Structure and Function of Human Amphiregulin: A Member of the Epidermal Growth Factor Family

Shoyab, Mohammed; Plowman, Gregory D.; McDonald, VL; Bradley, J. G.; Todaro, G. J.

doi:10.1126/science.2466334

Cited by 552 publications

(350 citation statements)

References 38 publications

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“…Ligand specificity, redundancy, processing and variable tissue expression patterns add to the signaling diversity of the EGF pathway. EGF [7,8], transforming growth factor-α (TGF-α) [9,10], and amphiregulin [11] uniquely bind EGFR. ErbB3 binds neuregulin-1 [12][13][14][15][16] and neuregulin-2 [17][18][19][20] and uniquely binds Neuroglycan C [21].…”

Section: Receptor Overviewmentioning

confidence: 99%

The epidermal growth factor receptor family: Biology driving targeted therapeutics

Wieduwilt

Moasser

2008

Cell. Mol. Life Sci.

647

503

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The epidermal growth factor family of receptor tyrosine kinases (ErbBs) plays essential roles in regulating cell proliferation, survival, differentiation and migration. The ErbB receptors carry out both redundant and restricted functions in mammalian development and in the maintenance of tissues in the adult mammal. Loss of regulation of the ErbB receptors underlies many human diseases, most notably cancer. Our understanding of the function and complex regulation of these receptors has fueled the development of targeted therapeutic agents for human malignancies in the last 15 years. Here we review the biology of ErbB receptors, including their structure, signaling, regulation, and roles in development and disease, then briefly touch on their increasing roles as targets for cancer therapy.

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Section: Receptor Overviewmentioning

confidence: 99%

The epidermal growth factor receptor family: Biology driving targeted therapeutics

Wieduwilt

Moasser

2008

Cell. Mol. Life Sci.

647

503

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“…One category, the ErbB-1 ligands, includes EGF, transforming growth factor a (TGFa), epiregulin, amphiregulin, betacellulin and the heparin-binding EGF (HB-EGF) (Higashiyama et al, 1991;Marquardt et al, 1984;Shing et al, 1993;Shoyab et al, 1989;Toyoda et al, 1995). To di erent extents, these ErbB-1 binding ligands can also activate other receptors of the ErbB family, and hence may mediate distinct signaling outputs for a given cell type (reviewed in Tzahar and Yarden, 1998).…”

Section: Introductionmentioning

confidence: 99%

Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase

et al. 1999

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The ErbB/HER family of receptor tyrosine kinases consists of four receptors that bind a large number of growth factor ligands sharing an epidermal growth factor-(EGF)-like motif. Whereas ErbB-1 binds seven di erent ligands whose prototype is EGF, the three families of neuregulins (NRGs) activate ErbB-3 and/or ErbB-4. Here we characterize a fourth neuregulin, NRG-4, that acts through ErbB-4. The predicted pro-NRG-4 is a transmembrane protein carrying a unique EGF-like motif and a short cytoplasmic domain. A synthetic peptide encompassing the full-length EGF-like domain can induce growth of interleukin-dependent cells ectopically expressing ErbB-4, but not cells expressing the other three ErbB proteins or their combinations. Consistent with speci®city to ErbB-4, NRG-4 can displace an ErbB-4-bound NRG-1 and can activate signaling downstream of this receptor. Expression of NRG-4 mRNA was detected in the adult pancreas and weakly in muscle; other tissues displayed no detectable NRG-4 mRNA. The primary structure and the pattern of expression of NRG-4, together with the strict speci®city of this growth factor to ErbB-4, suggest a physiological role distinct from that of the known ErbB ligands.

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“…One such group of ligands binds speci®cally to and activates EGFR but does not interact directly with ErbB-2, ErbB-3 or ErbB-4. These include epidermal growth factor (EGF) (Savage et al, 1972), transforming growth factor-a (TGF-a) (Marquardt et al, 1984), amphiregulin (AR) (Shoyab et al, 1989), also known as a schwanoma derived growth factor (Kimura et al, 1990) or keratinocyte autocrine growth factor (Cook et al, 1991), heparin binding-EGF likegrowth factor (HB-EGF) (Higashiyama et al, 1991), and betacellulin (Shing et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Epiregulin binds to epidermal growth factor receptor and ErbB-4 and induces tryosine phosphorylation of epidermal growth factor receptor, ErbB-2, ErbB-3 and ErbB-4

et al. 1997

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Epiregulin is a member of the epidermal growth factor (EGF) family, and has certain characteristics that are di erent from that of EGF, including mitogenic responses and binding to EGF receptor (EGFR). Epiregulin may also have another cell surface receptor and/or induces di erent receptor heterodimerizations for intracellular signaling. We investigated the binding ability of epiregulin to four ErbB family receptors using four human breast carcinoma cell lines that expressed di erent subsets of receptors. Chemical cross-linking experiments showed that [ 125 I]epiregulin directly bound to each of EGFR and ErbB-4 but not to ErbB-2 and ErbB-3. Furthermore, although epiregulin stimulated tyrosine phosphorylation of all four ErbB receptors, the main intracellular signal was mediated by ErbB-4 and/or EGFR. The pattern of activation of ErbB family receptors was di erent from that of other EGF-related ligands. Our ®ndings indicate that ErbB-4 and EGFR are receptors for epiregulin, and suggest that EGFrelated ligands transduce signals for di erent biological responses by the hierarchical mechanism.

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Structure and Function of Human Amphiregulin: A Member of the Epidermal Growth Factor Family

Cited by 552 publications

References 38 publications

The epidermal growth factor receptor family: Biology driving targeted therapeutics

The epidermal growth factor receptor family: Biology driving targeted therapeutics

Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase

Epiregulin binds to epidermal growth factor receptor and ErbB-4 and induces tryosine phosphorylation of epidermal growth factor receptor, ErbB-2, ErbB-3 and ErbB-4

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