1.Role of Shc and phosphoinositide 3-kinase in heregulin-induced mitogenic signaling via ErbB3.
The Korean Journal of Physiology and Pharmacology 2000;4(6):507-513
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.
Cell Cycle
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Cyclin D1
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DNA
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Neuregulin-1
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NIH 3T3 Cells
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Phosphatidylinositol 3-Kinases
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Phosphotransferases
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Protein Kinases
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Receptor Protein-Tyrosine Kinases
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Signal Transduction