TY - JOUR
T1 - Identification of SNT/FRS2 docking site on RET receptor tyrosine kinase and its role for signal transduction
AU - Kurokawa, Kei
AU - Iwashita, Toshihide
AU - Murakami, Hideki
AU - Hayashi, Hironori
AU - Kawai, Kumi
AU - Takahashi, Masahide
N1 - Funding Information:
We are grateful to K Imaizumi and M Kozuka for their technical assistance. This work was supported in part by a grant-in-aid for COE (Center of Excellence) research from the Ministry of Education, Science, Sports and Culture of Japan.
PY - 2001/4/12
Y1 - 2001/4/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0035848684&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035848684&partnerID=8YFLogxK
U2 - 10.1038/sj.onc.1204290
DO - 10.1038/sj.onc.1204290
M3 - Article
C2 - 11360177
AN - SCOPUS:0035848684
SN - 0950-9232
VL - 20
SP - 1929
EP - 1938
JO - Oncogene
JF - Oncogene
IS - 16
ER -
