scholarly journals The Interaction between the DrosophilaSecreted Protein Argos and the Epidermal Growth Factor Receptor Inhibits Dimerization of the Receptor and Binding of Secreted Spitz to the Receptor

2000 ◽  
Vol 20 (6) ◽  
pp. 2098-2107 ◽  
Author(s):  
Ming-hao Jin ◽  
Kazunobu Sawamoto ◽  
Mikiko Ito ◽  
Hideyuki Okano
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Egf Receptor ◽  
Transforming Growth Factor ◽  
Extracellular Domain ◽  
Terminal Region ◽  
Transforming Growth Factor Α ◽  
Epidermal Growth

ABSTRACT Drosophila Argos (Aos), a secreted protein with an epidermal growth factor (EGF)-like domain, has been shown to inhibit the activation of the Drosophila EGF receptor (DER). However, it has not been determined whether Aos binds directly to DER or whether regulation of the DER activation occurs through some other mechanism. Using DER-expressing cells (DER/S2) and a recombinant DER extracellular domain-Fc fusion protein (DER-Fc), we have shown that Aos binds directly to the extracellular domain of DER with its carboxyl-terminal region, including the EGF-like domain. Furthermore, Aos can block the binding of secreted Spitz (sSpi), a transforming growth factor α-like ligand of DER, to the extracellular domain of DER. We observed that sSpi stimulates the dimerization of both the soluble DER extracellular domain (sDER) and the intact DER in the DER/S2 cells and that Aos can block the sSpi-induced dimerization of both sDER and intact DER. Moreover, we have shown that, by directly interacting with DER, Aos and SpiAos (a chimeric protein that is composed of the N-terminal region of Spi and the C-terminal region of Aos) inhibit the dimerization and phosphorylation of DER that are induced by DER's overexpression in the absence of sSpi. These results indicate that Aos exerts its inhibitory function through dual molecular mechanisms: by blocking both the receptor dimerization and the binding of activating ligand to the receptor. This is the first description of this novel inhibitory mechanism for receptor tyrosine kinases.

Transforming growth factor-α, epidermal growth factor receptor, and proliferating potential in benign and malignant gliomas

1991 ◽  
Vol 75 (1) ◽  
pp. 97-102 ◽  
Author(s):  
Motohiko Maruno ◽  
John S. Kovach ◽  
Patrick J. Kelly ◽  
Takehiko Yanagihara
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Egf Receptor ◽  
Transforming Growth Factor ◽  
Malignant Gliomas ◽  
Proliferation Index ◽  
Ki 67 ◽  
Content Type ◽  
Transforming Growth Factor Α ◽  
Epidermal Growth

✓ Surgical specimens from six benign and 16 malignant human gliomas were investigated immunohistochemically to correlate the degree of malignancy, the distribution of transforming growth factor-alpha (TGF-α) and epidermal growth factor (EGF) receptor, and the potential for cell proliferation using monoclonal antibodies to TGF-α, EGF receptor, and Ki-67. Fourteen (88%) of the malignant gliomas and one (17%) of the benign gliomas were found to be positive for TGF-α, and 14 (88%) of the malignant gliomas and two (33%) of the benign gliomas expressed EGF receptor. The proliferation index with Ki-67 was 18.8% ± 8.1% (mean ± standard deviation) in malignant gliomas and 1.9% ± 1.8% in benign gliomas. In general, cells positive for EGF receptor and Ki-67 were randomly distributed throughout the tumor tissue, and cells positive for TGF-α tended to be clustered without obvious relationship to areas of necrosis or blood vessels. In some tumors, cells positive for TGF-α, EGF receptor, and Ki-67 were associated in a focal distribution. The more frequent expression of TGF-α and EGF receptor in the highly proliferative malignant gliomas is compatible with a role for TGF-α and EGF receptor in the induction or stimulation of malignant gliomas.

scholarly journals The linear C-terminal regions of epidermal growth factor (EGF) and transforming growth factor-α bind to different epitopes on the human EGF receptor

