Identification of SNT/FRS2 docking site on RET receptor tyrosine kinase and its role for signal transduction.
SNT/FRS2 is a lipid anchored docking protein that contains an amino-terminal myristylation signal, followed by a phosphotyrosine-binding (PTB) domain and a carboxy-terminal region with multiple tyrosine residues. Here we show that the SNT/FRS2 PTB domain binds to RET receptor tyrosine kinase activated by glial cell line-derived neurotrophic factor (GDNF) or ... multiple endocrine neoplasia (MEN) 2 mutations. Analyses by site directed-mutagenesis revealed that it binds to tyrosine 1062 in RET that is also known to be a binding site for the SHC adaptor protein. Whereas SHC bound to RET was associated with GRB2 and GAB1 proteins, SNT/FRS2 was associated with GRB2 only, suggesting that SNT/FRS2 is involved mainly in the activation of the RAS/mitogen activated protein kinase (MAPK) pathway but not the phosphatidylinositol 3-kinase (PI3-K)/AKT pathway. In addition, phosphorylated SNT/FRS2 appeared to directly complex with SHP-2 tyrosine phosphatase. These results suggest that tyrosine 1062 in RET provides a site for the interaction of multiple signaling molecules and that the balance of SHC and SNT/FRS2 binding may affect the nature of the intracellular signaling for cell proliferation, differentiation and survival induced by activated RET.
Mesh Terms:
3T3 Cells, Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Animals, Binding Sites, Drosophila Proteins, GRB2 Adaptor Protein, Glial Cell Line-Derived Neurotrophic Factor, Glial Cell Line-Derived Neurotrophic Factor Receptors, Humans, Intracellular Signaling Peptides and Proteins, Kinetics, Membrane Proteins, Mice, Molecular Sequence Data, Multiple Endocrine Neoplasia Type 2a, Mutation, Nerve Growth Factors, Nerve Tissue Proteins, Phosphoproteins, Protein Isoforms, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-ret, Receptor Protein-Tyrosine Kinases, Signal Transduction, Tumor Cells, Cultured, Tyrosine
3T3 Cells, Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Animals, Binding Sites, Drosophila Proteins, GRB2 Adaptor Protein, Glial Cell Line-Derived Neurotrophic Factor, Glial Cell Line-Derived Neurotrophic Factor Receptors, Humans, Intracellular Signaling Peptides and Proteins, Kinetics, Membrane Proteins, Mice, Molecular Sequence Data, Multiple Endocrine Neoplasia Type 2a, Mutation, Nerve Growth Factors, Nerve Tissue Proteins, Phosphoproteins, Protein Isoforms, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-ret, Receptor Protein-Tyrosine Kinases, Signal Transduction, Tumor Cells, Cultured, Tyrosine
Oncogene
Date: Apr. 12, 2001
PubMed ID: 11360177
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