Open AccessNovel adaptor protein S hf interacts with ALK receptor and negatively regulates its downstream signals in neuroblastoma
Author(s) -
Takagi Daisuke,
Tatsumi Yasutoshi,
Yokochi Tomoki,
Takatori Atsushi,
Ohira Miki,
Kamijo Takehiko,
Kondo Satoshi,
Fujii Yoshitaka,
Nakagawara Akira
Publication year - 2013
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12115
Subject(s) - neuroblastoma , anaplastic lymphoma kinase , signal transducing adaptor protein , gene knockdown , cancer research , signal transduction , biology , phosphorylation , tyrosine kinase , microbiology and biotechnology , chemistry , gene , medicine , cell culture , biochemistry , genetics , malignant pleural effusion , pleural effusion
Our neuroblastoma c DNA project previously identified S rc h omology 2 domain containing F ( S hf ) as one of the genes expressed at high levels in favorable neuroblastoma. S hf is an adaptor protein containing four putative tyrosine phosphorylation sites and an SH 2 domain. In this study, we found that S hf interacted with anaplastic lymphoma kinase ( ALK ), an oncogenic receptor tyrosine kinase in neuroblastoma. Real‐time PCR analysis showed that S hf m RNA is highly expressed in non‐metastatic neuroblastomas compared to metastatic tumor samples ( P < 0.030, n = 106). Interestingly, patients showing high ALK and low S hf m RNA expressions showed poor prognosis, whereas low ALK and high S hf expressions were related to better prognosis ( P < 0.023, n = 38). Overexpression of ALK and si RNA ‐mediated knockdown of S hf yielded similar results, such as an increase in cellular growth and phosphorylation of ALK , in addition to E rk1/2 and signal transducer and activator of transcription 3 (STAT3) that are downstream signals of the ALK ‐initiated phospho‐transduction pathway. Knockdown of S hf also increased the cellular mobility and invasive capability of neuroblastoma cells. These results suggest that S hf interacts with ALK and negatively regulates the ALK ‐initiated signal transduction pathway in neuroblastoma. We thus propose that S hf inhibits phospho‐transduction signals mediated by ALK , which is one of the major key players on neuroblastoma development, resulting in better prognosis of the tumor.