Activation of erbb2 and c-src in phorbol ester-treated mouse epidermis: possible role in mouse skin tumor promotion

ABSTRACT In recent work we showed that the EGF receptor (EGFr) was activated in tumor promoter treated mouse epidermis (_CELL GROWTH & DIFFERENTIATION_, 6: 1447 – 1455, 1995). In the

present study, we have investigated the possible role of other erbB family members in the process of tumor promotion. Both _ERB_B2 and _ERB_B3, but not _ERB_B4, were expressed in cultured

mouse keratinocytes and in mouse epidermis _IN VIVO_. In cultured mouse keratinocytes, EGF stimulated rapid tyrosine phosphorylation of _ERB_B2 followed by a time-dependent degradation of

_ERB_B2 protein. Furthermore, an increase in _ERB_B2 : EGFr heterodimer formation was also induced by EGF. In contrast to the results with _ERB_B2, EGF did not induce tyrosine

phosphorylation, the degradation of _ERB_B3, or _ERB_B3 : EGFr heterodimer formation in cultured keratinocytes. Further analyses revealed that c-_SRC_ kinase activity was dramatically

elevated in cultured mouse keratinocytes exposed to EGF. In mouse epidermis following multiple treatments with 12-_O_-tetradecanoylphorbol-13-acetate (TPA), the phosphotyrosine content of

_ERB_B2 was significantly elevated in a dose-dependent manner. Concomittantly, _ERB_B2 : EGFr heterodimer formation and c-_SRC_ kinase activity were also elevated in TPA-treated epidermis.

Structure-activity relationships with several phorbol ester analogs showed that the elevated phosphorylation of _ERB_B2 in mouse epidermis followed closely with tumor promoting ability.

Activation of _ERB_B2 and c-_SRC_ kinase were also observed in the epidermis of TGFα transgenic mice where expression of human TGFα was targeted to basal keratinocytes with the human K14

promoter. Collectively, the current data suggest that the activation of _ERB_B2 in phorbol ester treated skin can be explained solely by a mechanism involving elevation of EGFr ligands and

activation of the EGFr. In addition, activation of c-_SRC_ may be an important downstream effector in mouse keratinocytes both _IN VIVO_ and _IN VITRO_, following activation of the EGFr,

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CELL CARCINOMA Article Open access 07 September 2020 AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Carcinogenesis, Science Park-Research Division, The University of Texas, MD

Anderson Cancer Center, PO Box 389, Smithville, 78957, Texas, USA Wenjuan Xian & John DiGiovanni * Glaxo Wellcome Research, Inc, PO Box 13398, Research Triangle Park, 27709, North

Carolina, USA Michael P Rosenberg Authors * Wenjuan Xian View author publications You can also search for this author inPubMed Google Scholar * Michael P Rosenberg View author publications

You can also search for this author inPubMed Google Scholar * John DiGiovanni View author publications You can also search for this author inPubMed Google Scholar RIGHTS AND PERMISSIONS

Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Xian, W., Rosenberg, M. & DiGiovanni, J. Activation of _ERB_B2 and c-_SRC_ in phorbol ester-treated mouse epidermis:

possible role in mouse skin tumor promotion. _Oncogene_ 14, 1435–1444 (1997). https://doi.org/10.1038/sj.onc.1200980 Download citation * Received: 07 June 1996 * Revised: 25 November 1996 *

Accepted: 26 November 1996 * Issue Date: 27 March 1997 * DOI: https://doi.org/10.1038/sj.onc.1200980 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this

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KEYWORDS * _erb_B2 * c-_src_ * phosphorylation * tumor promotion