Novel adaptor protein Shf interacts with ALK receptor and negatively regulates its downstream signals in neuroblastoma. Issue 5 (13th March 2013)

• Record Type: Journal Article
• Authors: Takagi, Daisuke; Tatsumi, Yasutoshi; Yokochi, Tomoki; Takatori, Atsushi; Ohira, Miki; Kamijo, Takehiko; Kondo, Satoshi; Fujii, Yoshitaka; Nakagawara, Akira
• Is Part Of: Cancer science. Volume 104:Issue 5(2013:May)
• Page Start: 563
• Page End: 572
• Publication Date: 2013-03-13
• Subjects: Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.12115
• Languages: English
• ISSNs: 1347-9032

Abstract

<abstract abstract-type="main" xml:lang="en" id="cas12115-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Our neuroblastoma cDNA project previously identified <italic>S</italic>rc <italic>h</italic>omology 2 domain containing <italic>F</italic> (<italic>Shf</italic>) as one of the genes expressed at high levels in favorable neuroblastoma. Shf is an adaptor protein containing four putative tyrosine phosphorylation sites and an SH2 domain. In this study, we found that Shf interacted with anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase in neuroblastoma. Real‐time PCR analysis showed that <italic>Shf</italic> mRNA is highly expressed in non‐metastatic neuroblastomas compared to metastatic tumor samples (<italic>P</italic> < 0.030, <italic>n</italic> = 106). Interestingly, patients showing high <italic>ALK</italic> and low <italic>Shf</italic> mRNA expressions showed poor prognosis, whereas low <italic>ALK</italic> and high <italic>Shf</italic> expressions were related to better prognosis (<italic>P</italic> < 0.023, <italic>n</italic> = 38). Overexpression of ALK and siRNA‐mediated knockdown of <italic>Shf</italic> yielded similar results, such as an increase in cellular growth and phosphorylation of ALK, in addition to Erk1/2 and signal transducer and activator of transcription 3 (STAT3) that are downstream signals of the ALK‐initiated phospho‐transduction pathway. Knockdown of <italic>Shf</italic> also increased the cellular mobility and invasive capability of neuroblastoma cells. These results suggest that Shf interacts with ALK and negatively regulates the ALK‐initiated signal transduction pathway in neuroblastoma. We thus propose that Shf 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.</p> </abstract>