The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism

Abstract

Phosphatidylinositol 3-kinases (PI3Ks) evolved from a single enzyme that regulates vesicle trafficking in unicellular eukaryotes into a family of enzymes that regulate cellular metabolism and growth in multicellular organisms. In this review, we examine how the PI3K pathway has evolved to control these fundamental processes, and how this pathway is in turn regulated by intricate feedback and crosstalk mechanisms. In light of the recent advances in our understanding of the function of PI3Ks in the pathogenesis of diabetes and cancer, we discuss the exciting therapeutic opportunities for targeting this pathway to treat these diseases.

Phosphoinositide 3-OH kinase p85α and p110β are essential for androgen receptor transactivation and tumor progression in prostate cancers

“…It has been shown that p110b possesses both lipid and protein kinase activities (reviewed in Bader et al, 2005;Engelman et al, 2006). To determine which activity of p110b kinase is involved in AR transactivation, we tested the effect of different p110b mutants, a total kinase-dead mutant (K805R) and a protein kinase only mutant (PKO, lipid kinase deficient) on Figure 1 Phosphoinositide 3-OH kinases (PI3K) p85a and p110b isoforms are essential for androgen-induced androgen receptor (AR) transactivation and cell proliferation.…”

“…Because of their important roles in cell signaling, elevated activities of PI3K pathway due to PTEN inactive mutation has long been considered as a key player in cancer pathogenesis including prostate cancers (Li et al, 1997;Steck et al, 1997;Murillo et al, 2001; reviewed in Engelman et al, 2006). However, no information is currently available about the genetic phenotype and expression pattern of PI3K isoforms in human prostate cancers.…”

“…Phosphoinositide 3-OH kinases (PI3Ks) regulate multiple cellular signal pathways (reviewed in Bader et al, 2005;Engelman et al, 2006). In mammalian cells, there are three classes (I, II and III) of PI3K isoforms, and the class I PI3Ks are further divided into two subtypes (IA p110 a/b/d and IB p110g), of which IA catalytic isoforms are associated with p85 regulatory subfamily, while IB p110g is associated with p101/p84 regulatory subunit.…”

“…In mammalian cells, there are three classes (I, II and III) of PI3K isoforms, and the class I PI3Ks are further divided into two subtypes (IA p110 a/b/d and IB p110g), of which IA catalytic isoforms are associated with p85 regulatory subfamily, while IB p110g is associated with p101/p84 regulatory subunit. The classes I and III but not class II PI3Ks are dual functional kinases, namely lipid kinase and protein kinase (Engelman et al, 2006).…”

Lipid signalling in disease

“…Many known oncogenes, such as mutated ERBB, insulin-like growth factor-1 (IGF1), c-Kit (stem-cell factor receptor), overexpressed chemokine receptors, mutated Ras, BCR-ABL and elevated levels of the proto-oncogene Src, to name but a few, provide constitutive input signals to PI3K 6,30 . The finding that the 3-lipid phosphatase PTEN (phosphatase and tensin homologue deleted on chromosome ten) is frequently mutated in numerous late-stage tumours finally demonstrated that elevated levels of PtdIns(3,4,5)P 3 contribute to oncogenesis 31,32 .…”