The Structural Basis for the Specificity of Epidermal Growth Factor and Heregulin Binding

Barbacci, Elsa G.; Guarino, Bradley C.; Stroh, Justin G.; Singleton, David H.; Rosnack, Kenneth J.; Moyer, James D.; Andrews, Glenn C.

doi:10.1074/jbc.270.16.9585

Cited by 92 publications

(100 citation statements)

References 22 publications

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“…This method has been used before to synthesize functionally active derivatives of other EGF-like growth factors (Barbacci et al, 1995;Lin et al, 1988;Shelly et al, 1998). Previously we have established a series of derivatives of the 32D cell line engineered to express di erent ErbB receptors or their combinations (Pinkas-Kramarski et al, 1996;Shelly et al, 1998).…”

Section: Identi®cation Of a Candidate Novel Erbb Ligandmentioning

confidence: 99%

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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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Section: Identi®cation Of a Candidate Novel Erbb Ligandmentioning

confidence: 99%

“…The EGF-like domain of NRG-4 (residues 4 ± 50) was synthesized on an Applied Biosystems (ABI) 430A peptide synthesizer using standard tert-butyloxycarbonyl (t-Boc) chemistry protocols as described (Barbacci et al, 1995). Acetic anhydride capping was employed after each activated ester coupling.…”

Section: Peptide Synthesismentioning

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 emerging apparent promiscuity of some ErbB-1 ligands Riese et al, 1996a), the possibility that ligand multiplicity is related to a bivalent model of ligand-receptor interactions (Tzahar et al, 1997), and a recent observation that a limited structural change, namely replacement of only ®ve N-terminal amino acids, allowed EGF to bind to NDF-receptors (Barbacci et al, 1995), prompted us to survey the ability of ErbB-1 ligands to act through an alternative receptor. By using a sensitive NDF-speci®c cell di erentiation assay, we identi®ed two ligands, EGF and betacellulin, that can use an ErbB-2/ErbB-3 heterodimer to mediate cellular e ects in the absence of ErbB-1.…”

Section: Introductionmentioning

confidence: 99%

The oncogenic ErbB-2/ErbB-3 heterodimer is a surrogate receptor of the epidermal growth factor and betacellulin

et al. 1998

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The ErbB-1 receptor tyrosine kinase binds to six di erent growth factors, whose prototype is the epidermal growth factor (EGF). Two homologous epithelial receptors, ErbB-3 and ErbB-4, bind all isoforms of another family of growth factors, the Neu di erentiation factors (NDFs/neuregulins). The fourth member of the ErbB family, ErbB-2, acts as the preferred heterodimeric partner of ligand-occupied complexes of the three other ErbB proteins. Here we report that at high concentrations, EGF can induce cell growth and di erentiation in the absence of ErbB-1. This function is shared by betacellulin, but not by three other ligands, including the transforming growth factor a (TGFa). The functional receptor was identi®ed as a heterodimer between ErbB-3 and ErbB-2, a previously identi®ed oncogenic complex. When singly expressed, neither ErbB-3 nor ErbB-2 can mediate signaling by EGF. In addition, when co-expressed, blocking either receptor by using site-speci®c antibodies inhibited EGF and betacellulin activities, indicating strict cooperativity between ErbB-3 and ErbB-2. Through analysis of chimeras between EGF and TGFa, we identi®ed the middle portion of EGF (loop B) as the site that enables activation of ErbB-2/ErbB-3. In conclusion, cooperative and promiscuous binding of stroma-derived growth factors by the epithelium-expressed ErbB-2/ErbB-3 heterodimer may be signi®cant to cancer development. The mechanistic implications of our results for a model that attributes receptor dimerization to ligand bivalency, as well as to a recently proposed mechanism of secondary dimerization, are discussed.

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“…HRGa, also called neuregulin and Neu differentiation factor, 38,39 binds directly via the EGF-like domain [40][41][42] to HER3/ErbB3 and/or HER4/ErbB4, members of the EGF receptor family, which then homodimerize or heterodimerize with HER2/ErbB2 to initiate a transmembrane signal. [43][44][45][46] The moderate size (50-55 aa) and folding of the EGF-like domain of HRG [47][48][49] suggested that this domain could be inserted into the HI loop without affecting the integrity of fiber. Moreover, an HRG-targeted virus may be valuable for the treatment of a number of human malignancies, including breast and ovarian carcinomas, in which members of HER receptor family are frequently overexpressed.…”

Section: Introductionmentioning

confidence: 99%

HER3 targeting of adenovirus by fiber modification increases infection of breast cancer cells in vitro, but not following intratumoral injection in mice

et al. 2012

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Despite the tremendous potential of adenovirus (Ad) as a delivery vector for cancer gene therapy, its use in clinical settings has been limited, mainly as a result of the limited infectivity in many tumors and the wide tissue tropism associated with Ad. To modify the tropism of the virus, we have inserted the epidermal growth factor-like domain of the human heregulin-a (HRG) into the HI loop of Ad5 fiber. This insertion had no adverse effect on fiber trimerization nor did it affect incorporation of the modified fiber into infectious viral particles. Virions bearing modified fiber displayed growth characteristics and viral yields indistinguishable from those of wild-type (wt) virus. Most importantly, HRG-tagged virions showed enhanced infection of cells expressing the cognate receptors HER3/ErbB3 and HER4/ErbB4. This was significantly reduced in the presence of soluble HRG. Furthermore, HER3-expressing Chinese hamster ovary (CHO) cells were transduced by the HRG-modified virus, but not by wt virus. In contrast, CHO cells expressing the coxsackie-Ad receptor were transduced with both viruses. However, infection of an in vivo breast cancer xenograft model after intratumoral injection was similar with both viruses, suggesting that the tumor microenvironment and/or the route of delivery have important roles in infection of target cells with fiber-modified Ads.Cancer Gene Therapy (2012) 2,3 In addition to being among the most extensively studied viral vectors, Ads can be easily and economically manipulated, maintained and propagated to produce high titer stocks. 4,5 Moreover, they have the capacity to carry relatively large fragments of exogenous DNA into a wide range of cell and tissue types. 4,5 Subgroup C Ads (exemplified by the most widely used Ad5 and Ad2) attach to and enter host cells in a two-step process. 6 The initial recognition/attachment step is mediated by interactions between the knob component of fiber protein on the Ad capsid and the extracellular domain of the coxsackieadenovirus receptor (CAR) on the host cell surface. 7-11 This attachment is followed by a second interaction between the RGD motif in the penton base of the virus capsid and a v b 3 or a v b 5 cell surface integrins (secondary Ad receptors), which allows viral entry via receptor-mediated endocytosis. [12][13][14][15] Both the primary and secondary Ad receptors are expressed on a wide range of tissues leading to the observed broad tissue tropism of Ads. 16,17 Unfortunately, a large number of tumor cells appear relatively refractory to Ad infection because of limited surface expression of the primary Ad receptor. 1,[18][19][20][21][22][23] This observation has been a driving force behind recent intensive efforts to generate Ad viral vectors with altered tropism.

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The Structural Basis for the Specificity of Epidermal Growth Factor and Heregulin Binding

Cited by 92 publications

References 22 publications

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

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

The oncogenic ErbB-2/ErbB-3 heterodimer is a surrogate receptor of the epidermal growth factor and betacellulin

HER3 targeting of adenovirus by fiber modification increases infection of breast cancer cells in vitro, but not following intratumoral injection in mice

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