Serine phosphorylation of NPM-ALK, which is dependent on the auto-activation of the kinase activation loop, contributes to its oncogenic potential
| Autor: | Raymond Lai, Jingdong Zhang, Liang Li, Todd P. W. McMullen, Robert J. Ingham, Peng Wang, Leah C. Young, Fang Wu |
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| Rok vydání: | 2010 |
| Předmět: |
Serine/threonine-specific protein kinase
Cancer Research integumentary system MAP kinase kinase kinase General Medicine Protein Serine-Threonine Kinases Protein-Tyrosine Kinases Biology Molecular biology MAP2K7 Enzyme Activation Cell Line Tumor Neoplasms hemic and lymphatic diseases Serine Humans Tyrosine Phosphorylation Neoplasm Invasiveness Protein phosphorylation c-Raf Protein kinase C MAPK14 |
| Zdroj: | Carcinogenesis. 32:146-153 |
| ISSN: | 1460-2180 0143-3334 |
| Popis: | It is well established that the tumorigenic potential of nucleophosmin (NPM)―anaplastic lymphoma kinase (ALK), an oncogenic tyrosine kinase, is dependent on its tyrosine phosphorylation. Using tandem affinity purification―mass spectrometry, we found evidence of phosphorylation of three serine residues of NPM―ALK (Serine 135 , Serine 164 and Serine 497 ) ectopically expressed in GP293 cells. Using a specific anti-phosphoserine antibody and immunoprecipitation, we confirmed the presence of serine phosphorylation of NPM―ALK in all three NPM―ALK-expressing cell lines examined. Similar to the tyrosine phosphorylation, phosphorylation of these serine residues was dependent on the activation status of the kinase activation loop of ALK. All of these three serine residues are biologically important as mutation of any one of these residues resulted in a significant reduction in the tumorigenicity of NPM―ALK (assessed by cell viability and clonogenic assay), which correlated with a substantial reduction in the phosphorylation of extracellular signal-regulated kinase 1/2, c-jun N-terminal kinase and signal transducer and activator of transcription 6. Serine phosphorylation of NPM―ALK appears to be regulated by multiple serine kinases since it was markedly reduced by pharmacologic inhibitors for glycogen synthase kinase-3, casein kinase I or mitogen-activated protein kinases. In summary, our study is the first to identify serine phosphorylation of NPM―ALK and to provide evidence that it enhances the tumorigenic potential of this oncogenic protein. |
| Databáze: | OpenAIRE |
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