Identification and characterization of a new oncogene derived from the regulatory subunit of phosphoinositide 3-kinase

Abstract

6 Corresponding author p85/p110 phosphoinositide 3-kinase (PI3K) is a heterodimer composed of a p85-regulatory and a p110-catalytic subunit, which is involved in a variety of cellular responses including cytoskeletal organization, cell survival and proliferation. We describe here the cloning and characterization of p65-PI3K, a mutant of the regulatory subunit of PI3K, which includes the initial 571 residues of the wild type p85α-protein linked to a region conserved in the eph tyrosine kinase receptor family. We demonstrate that this mutation, obtained from a transformed cell, unlike previously engineered mutations of the regulatory subunit, induces the constitutive activation of PI3K and contributes to cellular transformation. This report links the PI3K enzyme to mammalian tumor development for the first time.

Phosphatidylinositol 3-Kinase Regulates the CD4/CD8 T Cell Differentiation Ratio

“…This complementation may reflect that both isoforms regulate this transition physiologically or that enhanced p65 PI3K -induced PI3K activity artificially compensates for the lack of p110␥. The p65 PI3K expression nonetheless enhances basal 3-polyphosphoinositide levels only moderately and requires stimulation of a tyrosine kinase-coupled receptor to enhance PI3K activity significantly (22,23). Pre-TCR, a receptor coupled to Lck tyrosine kinase (5,35), thus may activate class IA PI3K isoforms physiologically, thereby contributing to pre-TCR-mediated differentiation, as observed in p65 PI3K Tg mice.…”

“…In addition, to examine the role of the p85/p110 PI3K isoforms (class IA) in T cell development, we analyzed the phenotype of mice expressing an activating mutation of the p85 regulatory subunit, p65 PI3K , in T cells. This mutant regulatory subunit associates with the p110 catalytic subunit, moderately increasing basal PI-3,4,5-P 3 levels and significantly enhancing the transient PI3K activation that follows receptor activation (22,23). p65 PI3K potentially acts on all three class IA catalytic subunits, constituting a useful tool for the study of the role of class IA p85/p110 PI3K isoforms in T cell development.…”

Longitudinal inhibition of PI3K/Akt/mTOR signaling by LY294002 and rapamycin induces growth arrest of adult T-cell leukemia cells

“…Loss of expression of this phosphatase results in constitutive activation of Akt signaling [8][9][10][11]. Additional mechanisms which activate PI3K/Akt/mTOR signaling include gain of function mutation of receptor tyrosine kinase (e.g., c-Kit), mutations of an oncogene (e.g., Ras), active mutations in the p110 and p85 subunits of PI3K, and Akt overexpression [12][13][14].…”

A specific function for phosphatidylinositol 3-kinase α (p85α-p110α) in cell survival and for phosphatidylinositol 3-kinase β (p85α-p110β) in de novo DNA synthesis of human colon carcinoma cells

“…Expression of a constitutive active form of bovine p110a is transforming in rodent ®broblasts (Klippel et al, 1998). An oncogenic form of type I PI3K, which involves a mutated form of the regulatory subunit p85a, has also been described in mice (Jimenez et al, 1998). Expression of this allele associates with endogenous p110 and increases its activity in a constitutive manner, leading to cell transformation.…”