Activation of anaplastic lymphoma kinase is responsible for hyperphosphorylation of ShcC in neuroblastoma cell lines

• Published in: Oncogene Vol. 21; no. 38; pp. 5823 - 5834
• Main Authors: MIYAKE, Izumi, HAKOMORI, Yuko, SHINOHARA, Azusa, GAMOU, Toshie, SAITO, Masaki, IWAMATSU, Akihiro, SAKAI, Ryuichi
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 29.08.2002; Nature Publishing Group
• Subjects: Adult; ALK protein; Animals; Biological and medical sciences; Cancer; Cell physiology; Chromatography, Affinity - methods; Enzyme Activation; Fundamental and applied biological sciences. Psychology; Gene amplification; Humans; Infant; Kinases; Lymphoma; Male; Medical prognosis; Mice; Mice, Nude; Molecular and cellular biology; Myc protein; N-Myc protein; Nerve Tissue Proteins - metabolism; Nervous System Neoplasms - metabolism; Neuroblastoma; Neuroblastoma - genetics; Neuroblastoma - metabolism; Neuroblastoma cells; Neuropeptides; Phosphoproteins; Phosphoproteins - isolation & purification; Phosphoproteins - metabolism; Phosphorylation; Phosphotyrosine; Protein expression; Protein-tyrosine kinase; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Proteins; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Shc Signaling Adaptor Proteins; Signal Transduction; Src Homology 2 Domain-Containing, Transforming Protein 3; Tumor Cells, Cultured; Tumors; Tyrosine; Tyrosine - metabolism; Japan; Signal transduction; Regulation(control); Cell line; Enzyme; Kinase; Lymphoproliferative syndrome; Transferases; Malignant hemopathy; Neuroblastoma; Lymphoma
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1205735

Shc family of docking proteins, ShcA, ShcB and ShcC, play roles in cellular signal transduction by binding to phosphotyrosine residues of various activated receptor tyrosine kinases. Both ShcB and ShcC proteins are selectively expressed in the neural system of adult mouse tissues. In most of neuroblastoma cells, obvious tyrosine phosphorylation of ShcC was observed, whereas expression of ShcB was considerably low. Phosphoproteins associated with hyperphosphorylated ShcC were purified from neuroblastoma cell lines, and identified by mass-spectrometry. Anaplastic lymphoma kinase (ALK), which turned out to be one of these phosphoproteins, was constitutively activated and associated with the PTB domain of ShcC in three neuroblastoma cells. In vitro kinase assay revealed that ShcC is a potent substrate of the activated ALK kinase. The ALK gene locus was significantly amplified in both of these cell lines, suggesting that gene amplification leads to constitutive activation of the ALK kinase, which results in hyperphosphorylation of ShcC. Constitutive activation of ALK appeared to interfere with signals from other receptor tyrosine kinases. ALK-ShcC signal activation, possibly caused by co-amplification with the N-myc gene, might give additional effects on malignant tumor progression of neuroblastoma.