Korean J Physiol Pharmacol.  2000 Dec;4(6):507-513.

Role of Shc and phosphoinositide 3-kinase in heregulin-induced mitogenic signaling via ErbB3

Affiliations
  • 1Department of Pharmacology, College of Dentistry, Chosun University, Kwang-Ju, South Korea. msakim@mail.chosun.ac.kr

Abstract

ErbB3/HER3 is a cell surface receptor which belongs to the ErbB/HER subfamily of receptor protein tyrosine kinases. When expressed in NIH/3T3 cells, ErbB3 can form heterodimeric coreceptor with endogenous ErbB2. Among known intracellular effectors of the ErbB2/ErbB3 are mitogen-activated protein kinase (MAPK) and phosphoinositide (PI) 3-kinase. In the present study, we studied relative contributions of above two distinct signaling pathways to the heregulin-induced mitogenic response via activated ErbB3. For this, clonal NIH-3T3 cell lines expressing wild-type ErbB3 and ErbB3 mutants were stimulated with heregulin beta1. While cyclin D1 level was markedly high and further increased by treatment of heregulin in cells expressing wild-type ErbB3, the elimination of either Shc binding or PI 3-kinase binding lowered both levels. This result was supported by the reduction of cyclin D1 expression by preteatment with MAPK kinase inhibitor or PI 3-kinase inhibitor before stimulation with heregulin. In accordance with the cyclin D1 expression, elimination of either Shc binding or PI 3-kinase binding reduced the heregulin-induced DNA synthesis and cell growth rate. Our results obtained by the comparison of wild-type and ErbB3 mutants indicate that the full induction of the cell cycle progression through G1/S phase by ErbB3 activation is dependent on both Shc/MAPK and PI 3-kinase signal transduction pathways.

Keyword

ErbB3/HER3; Shc; PI 3-kinase; Cyclin D1; Mitogenesis

MeSH Terms

Cell Cycle
Cyclin D1
DNA
Neuregulin-1
NIH 3T3 Cells
Phosphatidylinositol 3-Kinases
Phosphotransferases
Protein Kinases
Receptor Protein-Tyrosine Kinases
Signal Transduction
Cyclin D1
DNA
Neuregulin-1
Phosphatidylinositol 3-Kinases
Phosphotransferases
Protein Kinases
Receptor Protein-Tyrosine Kinases
Full Text Links
  • KJPP
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr