Analysis of DOK-6 function in downstream signaling of RET in human neuroblastoma cells

Ai Kurotsuchi, Yoshiki Murakumo, Mayumi Jijiwa, Kei Kurokawa, Yasutomo Itoh, Yoshinori Kodama, Takuya Kato, Atsushi Enomoto, Naoya Asai, Hiroko Terasaki, Masahide Takahashi

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9 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1147-1155
Number of pages9
JournalCancer science
Volume101
Issue number5
DOIs
Publication statusPublished - 01-05-2010
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Kurotsuchi, A., Murakumo, Y., Jijiwa, M., Kurokawa, K., Itoh, Y., Kodama, Y., Kato, T., Enomoto, A., Asai, N., Terasaki, H., & Takahashi, M. (2010). Analysis of DOK-6 function in downstream signaling of RET in human neuroblastoma cells. Cancer science, 101(5), 1147-1155. https://doi.org/10.1111/j.1349-7006.2010.01520.x