The class IA subgroup of PI3Ks comprises heterodimeric enzymes made up of an SH2-domain-containing regulatory subunit in complex with a p110 catalytic subunit (16). PTEN inactivation, because of deletions or mutations in the PTEN gene, occurs in a large proportion of cancers and results in an accumulation of PI3K lipid products, leading to an up-regulation of the many PI3K-regulated cellular activities (reviewed in Refs. The realization that the tumor suppressor protein PTEN, initially thought to be a tyrosine phosphatase, is a phosphatase for 3-phosphoinositides, has provided one of the strongest indications for a role of PI3K in cancer. 9, 10, 11, 12), where it contributes to increased cell growth and survival. Overexpression of Akt/protein kinase B, a broad-spectrum protein kinase of which the activity is controlled by 3-phosphoinositides, has been documented in gastric, ovarian, breast, and prostate tumors (reviewed in Refs. In addition to deregulation of signaling pathways upstream of PI3K, downstream targets of these enzymes are also often altered in cancer. Tyrosine kinases and Ras, which are frequently overexpressed or mutationally activated in cancer (5, 6), use PI3Ks as essential intracellular signal relay molecules (7, 8). The potential clinical implications of p110δ expression in non-WBC-derived tumors are discussed.

These results show a nonredundant function of PI3K isoforms downstream of the epidermal growth factor receptor and indicate that the presence of p110δ may confer breast cancer cells with selective migratory capacities. In contrast, p110β was required for the direction but not the speed of migration, whereas p110α did not impact on either of these parameters. Isoform-specific neutralization of PI3K isoforms in breast cancer cell lines (by PI3K antibody microinjection or a p110δ-selective pharmacological inhibitor) demonstrated that p110δ is the most important class IA PI3K in the regulation of epidermal growth factor-driven motility in vitro, controlling the directionality and, to a lesser extent, the speed of migration. Originally found in WBCs, p110δ was also detected in some nonhematopoietic cell types especially those of breast or melanocytic origin, both in the untransformed and transformed state. We screened a large panel of tissues and cell lines for expression of class IA PI3Ks, and document a ubiquitous expression of the p110α and p110β isoforms but a variable and more restricted tissue distribution of the p110δ isoform. Despite a clear implication of PI3K in cancer, little is known about the distribution of the different PI3K isoforms in malignant cells.

Class IA phosphoinositide 3′-kinases (PI3Ks) regulate many cellular processes downstream of tyrosine kinases and Ras.

Bain by Sawyer Bennett