Systems level expression correlation of Ras GTPase regulators

E. Besray Unal, Christina Kiel, Hannah Benisty, Andrew Campbell, Karen Pickering, Nils Blüthgen, Owen J. Sansom, Luis Serrano

Proteins of the ubiquitously expressed core proteome are quantitatively correlated across multiple eukaryotic species. In addition, it was found that many protein paralogues exhibit expression anticorrelation, suggesting that the total level of protein with a given functionality must be kept constant. We performed Spearman's rank correlation analyses of gene expression levels for the RAS GTPase subfamily and their regulatory GEF and GAP proteins across tissues and across individuals for each tissue. A large set of published data for normal tissues from a wide range of species, human cancer tissues and human cell lines was analysed. We show that although the multidomain regulatory proteins of Ras GTPases exhibit considerable tissue and individual gene expression variability, their total amounts are balanced in normal tissues. In a given tissue, the sum of activating (GEFs) and deactivating (GAPs) domains of Ras GTPases can vary considerably, but each person has balanced GEF and GAP levels. This balance is impaired in cell lines and in cancer tissues for some individuals. Our results are relevant for critical considerations of knock out experiments, where functionally related homologs may compensate for the down regulation of a protein.