Signal transduction pathways induced by heregulin in MDA-MB-453 breast cancer cells.
Heregulins (HRGs) induce tyrosine phosphorylation of several members of the erb-B family of receptors. Although originally isolated as the ligands for p185c-erb-2, recent evidence suggests that other receptors of the erbB family, including p180erbB-3 and p180erbB-4, are their true cognate receptors. Stimulation of MDA MB-453 cells with HRG beta 2 resulted in the tyrosine phosphorylation of p185c-erbB-2 and p180erbB-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 p185c-erbB-2 and p180erbB-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 p185c-erbB-2, p180erbB-4 and SHC. Activation of mitogen-activated protein kinase (MAPK) ( > 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 p21ras activation plays a role in the HRG pathway. Furthermore, comparative analysis of the binding of p85-PI3K to 185c-erbB-2 and p180erbB-4, revealed a preferential association with activated p180erbB-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.
Sepp-Lorenzino
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L
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Eberhard
I
I
Ma
Z
Z
Cho
C
C
Serve
H
H
Liu
F
F
Rosen
N
N
Lupu
R
R
D019870:1-Phosphatidylinositol 4-Kinase; D000595:Amino Acid Sequence; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism* / Q000494:pharmacology*; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016762:Genes, fos; D006023:Glycoproteins / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D048057:Mitogen-Activated Protein Kinase 10; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D020890:Neuregulin-1; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains
D002352:Carrier Proteins; D006023:Glycoproteins; D020890:Neuregulin-1; D011518:Proto-Oncogene Proteins; C087230:heregulin beta1; D014443:Tyrosine; D048057:Mitogen-Activated Protein Kinase 10; D017853:Phosphotransferases (Alcohol Group Acceptor); D019870:1-Phosphatidylinositol 4-Kinase; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases