Phosphoproteomic analysis of anaplastic lymphoma kinase (ALK) downstream signaling pathways identifies signal transducer and activator of transcription 3 as a functional target of activated ALK in neuroblastoma cells

摘要: Activation of the anaplastic lymphoma kinase (ALK) receptor tyrosine is a key oncogenic mechanism in growing number tumor types. In majority cases, ALK activated by fusion with dimerizing partner protein as result chromosomal translocation events, most studied case nucleophosmin-ALK and echinoderm microtubule-associated protein-like 4-ALK oncoproteins. It now also appreciated that full-length can be point mutations deletions within extracellular domain, such those observed neuroblastoma. Several studies have employed phosphoproteomics approaches to find substrates proteins. this study, we used MS-based phosphotyrosine profiling characterize signaling events associated receptor. A previously identified novel targets were identified. One these, signal transducer activator transcription 3 (STAT3), has been response signaling, but significance from not explored further. We show here robustly activates STAT3 on Tyr705 independent neuroblastoma cell lines. Furthermore, knockdown RNA interference resulted reduction myelocytomatosis neuroblastom (MYCN) levels downstream signaling. These observations, together decreased level MYCN inhibition growth presence inhibitors, suggest activation important for activity