%0 Journal Article
%T Phylogenomics of phosphoinositide lipid kinases: perspectives on the evolution of second messenger signaling and drug discovery
%A James R Brown
%A Kurt R Auger
%J BMC Evolutionary Biology
%D 2011
%I BioMed Central
%R 10.1186/1471-2148-11-4
%X Our analyses reveal four core eukaryotic PIKs which are type III PIK4A and PIK4B, and at least one homolog each from PI3K (possibly PIK3C3 as the ancestor) and PIP5K families. We also applied evolutionary analyses to PIK disease ontology and drug discovery. Mutated PIK3CA are known to be oncogenic and several inhibitors are in anti-cancer clinical trials. We found conservation of activating mutations of PIK3CA in paralogous isoforms suggesting specific functional constraints on these residues. By mapping published compound inhibition data (IC50s) onto a phylogeny of PI3Ks, type II PI4Ks and distantly related, MTOR, ATM, ATR and PRKDC kinases, we also show that compound polypharmacology corresponds to kinase evolutionary relationships. Finally, we extended the rationale for drugs targeting PIKs of malarial Plasmodium falciparum, and the parasites, Leishmania sp. and Trypanosoma sp. by identifying those PIKs highly divergent from human homologs.Our phylogenomic analysis of PIKs provides new insights into the evolution of second messenger signaling. We postulate two waves of PIK diversification, the first in metazoans with a subsequent expansion in cold-blooded vertebrates that was post-emergence of Deutrostomia\Chordata but prior to the appearance of mammals. Reconstruction of the evolutionary relationships among these lipid kinases also adds to our understanding of their roles in various diseases and assists in their development as potential drug targets.Eukaryotic signal transduction is dependent upon various secondary messenger signaling molecules in particular the cellular phospholipids called phosatidylinositols (PtdIns). These phospholipids activate a spectrum of intracellular pathways that regulate multiple core functions including cellular metabolism, cell cycle and survival, protein synthesis, cell polarity and motility, and vesicle trafficking. Phosphorylations around the inositol ring generates various phosphoinositides (PIs) which allow for functional spec
%U http://www.biomedcentral.com/1471-2148/11/4