SNT-2 interacts with ERK2 and negatively regulates ERK2 signaling in response to EGF stimulation.
The control of cellular responses with fibroblast growth factors and neurotrophins is mediated through membrane-linked docking proteins, SNT (suc1-binding neurotrophic target)-1/FRS2alpha and SNT-2/FRS2beta. ERK1/2 are members of the mitogen-activated protein kinase family that regulate diverse cellular activities in response to various stimuli. Here, we demonstrate that SNT-2 does not become tyrosine phosphorylated significantly in response to EGF but forms a complex with ERK2 via the region of 186-252 amino acid residues, and the complex formation is enhanced upon EGF stimulation. SNT-2 downregulates ERK2 phosphorylation, suppresses and delays ERK2 nuclear accumulation which occurs following EGF stimulation. In contrast, the mutant SNT-2 which carries deletion of 186-252 amino acids and lacks ERK2 binding does not have these effects. These observations suggest that SNT-2 negatively regulates ERK2 signaling activated via EGF stimulation through direct binding to ERK2.
Department of Molecular Cellular Oncology and Microbiology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yujima, Bunkyo-ku, Tokyo 113-8510, Japan.
Lin
L
Huang
Noriko
N
Gotoh
Shengliang
S
Zhang
Masabumi
M
Shibuya
Tadashi
T
Yamamoto
Nobuo
N
Tsuchida
D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids / Q000737:chemistry; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D009154:Mutation; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D020798:Two-Hybrid System Techniques; D014443:Tyrosine / Q000737:chemistry
D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; C106534:FRS2 protein, human; D008565:Membrane Proteins; D010750:Phosphoproteins; D010982:Platelet-Derived Growth Factor; D014443:Tyrosine; D004815:Epidermal Growth Factor; D005982:Glutathione Transferase; D019950:Mitogen-Activated Protein Kinase 1