Novel adaptor protein <scp>S</scp>hf interacts with <scp>ALK</scp> receptor and negatively regulates its downstream signals in neuroblastoma

<jats:p>Our neuroblastoma c<jats:styled-content style="fixed-case">DNA</jats:styled-content> project previously identified <jats:italic><jats:styled-content style="fixed-case">S</jats:styled-content></jats:italic>rc <jats:italic>h</jats:italic>omology 2 domain containing <jats:italic><jats:styled-content style="fixed-case">F</jats:styled-content></jats:italic> (<jats:italic><jats:styled-content style="fixed-case">S</jats:styled-content>hf</jats:italic>) as one of the genes expressed at high levels in favorable neuroblastoma. <jats:styled-content style="fixed-case">S</jats:styled-content>hf is an adaptor protein containing four putative tyrosine phosphorylation sites and an <jats:styled-content style="fixed-case">SH</jats:styled-content>2 domain. In this study, we found that <jats:styled-content style="fixed-case">S</jats:styled-content>hf interacted with anaplastic lymphoma kinase (<jats:styled-content style="fixed-case">ALK</jats:styled-content>), an oncogenic receptor tyrosine kinase in neuroblastoma. Real‐time <jats:styled-content style="fixed-case">PCR</jats:styled-content> analysis showed that <jats:italic><jats:styled-content style="fixed-case">S</jats:styled-content>hf</jats:italic> m<jats:styled-content style="fixed-case">RNA</jats:styled-content> is highly expressed in non‐metastatic neuroblastomas compared to metastatic tumor samples (<jats:italic>P</jats:italic> < 0.030, <jats:italic>n</jats:italic> = 106). Interestingly, patients showing high <jats:italic><jats:styled-content style="fixed-case">ALK</jats:styled-content></jats:italic> and low <jats:italic><jats:styled-content style="fixed-case">S</jats:styled-content>hf</jats:italic> m<jats:styled-content style="fixed-case">RNA</jats:styled-content> expressions showed poor prognosis, whereas low <jats:italic><jats:styled-content style="fixed-case">ALK</jats:styled-content></jats:italic> and high <jats:italic><jats:styled-content style="fixed-case">S</jats:styled-content>hf</jats:italic> expressions were related to better prognosis (<jats:italic>P</jats:italic> < 0.023, <jats:italic>n</jats:italic> = 38). Overexpression of <jats:styled-content style="fixed-case">ALK</jats:styled-content> and si<jats:styled-content style="fixed-case">RNA</jats:styled-content>‐mediated knockdown of <jats:italic><jats:styled-content style="fixed-case">S</jats:styled-content>hf</jats:italic> yielded similar results, such as an increase in cellular growth and phosphorylation of <jats:styled-content style="fixed-case">ALK</jats:styled-content>, in addition to <jats:styled-content style="fixed-case">E</jats:styled-content>rk1/2 and signal transducer and activator of transcription 3 (STAT3) that are downstream signals of the <jats:styled-content style="fixed-case">ALK</jats:styled-content>‐initiated phospho‐transduction pathway. Knockdown of <jats:italic><jats:styled-content style="fixed-case">S</jats:styled-content>hf</jats:italic> also increased the cellular mobility and invasive capability of neuroblastoma cells. These results suggest that <jats:styled-content style="fixed-case">S</jats:styled-content>hf interacts with <jats:styled-content style="fixed-case">ALK</jats:styled-content> and negatively regulates the <jats:styled-content style="fixed-case">ALK</jats:styled-content>‐initiated signal transduction pathway in neuroblastoma. We thus propose that <jats:styled-content style="fixed-case">S</jats:styled-content>hf inhibits phospho‐transduction signals mediated by <jats:styled-content style="fixed-case">ALK</jats:styled-content>, which is one of the major key players on neuroblastoma development, resulting in better prognosis of the tumor.</jats:p>