An essential role for Src kinase in ErbB receptor signaling through the MAPK pathway.
ErbB receptor tyrosine kinases are activated by multiple ligands such as epidermal growth factor (EGF) and neuregulins (NRGs), leading to stimulation of intracellular signaling pathways, including the mitogen-activated protein kinase (MAPK) cascade. We show here that Src kinase is essential for rapid EGF- and NRG-induced MAPK activation when the breast carcinoma cell lines T47D and SKBR3 are stimulated with low concentrations of ligand. In the presence of the pharmacological inhibitor CGP77675, which specifically blocks the activity of Src family kinases, ligand-induced MAPK activation was almost completely blocked at 5 min. Although this block was only transient, inactivation of Src suppressed ligand-induced transcription from a MAPK-responsive promoter. At the molecular level, the initial inhibition of MAPK by Src inactivation correlated with impaired ligand-induced Shc phosphorylation. Surprisingly, Src inhibition affected neither association of Shc with ErbB receptors nor phosphorylation of receptor-bound Shc. Thus, ErbB signaling requires the engagement of a novel Src-dependent route to MAPK, to trigger its rapid activation and subsequent efficient stimulation of transcription.
Olayioye
M A
MA
Friedrich Miescher Institute, Basel, CH-4002, Switzerland.
Badache
A
A
Daly
J M
JM
Hynes
N E
NE
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D001943:Breast Neoplasms; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D051380:GRB2 Adaptor Protein; D018815:Genes, erbB; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020880:Neuregulins / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D020880:Neuregulins; D011506:Proteins; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D004815:Epidermal Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases