EGF receptor ligands

Harris, Raymond C.; Chung, Eun-Kyung; Coffey, Robert J.

doi:10.1016/s0014-4827(02)00105-2

Cited by 686 publications

(418 citation statements)

References 112 publications

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“…We next investigated the possibility that the increased activation of EGFR and ErbB-2 induced by ADAMTS-1 is achieved through shedding/activating the transmembrane precursors of these GFs, the ligands of ErbB receptor tyrosine kinases. The EGF family GFs include EGF, transforming growth factor-a (TGF-a), HB-EGF, AR, betacellulin, epiregulin, neuregulin, and epigen (Massague´and Pandiella, 1993;Harris et al, 2003); all of these are shed from the cell surface (Peschon et al, 1998;Lee et al, 2003;Sahin et al, 2004). Increasing evidence suggests that shedding of EGF family GF precursors regulates the availability and bioactivity of these factors and is essential for the activation of the ErbB-signaling pathways Jackson et al, 2003;Lee et al, 2003;Yamazaki et al, 2003).…”

Section: Resultsmentioning

confidence: 99%

Full-length ADAMTS-1 and the ADAMTS-1 fragments display pro- and antimetastatic activity, respectively

2005

Oncogene

150

157

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The exact role of a disintegrin and metalloproteinase with thrombospondin motifs-1 (ADAMTS-1) and the underlying mechanism of its involvement in tumor metastasis have not been established. We have now demonstrated that overexpression of ADAMTS-1 promotes pulmonary metastasis of TA3 mammary carcinoma and Lewis lung carcinoma cells and that a proteinase-dead mutant of ADAMTS-1 (ADAMTS-1E/Q) inhibits their metastasis, indicating that the prometastatic activity of ADAMTS-1 requires its metalloproteinase activity. Overexpression of ADAMTS-1 in these cells promoted tumor angiogenesis and invasion, shedding of the transmembrane precursors of heparin-binding epidermal growth factor (EGF) and amphiregulin (AR), and activation of the EGF receptor and ErbB-2, while overexpression of ADAMTS-1E/Q inhibited these events. Furthermore, we found that ADAMTS-1 undergoes auto-proteolytic cleavage to generate the NH 2 -and COOH-terminal cleavage fragments containing at least one thrombospondin-type-I-like motif and that overexpression of the NH 2 -terminal ADAMTS-1 fragment and the COOH-terminal ADAMTS-1 fragment can inhibit pulmonary tumor metastasis. These fragments also inhibited Erk1/2 kinase activation induced by soluble heparin-binding EGF and AR. Taken together, our results suggest that the proteolytic status of ADAMTS-1 determines its effect on tumor metastasis, and that the ADAMTS-1E/Q and the ADAMTS-1 fragments likely inhibit tumor metastasis by negatively regulating the availability and activity of soluble heparin-binding EGF and AR.

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Section: Resultsmentioning

confidence: 99%

Full-length ADAMTS-1 and the ADAMTS-1 fragments display pro- and antimetastatic activity, respectively

2005

Oncogene

150

157

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“…8). However, auto-and cross-induction, and autocrine signalling, occurs extensively among the EGF receptor ligands (Barnard et al, 1994;Piepkorn et al, 1998) with HBEGF in particular having a proposed juxtacrine interaction with its receptor (Harris et al, 2003), which might be pertinent to placode formation and the creation of a follicular/non-follicular cell boundary in adjacent basal epidermal cells. Crucially, some EGF ligands are able to downregulate the EGFR receptor (Singh and Harris, 2005) and, more generally, different ligands are known to alter the magnitude and duration of EGFR signals (Wells, 1999).…”

