Role of Shc and phosphoinositide 3-kinase in heregulin-induced mitogenic signaling via ErbB3.
- Author:
Myong Soo KIM
1
;
John G KOLAND
Author Information
1. Department of Pharmacology, College of Dentistry, Chosun University, Kwang-Ju, South Korea. msakim@mail.chosun.ac.kr
- Publication Type:Original Article
- Keywords:
ErbB3/HER3;
Shc;
PI 3-kinase;
Cyclin D1;
Mitogenesis
- MeSH:
Cell Cycle;
Cyclin D1;
DNA;
Neuregulin-1;
NIH 3T3 Cells;
Phosphatidylinositol 3-Kinases;
Phosphotransferases;
Protein Kinases;
Receptor Protein-Tyrosine Kinases;
Signal Transduction
- From:The Korean Journal of Physiology and Pharmacology
2000;4(6):507-513
- CountryRepublic of Korea
- Language:English
-
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.
