Distinct characteristics of heregulin signals mediated by HER3 or HER4.

Abstract:

:Members of the epidermal growth-factor-receptor tyrosine-kinase (EGFR) family play important roles both in normal growth regulation/cell differentiation and in the genesis and progression of human neoplasia. In the present study, we analysed distinct heregulin (HRG) signals mediated by the HRG receptors HER3 and HER4. In overexpression cell systems, we demonstrate that HRG-induced transformation by "kinase-impaired" HER3 is dependent on coexpression of kinase active HER2. In cells coexpressing HER2 and HER4, however, both kinases significantly contribute to the HRG-induced mitogenic stimulus. In addition, we show that HER3 is no substrate of HRG-activated HER4. Analysis of EGFR crosstalk in a panel of human carcinoma cell lines revealed mainly HRG-induced activation of HER2/HER3, whereas HER4 activation is also detectable to various extents. Evidence for HRG-induced activation of HER3 and/or HER4 indicates relevance of cell-specific expression patterns of these high- and low-affinity HRG receptors in the modulation of a ligand-induced stimulus. Specific signal modulation and definition can be demonstrated further by distinct time courses of mitogen-activated protein (MAP) kinase (MAPK) activation, which are induced by distinct HRG isotypes via differential binding to HER2/HER3 versus HER2/HER4. In concert, these mechanisms of signal modulation may be decisive for the diverse biological activities of HRG in different cell types.

journal_name

J Cell Physiol

authors

Weiss FU,Wallasch C,Campiglio M,Issing W,Ullrich A

doi

10.1002/(SICI)1097-4652(199711)173:2<187::AID-JCP1

subject

Has Abstract

pub_date

1997-11-01 00:00:00

pages

187-95

issue

2

eissn

0021-9541

issn

1097-4652

pii

10.1002/(SICI)1097-4652(199711)173:2<187::AID-JCP1

journal_volume

173

pub_type

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