Activation of anaplastic lymphoma kinase is responsible for hyperphosphorylation of ShcC in neuroblastoma cell lines.
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.
Cancer Signal Transduction Project, National Cancer Center Research Institute, 5-1-1 Tsukuji, Chuo-ku, Tokyo 104-0045, Japan.
Izumi
I
Miyake
Yuko
Y
Hakomori
Azusa
A
Shinohara
Toshie
T
Gamou
Masaki
M
Saito
Akihiro
A
Iwamatsu
Ryuichi
R
Sakai
D000328:Adult; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002846:Chromatography, Affinity / Q000379:methods; D004789:Enzyme Activation; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009423:Nervous System Neoplasms / Q000378:metabolism; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism*; D009479:Neuropeptides; D010750:Phosphoproteins / Q000302:isolation & purification / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071427:Src Homology 2 Domain-Containing, Transforming Protein 3; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D010750:Phosphoproteins; C122029:SHC3 protein, human; D055765:Shc Signaling Adaptor Proteins; C485682:Shc3 protein, mouse; D000071427:Src Homology 2 Domain-Containing, Transforming Protein 3; D014443:Tyrosine; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases