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: 1147-1155 T he RET proto-oncogene encodes receptor tyrosine kinase (RTK) expressed in a wide variety of neurons and the developing kidney.(1-4) RET tyrosine kinase is activated by stimulation of the glial cell line-derived neurotrophic factor (GDNF) family of ligands including GDNF, neurturin, artemin, and persephin in the presence of glycosylphosphatidylinositolanchored co-receptors called GDNF family receptor alpha 1-4.(5) Consistent with the expression pattern of RET during embryogenesis, signaling through RET plays crucial roles in the development of the enteric nervous system and the kidney. RET mutations are responsible for the development of several human diseases including multiple endocrine neoplasia (MEN) type 2A and 2B, familial medullary thyroid carcinoma (FMTC), papillary thyroid carcinoma (PTC), and Hirschsprung's disease.(8-10) RET mutations in MEN2A, MEN2B, FMTC, and PTC are gain-of-function mutations, whereas Hirschsprung mutations are loss-of-function mutations.(11-17) Specific tyrosine residues in the RET intracellular domain are phosphorylated by GDNF stimulation or RET mutations, which results in the activation of several signaling pathways, including the RAS ⁄ ERK (extracellular signal-regulated kinase), PI3K (phosphatidylinositol-3 kinase) ⁄ AKT, p38MAPK (mitogen activated protein kinase), phospholipase Cc, and RAC ⁄ JNK (c-Jun N-terminal kinase) pathways.(8-10) These signaling pathways are important for cell proliferation, survival, migration, and invasion.Signal transduction through RET requires various adaptor proteins such as SHC,...
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