An incomplete program of cellular tyrosine phosphorylations induced by kinase-defective epidermal growth factor receptors.
Although signaling by the epidermal growth factor (EGF) receptor is thought to be dependent on receptor tyrosine kinase activity, it is clear that mitogen-activated protein (MAP) kinase can be activated by receptors lacking kinase activity. Since analysis of the signaling pathways used by kinase-defective receptors could reveal otherwise masked capabilities, ... we examined in detail the tyrosine phosphorylations and enzymes of the MAP kinase pathway induced by kinase-defective EGF receptors. Following EGF stimulation of B82L cells expressing a kinase-defective EGF receptor mutant (K721M), we found that ERK2 and ERK1 MAP kinases, as well as MEK1 and MEK2 were all activated, and SHC became prominently tyrosine-phosphorylated. By contrast, kinase-defective receptors failed to induce detectable phosphorylations of GAP (GTPase-activating protein), p62, JAK1, or p91STAT1, all of which were robustly phosphorylated by wild-type receptors. These data demonstrate that kinase-defective receptors induce several protein tyrosine phosphorylations, but that these represent only a subset of those seen with wild-type receptors. This suggests that kinase-defective receptors activate a heterologous tyrosine kinase with a specificity different from the EGF receptor. We found that kinase-defective receptors induced ErbB2/c-Neu enzymatic activation and ErbB2/c-Neu binding to SHC at a level even greater than that induced by wild-type receptors. Thus, heterodimerization with and activation of endogenous ErbB2/c-Neu is a possible mechanism by which kinase-defective receptors stimulate the MAP kinase pathway.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Calcium-Calmodulin-Dependent Protein Kinases, Cell Line, DNA-Binding Proteins, Enzyme Activation, GRB2 Adaptor Protein, GTPase-Activating Proteins, Humans, Janus Kinase 2, MAP Kinase Kinase 1, MAP Kinase Kinase 2, Mice, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinase Kinases, Mitogen-Activated Protein Kinases, Phosphorylation, Phosphotyrosine, Protein Processing, Post-Translational, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, Receptor Protein-Tyrosine Kinases, Receptor, Epidermal Growth Factor, Receptor, erbB-2, Recombinant Fusion Proteins, STAT1 Transcription Factor, Signal Transduction, Trans-Activators, Tyrosine
Adaptor Proteins, Signal Transducing, Animals, Calcium-Calmodulin-Dependent Protein Kinases, Cell Line, DNA-Binding Proteins, Enzyme Activation, GRB2 Adaptor Protein, GTPase-Activating Proteins, Humans, Janus Kinase 2, MAP Kinase Kinase 1, MAP Kinase Kinase 2, Mice, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinase Kinases, Mitogen-Activated Protein Kinases, Phosphorylation, Phosphotyrosine, Protein Processing, Post-Translational, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, Receptor Protein-Tyrosine Kinases, Receptor, Epidermal Growth Factor, Receptor, erbB-2, Recombinant Fusion Proteins, STAT1 Transcription Factor, Signal Transduction, Trans-Activators, Tyrosine
J. Biol. Chem.
Date: May. 19, 1995
PubMed ID: 7538132
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