| Abstract: |
Heregulins (HRGs) induce tyrosine phosphorylation of several members of the erb-B family of receptors. Although originally isolated as the ligands for p185(c-erbB-2), recent evidence suggests that other receptors of the erbB family, including p180(erbB-3) and p180(erbB-4), are their true cognate receptors. Stimulation of MDA MB-453 cells with HRGβ2 resulted in the tyrosine phosphorylation of p185(c-erbB-2), and p180(erbB-4) in a time-and dose-dependent fashion. This event was accompanied by the formation of multimeric complexes between the activated receptors and SH2-containing proteins. Ligand caused p120-rasGTPase activating protein (GAP), SHC and the p85 subunit of phosphatidylinositol-3'-kinase (PI3K) to be associated with both p185(c-erbB-2) and p180(erbB-4). In addition, tyrosine phosphorylation of p85-PI3K and SHC, but not of GAP or of its associated p62 and p190 proteins, was also detected. HRG also induced the association of GRB2 with tyrosine phosphorylated p185(c-erbB-2), p180(erbB-4) and SHC. Activation of mitogen-activated protein kinase (MAPR) (> 30-fold over untreated controls) was observed upon receptor(s) activation, as it was the induction of the immediate early gene c-fos (> 200-fold). These observations suggest that p21(ras) activation plays a role in the HRG pathway. Furthermore, comparative analysis of the binding of p85-PI3K to 185(c-erbB-2) and p180(erbB-4), revealed a preferential association with activated p180(erbB-4). These findings might suggest a model of HRG action in which the relative expression of the various erb-B family members and the partitioning of signal transduction molecules between each type of receptor might determine the nature of the signal elicited by the ligand and the biological response attained. |
| Keywords: |
signal transduction; mitogen activated protein kinase; controlled study; protein phosphorylation; oncoprotein; human cell; proto-oncogene proteins; complex formation; breast cancer; signaling; protein protein interaction; protein binding; receptor, epidermal growth factor; transcription, genetic; cancer cell culture; enzyme activation; tumor cells, cultured; protein tyrosine kinase; tyrosine; breast neoplasms; phosphorylation; phosphatidylinositol 3 kinase; gene expression regulation, neoplastic; amino acid sequence; molecular sequence data; protein-serine-threonine kinases; carrier proteins; phosphotransferases (alcohol group acceptor); guanosine triphosphatase activating protein; protein-tyrosine kinases; gene induction; mitogen-activated protein kinases; enzyme subunit; glycoproteins; neu differentiation factor; neuregulin-1; receptor, erbb-3; promoter regions (genetics); erbb receptors; humans; human; female; priority journal; article; src homology domains; immediate early gene; oncogene c erb; oncogene c fos; genes, fos; heregulin; 1-phosphatidylinositol 4-kinase; mitogen-activated protein kinase 10
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