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 specificity in cell signaling and cellular membrane remodeling [1
]. Known PIs include PtdIns-3-phosphate (PtdIns-3-P), PtdIns-4-phosphate (PtdIns-4-P), PtdIns-5-phosphate (PtdIns-5-P), PtdIns-3,4-bis
), and PtdIns-3,4,5-tris
). Cellular syntheses of these various PIs are regulated by certain phosphatases and distinct families of lipid-specific kinases called phosphoinositide lipid kinases or PIKs (Figure ).
Figure 1 General pathway for phosphatidylinositide (PI) synthesis. Major PI types with phosphorylation sites labeled (3,4,5 in red) are shown along with the phophorylation and dephosphorylation reactions catalyzed by different phosphoinositide kinase (PIK) types (more ...)
PIKs can be broadly categorized into three major protein types: PtIns 3-kinases (PI3Ks), PtdIns 4-kinases (PI4Ks), and PtdIns-P (PIP) kinases (PIP5Ks and PIP4Ks). PI3Ks has eight known isoforms in mammals which are differentiated into three to four classes by amino acid sequence homology, regulator domains and activation cascades [2
]. Mammals have three Class Ia PI3Ks sharing homologous catalytic polypeptide subunits p110α (PIK3CA), p110β (PIK3CB) and p110δ (PIK3CB). (For clarity, HUGO gene names are in parenthesis and used throughout to refer to their protein products.) Class Ia PI3Ks are heterodimeric protein complexes consisting of the catalytic and regulatory subunits. Class Ia kinases are multi-domain proteins having, in order from the N-terminus, a binding domain for p85 regulatory proteins, a RAS binding domain (RBD) as well as C2, helical (PIK) and catalytic domains. The sole Class Ib PI3K, PIK3CG, has a distinctive p101 regulatory domain as well as homologous, RBD, C2, helical and p110γ catalytic domains. Class II PI3Ks lack either p85 or p101 regulatory domains yet have a p110 catalytic domain and the other domains. In humans, there are three Class II isoforms, PIK3C2α (PIK3C2A), PIK3C2β (PIK3C2B) and PIK3C2γ (PIK3CG). Class III PI3K is represented by a single isoform, PIK3C3 (also known from yeast studies as vacuolar protein-sorting defective 34 or Vps34), and is the least complex PI3K kinases having only C2, helical and catalytic domains.
There are two types of PI4Ks each comprised of two known paralogous isoforms in vertebrates. These are known as Type II, PI4KIIα (PI4K2A) and PI4KIIβ (PI4K2B), and Type III PI4KIIIα (PIK4CA) and PI4KIIIβ (PIK4CB) [4
]. PI4KIIIs share sequence homology with PI3K and together comprise the largest family of phosphoinositide lipid kinases. PI4KII isoforms do not share sequence homology with either PI4KIII or PI3K kinases. The third PIK family is the phosphatidylinositol-4-phosphate 5-kinases (PIP5K) or PIP kinases which lack primary sequence or structural homology to either PI3Ks or any type of PI4Ks [6
]. In mammals, there are three types of PIP kinases or PIPKs. Type I PIP5K occurs as three homologs known as PIP5K1-α (PIP5K1A), PIP5K1-β (PIP5K1B) and PIP5K1-γ (PIP5K1C). Type II phosphatidylinositol-4-phosphate 5-kinase also has three isoforms called PIP4K2-α (PIP4K2A), PIP4K2-β (PIP4K2B) and PIP4K2-γ (PIP4K2C). Both Type I and II PIPKs are homologs to yeast Mss4p. A third PIPK is PIKFYVE has been recently designated as PIP5K3 and includes yeast Fab1p.
PI3K-AKT-mTOR signaling is a central regulatory axis for many key cellular functions including cell cycle, protein synthesis and glucose metabolism. Thus it is not surprising that many diverse disease etiologies have been associated with dysfunctional PIKs including cancer, diabetes and heart disease [7
]. Phosphatidylinositol 3-kinase α peptide (PIK3CA) is highly mutated in colon, brain and gastric cancers where apparent gain-of-function mutations confer increased activity for this lipid kinase [8
]. Several small molecule inhibitors of PIK3CA are in anti-cancer clinical trials [10
]. The paralog PIK3C-γ or PIK3CG is broadly implicated in many diseases due to its role as a downstream signaling component of chemokine receptors that modulate inflammatory pathways [12
]. For example, PIK3CG has been suggested as a heart disease target because of its roles in atherosclerosis related inflammation [13
] and pathogenesis of cardiac hypertrophy and heart failure [14
]. Recent studies also suggest that PI4KIIIs are essential host factors utilized by the hepatitis C virus (HCV) to remodel the intracellular matrix for virus replication and release [15
PtdIns and PIKs are evolutionary well conserved. In fact, inositol precursors are found in bacteria and archaea although phosphorylated derivatives are strictly eukaryotic [17
]. Homologs for all three PIKs groups (PI3K, PI4K, and PIPK) occur across major taxonomic clusters of eukaryotes although the number of isoforms is highly variable with greater complexity among metazoans, especially the vertebrates [18
]. Clearly, the emergence and diversification of PIKs second messenger signaling is a hallmark, and potential facilitator, of eukaryotic evolution. However, questions remain about the antiquity of the various PIK subfamilies and the timing of the radiation and divergence of these lipid kinases relative to the emergence of major taxonomic groups. This knowledge is potentially relevant to biomedical interests in PIKs such as in the interpretation and design of model organism studies, characterization of mutations and polymorphic variants and evaluation of potential polypharmacology [19
]. In addition, kinase inhibitors have been suggested as novel therapeutics against devastating eukaryotic parasitic diseases such as malaria, caused by the Apicomplexa protists, Plasmodium falciparum
and P. vivax
], as well as leishmaniasis and trypanosomiasis that result from infections of Leishmania
sp., and Trypanosoma
sp., respectively, both members of the Kinetoplastids [21
]. Here, we provide a comprehensive genomic survey and phylogenetic analyses of the major types of PIKs. We show the significance of these results in understanding the evolution of second messenger signaling as well as exploiting PIKs as drug targets for various therapeutic areas.