1998 ◽  
Vol 336 (1) ◽  
pp. 147-151 ◽  
Author(s):  
Anne E. G. LENFERINK ◽  
Albert D. G. De ROOS ◽  
Marianne J. H. Van VUGT ◽  
Monique L. M. Van De POLL ◽  
Everardus J. J. Van ZOELEN
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Calcium Release ◽  
Egf Receptor ◽  
Transforming Growth Factor ◽  
Binding Characteristics ◽  
Transforming Growth Factor Α ◽  
Identical Manner ◽  
Epidermal Growth ◽  
Factor Α

Epidermal growth factor (EGF) and transforming growth factor-α (TGFα) bind with similar affinities in a competitive fashion to the human EGF receptor, and basically induce similar mitogenic responses. In spite of the fact that EGF and TGFα are structurally alike, it is still not clear if the two growth factors bind the receptor in an identical manner. The observation that the 13A9 antibody blocks binding of TGFα, but not that of EGF, to the human EGF receptor [Winkler, O'Connor, Winget and Fendly (1989) Biochemistry 28, 6373–6378] suggests that their binding characteristics are not identical. In the present study we have made use of a set of EGF/TGFα chimaeric molecules to show that the 13A9 antibody blocks receptor binding of ligands with TGFα sequences, but not of ligands with EGF sequences, in their C-terminal linear regions. Using HaCaT human keratinocyte cells in culture, it was determined that ligands that are able to bind the EGF receptor in the presence of 13A9 are also able to induce calcium release from intracellular stores in these cells, indicating that these ligands have the ability to activate the EGF receptor in the presence of the antibody. From these data it is concluded that the flexible C-terminal linear domains of EGF and TGFα bind to separate sequences on the EGF receptor, such that the binding domain of TGFα, but not that of EGF, overlaps with the binding epitope of the 13A9 antibody.

Regulation of the expression and bioactivation of the epidermal growth factor receptor system by estradiol in pig oviduct and endometrium

2001 ◽  
Vol 13 (3) ◽  
pp. 167 ◽  
Author(s):  
Karin Wollenhaupt ◽  
Axel Kettler ◽  
Klaus-Peter Brüssow ◽  
Falk Schneider ◽  
Wilhelm Kanitz ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Egf Receptor ◽  
Transforming Growth Factor ◽  
Endometrial Tissue ◽  
Receptor Protein ◽  
Estradiol Treatment ◽  
Receptor System ◽  
Transforming Growth Factor Α ◽  
Epidermal Growth

Growth factors, such as epidermal growth factor (EGF), have been suggested to mediate local effects of steroid hormones within female reproductive tissue. In the present study, the influence of estrogen on the expression and bioactivity of the EGF receptor (EGF-R) system was investigated in pigs. Oviducal and endometrial tissue from gilts was analysed either at two different time points after ovulation (Day 12 and Day 20), or from ovariectomized animals, with or without steroid-replacement treatment. Estrogen receptor protein concentrations were significantly down-regulated both in oviducal and endometrial tissue under estrogen-influence, in contrast to increased progesterone receptor concentrations. Transcript levels of EGF and transforming growth factor α remained unchanged in both the oviduct and endometrium during treatment. Oviducal EGF-R mRNA was found to be increased after estradiol treatment with concurrent increases in EGF-R protein. However, in endometrial tissue of estradiol-substituted ovariectomized pigs, the receptor transcript was significantly reduced, indicating a different regulation of EGF-R transcription within the endometrium. The bioactivity of the EGF-R, analysed by tyrosine kinase assays, was preserved throughout experiments in the porcine oviduct and endometrium without obvious changes caused by the steroids. In conclusion, estradiol may play a key role during the proliferation and differentiation of porcine oviducal tissue by activating the important paracrine or autocrine EGF system through its receptor. The cell-specific influence of progesterone during regulation of the EGF-R expression in the endometrium requires further investigation.

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