Section: Hbegf and Kgf Promote Epidermal Fate At The Expense Of Hf Dementioning

confidence: 99%

KGF and EGF signalling block hair follicle induction and promote interfollicular epidermal fate in developing mouse skin

et al. 2009

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A key initial event in hair follicle morphogenesis is the localised thickening of the skin epithelium to form a placode, partitioning future hair follicle epithelium from interfollicular epidermis. Although many developmental signalling pathways are implicated in follicle morphogenesis, the role of epidermal growth factor (EGF) and keratinocyte growth factor (KGF, also known as FGF7) receptors are not defined. EGF receptor (EGFR) ligands have previously been shown to inhibit developing hair follicles; however, the underlying mechanisms have not been characterised. Here we show that receptors for EGF and KGF undergo marked downregulation in hair follicle placodes from multiple body sites, whereas the expression of endogenous ligands persist throughout hair follicle initiation. Using embryonic skin organ culture, we show that when skin from the sites of primary pelage and whisker follicle development is exposed to increased levels of two ectopic EGFR ligands (HBEGF and amphiregulin) and the FGFR2(IIIb) receptor ligand KGF, follicle formation is inhibited in a time-and dose-dependent manner. We then used downstream molecular markers and microarray profiling to provide evidence that, in response to KGF and EGF signalling, epidermal differentiation is promoted at the expense of hair follicle fate. We propose that hair follicle initiation in placodes requires downregulation of the two pathways in question, both of which are crucial for the ongoing development of the interfollicular epidermis. We have also uncovered a previously unrecognised role for KGF signalling in the formation of hair follicles in the mouse.

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“…The second one includes heparin-binding EGF-like growth factor (HB-EGF), betacellulin (BTC) and epiregulin (EPR) which bind to both ErbB1/EGFR and ErbB4. The last one includes the four neuregulins (NRG1, NRG2, NRG3 and NRG4) which bind to ErbB3 and/or ErbB4 (Harris et al, 2003). ErbB2 has no ligand but is the preferred heterodimerization partner for other ErbBs (Citri et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Heparan sulphate proteoglycans are essential for the myeloma cell growth activity of EGF-family ligands in multiple myeloma

et al. 2006

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The epidermal growth factor (EGF)/EGF-receptor (ErbB1-4) family is involved in the biology of multiple myeloma (MM). In particular, ErbB-specific inhibitors induce strong apoptosis of myeloma cells (MMC) in vitro.To delineate the contribution of the 10 EGF-family ligands to the pathogenesis of MM, we have assessed their expression and biological activity. Comparing Affymetrix DNA-microarray-expression-profiles of CD138-purified plasma-cells from 65 MM-patients and 7 normal individuals to those of plasmablasts and B-cells, we found 5/10 EGF-family genes to be expressed in MMC. Neuregulin-2 and neuregulin-3 were expressed by MMC only, while neuregulin-1, amphiregulin and transforming growth factor-a were expressed by both MMC and normal plasma-cells. Using real-time polymerase chain reaction, we found HB-EGF, amphiregulin, neuregulin-1 and epiregulin to be expressed by cells from the bone marrow-environment. Only the EGF-members able to bind heparan-sulphate proteoglycans (HSPGs) -neuregulin-1, amphiregulin, HB-EGF -promote the growth of MMC. Those ligands strongly bind MMC through HSPGs. The binding and the MMC growth activity was abrogated by heparitinase, heparin or deletion of the HS-binding domain. The number of HS-binding EGF ligand molecules bound to MMC was higher than 10 5 molecules/cell and paralleled that of syndecan-1. Syndecan-1, the main HSPG present on MM cells, likely concentrates high levels of HS-binding-EGF-ligands at the cell membrane and facilitates ErbB-activation. Altogether, our data further identify EGF-signalling as promising target for MM-therapy.

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EGF receptor ligands

Cited by 686 publications

References 112 publications

Full-length ADAMTS-1 and the ADAMTS-1 fragments display pro- and antimetastatic activity, respectively

Full-length ADAMTS-1 and the ADAMTS-1 fragments display pro- and antimetastatic activity, respectively

KGF and EGF signalling block hair follicle induction and promote interfollicular epidermal fate in developing mouse skin

Heparan sulphate proteoglycans are essential for the myeloma cell growth activity of EGF-family ligands in multiple myeloma

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