胶质细胞源性神经生长因子
GDNF配体家族
神经突
原癌基因蛋白质c-ret
信号转导衔接蛋白
生物
细胞生物学
信号转导
酪氨酸激酶
癌症研究
受体酪氨酸激酶
分子生物学
内科学
内分泌学
神经营养因子
受体
医学
生物化学
体外
作者
Ai Kurotsuchi,Yoshiki Murakumo,Mayumi Jijiwa,Kei Kurokawa,Yasutomo Itoh,Yoshinori Kodama,Takuya Kato,Atsushi Enomoto,Naoya Asai,Hiroko Terasaki,Masahide Takahashi
出处
期刊:Cancer Science
[Wiley]
日期:2010-04-19
卷期号:101 (5): 1147-1155
被引量:15
标识
DOI:10.1111/j.1349-7006.2010.01520.x
摘要
Point mutations and structural alterations of the RET tyrosine kinase gene cause multiple endocrine neoplasia type 2 (MEN 2) and papillary thyroid carcinoma, respectively. RET activation by glial cell line‐derived neurotrophic factor (GDNF) is essential for the development of the enteric nervous system and the kidney. The signal through RET tyrosine kinase requires several adaptor proteins including the DOK (downstream of kinase) family of proteins. Of the seven members of the DOK protein family, DOK‐1, ‐4, ‐5, and ‐6 have been reported to play roles in the GDNF–RET signaling pathway. Although DOK‐6 has been shown to bind to RET and promote GDNF‐induced neurite outgrowth in mouse Neuro2A cells, DOK‐6 function in human cells remains unclear. In the present study, we investigated the role of DOK‐6 in GDNF–RET signaling in human cells including neuroblastoma cells. DOK‐6 was constitutively localized to the plasma membrane via its pleckstrin homology (PH) domain, and was phosphorylated following RET activation via a MEN2A mutation or GDNF stimulation. However, DOK‐6 could not significantly affect downstream signaling and neurite outgrowth in human neuroblastoma cells. The binding affinity of the DOK‐6 phosphotyrosine‐binding (PTB) domain to RET was much lower than that of the DOK‐1, DOK‐4, and SHC PTB domains to RET. These findings indicate that DOK‐6 is involved in RET signaling with less influence when compared with DOK‐1, DOK‐4, and SHC. ( Cancer Sci 2010; 101: 1047–1155)
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