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Identification of nuclear protein targets for six leukemogenic tyrosine kinases governed by post-translational regulation.

Pierce, Andrew; Williamson, Andrew; Jaworska, Ewa; Griffiths, John R; Taylor, Sam; Walker, Michael; O'Dea, Mark Aspinall; Spooncer, Elaine; Unwin, Richard D; Poolman, Toryn; Ray, David; Whetton, Anthony D

PloS one. 2012;7(6):e38928.

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Abstract

Mutated tyrosine kinases are associated with a number of different haematological malignancies including myeloproliferative disorders, lymphoma and acute myeloid leukaemia. The potential commonalities in the action of six of these leukemogenic proteins on nuclear proteins were investigated using systematic proteomic analysis. The effects on over 3600 nuclear proteins and 1500 phosphopeptide sites were relatively quantified in seven isogenic cell lines. The effects of the kinases were diverse although some commonalities were found. Comparison of the nuclear proteomic data with transcriptome data and cytoplasmic proteomic data indicated that the major changes are due to post-translational mechanisms rather than changes in mRNA or protein distribution. Analysis of the promoter regions of genes whose protein levels changed in response to the kinases showed the most common binding site found was that for NFκB whilst other sites such as those for the glucocorticoid receptor were also found. Glucocorticoid receptor levels and phosphorylation were decreased by all 6 PTKs. Whilst Glucocorticoid receptor action can potentiate NFκB action those proteins where genes have NFκB binding sites were in often regulated post-translationally. However all 6 PTKs showed evidence of NFkB pathway modulation via activation via altered IkB and NFKB levels. Validation of a common change was also undertaken with PMS2, a DNA mismatch repair protein. PMS2 nuclear levels were decreased in response to the expression of all 6 kinases, with no concomitant change in mRNA level or cytosolic protein level. Response to thioguanine, that requires the mismatch repair pathway, was modulated by all 6 oncogenic kinases. In summary common targets for 6 oncogenic PTKs have been found that are regulated by post-translational mechanisms. They represent potential new avenues for therapies but also demonstrate the post-translational regulation is a key target of leukaemogenic kinases.

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Place of publication:
United States
Volume:
7
Issue:
6
Pagination:
e38928
Digital Object Identifier:
10.1371/journal.pone.0038928
Pubmed Identifier:
22745689
Pii Identifier:
PONE-D-12-08327
Access state:
Active

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Record metadata

Manchester eScholar ID:
uk-ac-man-scw:219344
Created by:
Whetton, Anthony
Created:
14th February, 2014, 14:01:17
Last modified by:
Whetton, Anthony
Last modified:
1st February, 2015, 19:13:02

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