The Epidermal Growth Factor Receptor Couples Transforming Growth Factor-α, Heparin-binding Epidermal Growth Factor-like Factor, and Amphiregulin to Neu, ErbB-3, and ErbB-4

doi:10.1074/jbc.271.33.20047

The Epidermal Growth Factor Receptor Couples Transforming Growth Factor-α, Heparin-binding Epidermal Growth Factor-like Factor, and Amphiregulin to Neu, ErbB-3, and ErbB-4*

From the ^‡ Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520-8023,
^¶ Department of Surgical Research, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115-5746,
** Bristol-Myers-Squibb Pharmaceutical Research Institute, Seattle, Washington 98121, and Sugen, Inc., Redwood City, California 94063-4720

^§§To whom correspondence should be addressed:
Dept. of Pathology, Yale University School of Medicine, P. O. Box 208023, New Haven, CT 06520-8023.
Tel.: 203-785-4832; Fax: 203-785-7467; E-mail: Stern{at}Biomed.med.yale.edu.

Abstract

The epidermal growth factor (EGF) family hormones amphiregulin (AR), transforming growth factor-α (TGF-α), and heparin-binding EGF-like growth factor (HB-EGF) are thought to play significant roles in the genesis or progression of a number of human malignancies. However, the ability of these ligands to activate all four erbB family receptors has not been evaluated. Therefore, we have assessed the stimulation of erbB family receptor tyrosine phosphorylation by these hormones in a panel of mouse Ba/F3 cell lines expressing the four erbB family receptors, singly and in pairwise combinations. We also measured the stimulation of interleukin-3-independent survival or proliferation in this panel of Ba/F3 cell lines to compare the patterns of erbB family receptor coupling to physiologic responses induced by these peptides. EGF, TGF-α, AR, and HB-EGF all stimulated qualitatively similar patterns of erbB family receptor tyrosine phosphorylation and coupling to physiologic responses. Therefore, EGF, TGF-α, AR, and HB-EGF are functionally identical in this model system and behave differently from the EGF family hormones betacellulin and neuregulins.

Footnotes

↵^§ Supported by National Cancer Institute, United States Public Health Service Postdoctoral Training Grant HD-07149 and by United States Army Medical Research and Materiel Command Postdoctoral Fellowship DAMD-17-94-J-4036.
↵^∥ Supported by United States Public Health Service Grant GM-47397 (to M. K.).
↵^‡‡ Supported by United States Public Health Service Grant GM-47397
↵* This work was supported in part by National Cancer Institute, United States Public Health Service Grant CA-45708 and by United States Army Medical Research and Materiel Command Grant DAMD-17-94-J-4476 (to D. F. S.). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

EGF

epidermal growth factor

EGFR

epidermal growth factor receptor

AR

amphiregulin

NRG

neuregulin

TGF-α

transforming growth factor-α

HB

heparin binding

BTC

betacellulin

IL

interleukin

CAPS

3-(cyclohexylamino)propanesulfonic acid.
↵²K. Elenius and M. Klagsbrun, unpublished results.
↵³D. J. Riese II and D. F. Stern, unpublished results.
- Received March 22, 1996.