Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells
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Adaptor Proteins, Signal Transducing*
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Amino Acid Sequence
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Animals
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Binding Sites
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Drosophila Proteins*
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GRB2 Adaptor Protein
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Glial Cell Line-Derived Neurotrophic Factor
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Glial Cell Line-Derived Neurotrophic Factor Receptors
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Humans
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Intracellular Signaling Peptides and Proteins
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Kinetics
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Membrane Proteins / metabolism
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Membrane Proteins / physiology*
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Mice
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Molecular Sequence Data
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Multiple Endocrine Neoplasia Type 2a / genetics
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Mutation
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Nerve Growth Factors*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / physiology
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Phosphoproteins / metabolism
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Phosphoproteins / physiology*
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Protein Isoforms
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases / metabolism
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Proteins / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-ret
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Receptor Protein-Tyrosine Kinases / metabolism
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Receptor Protein-Tyrosine Kinases / physiology*
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Signal Transduction / physiology*
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Tumor Cells, Cultured
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Tyrosine / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Drosophila Proteins
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FRS2 protein, human
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GDNF protein, human
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GRB2 Adaptor Protein
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GRB2 protein, human
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Gdnf protein, mouse
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Glial Cell Line-Derived Neurotrophic Factor
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Glial Cell Line-Derived Neurotrophic Factor Receptors
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Grb2 protein, mouse
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Nerve Growth Factors
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Nerve Tissue Proteins
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Phosphoproteins
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Protein Isoforms
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Proteins
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Proto-Oncogene Proteins
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Tyrosine
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Proto-Oncogene Proteins c-ret
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Receptor Protein-Tyrosine Kinases
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Ret protein, Drosophila
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Ret protein, mouse
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PTPN11 protein, human
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PTPN6 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases
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Ptpn11 protein, mouse
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Ptpn6 protein, mouse