Introduction Phosphatidylinositol 3-kinase (PI3K) was first discovered in the 1980s through the association of its enzymatic activity with viral oncoproteins (1–5). Since that time, a firm connection between PI3K and cancer has been established. Components of the PI3K signaling pathway are among the most frequently altered in human cancer, leading to deregulation of a signaling cascade that is central to normal cell metabolism, proliferation, motility, and survival (6,7). Intact PI3K signaling is also critical for the processes of angiogenesis and anti-tumor immune surveillance that support and combat tumor growth, respectively (8–10). The enzymes involved in this pathway consequently have become attractive targets for cancer therapy. It is therefore crucial that we examine the diverse roles that components of PI3K signaling play if we are to optimally target these enzymes for therapeutic gain. PI3K family members Mammalian PI3K is comprised of three classes of lipid kinases (11). These evolved from a single enzyme that is conserved in all eukaryotes and was first described in yeast as vacuolar protein-sorting defective 34 (Vps34), corresponding to class III PI3K in mammals (6,12). Class III PI3K catalyzes the phosphorylation of phosphatidylinositol (PI) to phophatidylinositol-3-phosphate (PI-3-P; 6,12). Three genes encode isoforms of class II PI3K, which converts PI to PI-3-P and PI-4-P to PI-3,4-P2. Class II PI3Ks have been proposed to be involved in membrane trafficking (6). Class I PI3Ks include both a catalytic and a separate regulatory subunit and catalyze the phosphorylation of PI-4,5-P2 to PI-3,4,5-P3. Class I PI3Ks are further categorized into class IA and class IB enzymes. For class IA PI3K, the genes PIK3R1, PIK3R2, and PIK3R3 encode the regulatory subunits p85α (p85α, p55α, and p50α isoforms), p85β, and p55γ, respectively, which are referred to collectively as p85 (6,7,12). The catalytic isoforms of class IA PI3K, p110α, p110β, and p110δ, are the products of PIK3CA, PIK3CB, and PIK3CD genes, respectively. The p110α and -β isoforms are ubiquitously expressed in mammals, while p110δ expression is predominantly leukocyte-restricted (13). The catalytic subunit p110γ, which is also leukocyte-restricted, and the regulatory subunits p101, p84, or p87PIKAP, constitute Class IB PI3K (6,13). Unlike the catalytic subunits of class IA PI3Ks, p110γ can be active without binding to its regulatory subunit (14). Class IA PI3Ks are the most widely studied in mammalian systems and have been directly linked to cancer.
|Original language||English (US)|
|Title of host publication||Molecular Oncology: Causes of Cancer and Targets for Treatment|
|Publisher||Cambridge University Press|
|Number of pages||13|
|ISBN (Print)||9781139046947, 9780521876629|
|Publication status||Published - Jan 1 2015|
ASJC Scopus subject areas