Novel adaptor protein Shf interacts with ALK receptor and negatively regulates its downstream signals in neuroblastoma.
Our neuroblastoma cDNA project previously identified Src homology 2 domain containing F (Shf) 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 Shf mRNA is highly expressed in non-metastatic neuroblastomas compared to metastatic tumor samples (P < 0.030, n = 106). Interestingly, patients showing high ALK and low Shf mRNA expressions showed poor prognosis, whereas low ALK and high Shf expressions were related to better prognosis (P < 0.023, n = 38). Overexpression of ALK and siRNA-mediated knockdown of Shf 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 Shf 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.
Division of Biochemistry and Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chiba, Japan.
Daisuke
D
Takagi
Yasutoshi
Y
Tatsumi
Tomoki
T
Yokochi
Atsushi
A
Takatori
Miki
M
Ohira
Takehiko
T
Kamijo
Satoshi
S
Kondo
Yoshitaka
Y
Fujii
Akira
A
Nakagawara
D000077548:Anaplastic Lymphoma Kinase; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D009361:Neoplasm Invasiveness; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011379:Prognosis; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D047908:Intracellular Signaling Peptides and Proteins; C417258:SHF protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases