Dysregulation of the PI3K/PTEN pathway is a frequent event in cancer, and PIK3CA and PTEN are the most commonly mutated genes after TP53. PIK3R1 is the predominant regulatory isoform of PI3K. PIK3R2 is an ubiquitous isoform that has been so far overlooked, but data from The Cancer Genome Atlas shows that increased expression of PIK3R2 is also frequent in cancer. In contrast to PIK3R1, which is a tumor-suppressor gene, PIK3R2 is an oncogene. We review here the opposing roles of PIK3R1 and PIK3R2 in cancer, the regulatory mechanisms that control PIK3R2 expression, and emerging therapeutic approaches targeting PIK3R2.Antagonistic Roles of PIK3R1/p85a and PIK3R2/p85b in Cancer PI3K enzymes are a conserved family of lipid kinases that phosphorylate the inositol 3 0 -OH groups of membrane phosphoinositides (PI). Class I PI3K enzymes convert PI(4,5)bisphosphate (PIP 2 ) into PI(3,4,5)trisphosphate (PIP 3 ), a second messenger. Class IA PI3K is composed of a heterodimer between a p110 catalytic subunit and a p85 regulatory subunit. Of the four PI3K catalytic subunit isoforms (PI3Ka, PI3Kb, PI3Kg, and PI3Kd), only PI3Ka and PI3Kb are expressed ubiquitously and are frequently altered in cancer [1,2]. Three different genes encode p85-type subunits: PIK3R1, PIK3R2, and PIK3R3, and these code for p85a (and alternative splice forms), p85b and p55g, respectively. PIK3R1 and PIK3R2 are broadly expressed, whereas PIK3R3 is selectively expressed in adult testis and the brain [1][2][3][4].PIK3R1/p85a is the most abundant isoform in normal tissues [5][6][7] but its expression is reduced in cancer. Conversely, PIK3R2/p85b expression levels are elevated in advanced cancer stages ([7,8]; data from The Cancer Genome Atlas, TCGA i ). Physiological activation of PI3K is induced by binding of p85 to activated receptor tyrosine kinases (RTKs) and is further enhanced by GTPases of the Ras family. Rho GTPases and G protein-coupled receptors also activate PI3Kb [1,2,9,10]. Classically, p85a and p85b have been considered to be similar proteins that associate with RTKs and with catalytic subunits that induce PI3K activation. This may represent an oversimplification because a growing number of studies support different and opposite functions of p85a and p85b in cancer [7,8]. In this review article we summarize available data on the function p85a and p85b, and attempt to make sense of the observation that PIK3R1 and PIK3R2 have opposing functions in tumor progression. This is important because distinct consequences of interfering with PIK3R1/p85a or PIK3R2/p85b should be considered in the design and development on new therapies. Domains, Localization, and Activities of PIK3R1 and PIK3R2p85 subunits control PI3K activation by modulating the stability, conformation, and localization of the catalytic subunit [4,11,12]. The primary structure of p85 includes an N-terminal region composed of an Src homology 3 (SH3) domain followed by a RhoGap HighlightsThe Cancer Genome Atlas Project revealed that specific changes in gene expression are hallmarks of som...

Oncogenic mutations in the PI3K/AKT pathway are present in nearly half of human tumors. Nonetheless, inhibitory compounds of the pathway often induce pathway rebound and tumor resistance. We find that lung squamous cell carcinoma (SQCC), which accounts for ~20% of lung cancer, exhibits increased expression of the PI3K subunit PIK3R2, which is at low expression levels in normal tissues. We tested a new approach to interfere with PI3K/AKT pathway activation in lung SQCC. We generated tumor xenografts of SQCC cell lines and examined the consequences of targeting PIK3R2 expression. In tumors with high PIK3R2 expression, and independently of PIK3CA, KRAS, or PTEN mutations, PIK3R2 depletion induced lung SQCC xenograft regression without triggering PI3K/AKT pathway rebound. These results validate the use PIK3R2 interfering tools for the treatment of lung squamous cell carcinoma.

3-poly-phosphoinositides (PIP3) regulate cell survival, division, and migration. Both PI3-kinase (phosphoinositide-3-kinase) and PTEN (phosphatase and tensin-homolog in chromosome 10) control PIP3 levels, but the mechanisms connecting PI3-kinase and PTEN are unknown. Using non-transformed cells, the activation kinetics of PTEN and of the PIP3-effector AKT were examined after the addition of growth factors. Both epidermal growth factor and serum induced the early activation of AKT and the simultaneous inactivation of PTEN (at ~5 min). This PIP3/AKT peak was followed by a general reduction in AKT activity coincident with the recovery of PTEN phosphatase activity (at ~10–15 min). Subsequent AKT peaks and troughs followed. The fluctuation in AKT activity was linked to that of PTEN; PTEN reconstitution in PTEN-null cells restored AKT fluctuations, while PTEN depletion in control cells abrogated them. The analysis of PTEN activity fluctuations after the addition of growth factors showed its inactivation at ~5 min to be simultaneous with its transient ubiquitination, which was regulated by the ubiquitin E3 ligase cCBL (casitas B-lineage lymphoma proto-oncogene). Protein-protein interaction analysis revealed cCBL to be brought into the proximity of PTEN in a PI3-kinase-dependent manner. These results reveal a mechanism for PI3-kinase/PTEN crosstalk and suggest that cCBL could be new target in strategies designed to modulate PTEN activity in cancer.