Abstract
BackgroundPhosphatidylinositol-3-kinases (PI3Ks) are a family of eukaryotic enzymes modifying phosphoinositides in phosphatidylinositols-3-phosphate. Located upstream of the AKT/mTOR signalling pathway, PI3Ks activate secondary messengers of extracellular signals. They are involved in many critical cellular processes such as cell survival, angiogenesis and autophagy. PI3K family is divided into three classes, including 14 human homologs. While class II enzymes are composed of a single catalytic subunit, class I and III also contain regulatory subunits. Here we present an in-depth phylogenetic analysis of all PI3K proteins.ResultsWe confirmed that PI3K catalytic subunits form a monophyletic group, whereas regulatory subunits form three distinct groups. The phylogeny of the catalytic subunits indicates that they underwent two major duplications during their evolutionary history: the most ancient arose in the Last Eukaryotic Common Ancestor (LECA) and led to the emergence of class III and class I/II, while the second – that led to the separation between class I and II – occurred later, in the ancestor of Unikonta (i.e., the clade grouping Amoebozoa, Fungi, and Metazoa). These two major events were followed by many lineage specific duplications in particular in vertebrates, but also in various protist lineages. Major loss events were also detected in Vidiriplantae and Fungi. For the regulatory subunits, we identified homologs of class III in all eukaryotic groups indicating that, for this class, both the catalytic and the regulatory subunits were presents in LECA. In contrast, homologs of the regulatory class I have a more recent origin.ConclusionsThe phylogenetic analysis of the PI3K shed a new light on the evolutionary history of these enzymes. We found that LECA already contained a PI3K class III composed of a catalytic and a regulatory subunit. Absence of class II regulatory subunits and the recent origin of class I regulatory subunits is puzzling given that the class I/II catalytic subunit was present in LECA and has been conserved in most present-day eukaryotic lineages. We also found surprising major loss and duplication events in various eukaryotic lineages. Given the functional specificity of PI3K proteins, this suggests dynamic adaptation during the diversification of eukaryotes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12862-015-0498-7) contains supplementary material, which is available to authorized users.
Highlights
Phosphatidylinositol-3-kinases (PI3Ks) are a family of eukaryotic enzymes modifying phosphoinositides in phosphatidylinositols-3-phosphate
First we found that catalytic and regulatory class III proteins were already present in the Last Eukaryotic Common Ancestor (LECA)
Phylogeny of PI3K We applied a two-step strategy to decipher the evolutionary history of PI3Ks catalytic and regulatory subunits
Summary
Phosphatidylinositol-3-kinases (PI3Ks) are a family of eukaryotic enzymes modifying phosphoinositides in phosphatidylinositols-3-phosphate. Located upstream of the AKT/mTOR signalling pathway, PI3Ks activate secondary messengers of extracellular signals They are involved in many critical cellular processes such as cell survival, angiogenesis and autophagy. Phosphatidylinositol-3-kinases (PI3Ks) are enzymes that phosphorylate the 3’-position of inositol ring to generate different phosphoinositides (PIs). They are involved in many critical cellular processes such as cell survival, angiogenesis [1] or autophagy[2] and are deregulated in Philippon et al BMC Evolutionary Biology (2015) 15:226. Class IA catalytic subunits (p110α, p110β and p110δ) can bind the p85α (and its two alternatives forms p55α and p50α), p85β and p55γ regulatory subunits. P110γ , the only catalytic human protein of class IB, can bind two regulatory subunits named p87 and p101. The major activators of class IA are RTKs (Receptor Tyrosine Kinases) [19,20,21] and IGF1 (Insulin-like Growth Factor 1) [21], whereas class IB is principally activated by GPCRs (G Protein-Coupled Receptors) [19, 21]
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