ERK1/2 in certain cell types and direct evidence for TβRI-independent TβRII signaling to a R-Smad-independent pathway.

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“…This has been reported to be due to autocrine activation, which has been reported in human keratinocytes in which autocrine phosphorylation is correlated with the appearance of the soluble ligand, amphiregulin. 45 When we determined whether recruitment of docking molecules was time dependent, we found no difference in binding of PLC␥1 or Src in either epithelial cells or E1-PAE. Cells stimulated with both concentrations of EGF showed internalization and enhanced binding of Grb2 at the longer time points.…”

Section: Discussionmentioning

confidence: 90%

Distinct Activation of Epidermal Growth Factor Receptor by UTP Contributes to Epithelial Cell Wound Repair

Boucher

Kehasse

Marcincin

et al. 2011

The American Journal of Pathology

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The release of nucleotides after injury activates purinergic receptors, leading to phosphorylation of site-specific residues on epidermal growth factor receptor (EGFR). To elucidate the differences between the injuryinduced response and that induced by exogenous EGF, we examined recruitment of docking proteins, internalization of EGFR, and migration after injury. Injury induced by scratch wounds or stimulation by addition of UTP caused a brief internalization of EGFR, which paralleled the lesser association with growth factor receptor-bound protein 2 (Grb2) and phosphorylation of EGFR. The internalization caused by EGF was sustained and detected for longer than 60 minutes and correlated with phosphorylation of the receptor. The EGF caused recruitment of Grb2, phospholipase C-␥-1 (PLC␥1), Shc, and Src to EGFR. Glutathione S-transferase pull downs were performed, and glutathione S-transferase-PLC␥1 showed binding of Grb2 when stimulated with EGF but not with UTP or injury. Furthermore, UTP did not induce PLC␥1 phosphorylation, and the phosphorylation induced by EGF was attenuated by costimulation with UTP. The response to heparin-binding EGF was equivalent to that of EGF. Site-directed mutagenesis showed that phosphorylation of Y1068 and Y1086 of EGFR is required for repair. Together, our results show that injury and activation of purinergic receptors and direct activation of EGFR via EGF induce distinct downstream pathways.

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Autocrine Extracellular Signal-regulated Kinase (ERK) Activation in Normal Human Keratinocytes: Metalloproteinase-mediated Release of Amphiregulin Triggers Signaling from ErbB1 to ERK

Cited by 47 publications

References 72 publications

Loss of HSulf-1 Expression Enhances Autocrine Signaling Mediated by Amphiregulin in Breast Cancer

Loss of HSulf-1 Expression Enhances Autocrine Signaling Mediated by Amphiregulin in Breast Cancer

TβRI/Alk5-independent TβRII signaling to ERK1/2 in human skin cells according to distinct levels of TβRII expression

Distinct Activation of Epidermal Growth Factor Receptor by UTP Contributes to Epithelial Cell Wound Repair

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