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Eight-channel iTRAQ Enables Comparison of the Activity of Six Leukemogenic Tyrosine Kinases
Pierce, A, Unwin, RD, Evans, C, Griffiths, S, Carney, L, Zhang, L, Jaworska, E, Lee, C, Blinco, D, Okoniewski, M, Miller, C, Bitton, D, Spooncer, E, Whetton, A.
Molecular & Cellular Proteomics. 2008;7(5):853-863.
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Abstract
There are a number of leukemogenic protein tyrosine kinases (PTKs) associated with leukaemic transformation. Whilst each is linked with a specific disease their functional activity poses the question whether they have a degree of commonality in their effects upon target cells. Exon array analysis of the effects of 6 leukemogenic PTKs (BCR/ABL, TEL/PDGFRbeta, FIP1/PDGFRalpha, D816V KIT, NPM/ALK and FLT3ITD) revealed few common effects on the transcriptome. It is apparent, however, that proteome changes are not directly governed by transcriptome changes. Therefore, we have assessed and used a new generation of iTRAQ tagging, enabling eight-channel relative quantification discovery proteomics, to analyse the effects of these 6 leukemogenic PTKs. Again these were found to have disparate effects on the proteome with few common targets. BCR/ABL had the greatest effect on the proteome and had more effects in common with FIP1/PDGFRalpha. The proteomic effects of the 4 type III receptor kinases were relatively remotely related. The only protein commonly affected was eosinophil-associated ribonuclease 7. Five out of 6 PTKs affected the motility-related proteins CapG and vimentin, though this did not correspond to changes in motility. However, correlation of the proteomics data with that from the exon microarray not only showed poor levels of correlation between transcript and protein levels, but also revealed alternative patterns of regulation of the CapG protein by different oncogenes, illustrating the utility of such a combined approach.