Role of Shc and Phosphoinositide 3-Kinase in Heregulin-Induced Mitogenic Signaling via ErbB3
Role of Shc and Phosphoinositide 3-Kinase in Heregulin-Induced Mitogenic Signaling via ErbB3
- Myong Soo Kim John G. Koland
- 대한생리학회-대한약리학회
- The Korean Journal of Physiology & Pharmacology
- 제4권 제6호
- 등재여부 : KCI등재
- 2000.01
- 497 - 506 (10 pages)
<P> 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 heregulinβ<SUB>1</SUB>. 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 D<SUB>1</SUB> expression by preteatment with MAPK kinase inhibitor or PI 3-kinase inhibitor before stimulation with heregulin. In accordance with the cyclin D<SUB>1</SUB> 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 G<SUB>1</SUB>/S phase by ErbB3 activation is dependent on both Shc/MAPK and PI 3-kinase signal transduction pathways.