RAS Does Not Regulate All PI3K Isoforms

Type I phosphoinositide 3-kinases (PI3K) play central roles in cell signaling and are frequently activated in human cancers. There are 4 isoforms of the PI3K catalytic subunit, p110: α and β, which are ubiquitously expressed, and δ and γ, which are specifically expressed in hematopoietic cells. RAS proteins transduce signals from receptor tyrosine kinases (RTK) and directly bind and activate p110α, p110δ, and p110γ. However, despite structural similarities with the other p110 isoforms, Fritsch and colleagues found that p110β is not bound or activated by HRAS, KRAS, or NRAS. Instead, the RHO family GTPases RAC1 and CDC42 bound and activated p110β in vitro through its RAS binding domain (RBD). Mice with a mutated p110β RBD were viable and fertile but had reduced survival and body weight compared with wild-type mice, and p110β RBD-mutant murine embryonic fibroblasts (MEF) showed a slower proliferation rate in association with lower steady-state activation of the PI3K target AKT. Expression of constitutively active RAC1 and CDC42 increased steady-state AKT phosphorylation in wild-type but not p110β RBD-mutant MEFs, suggesting that RAC1 and CDC42 are required for p110β isoform-specific PI3K signaling in vivo. p110β has been shown to be insensitive to RTK signaling and instead appears to be largely regulated by G protein–coupled receptors (GPCR). Activation of p110β in response to GPCR agonists was dependent on an intact RBD and RAC1 both in vitro and in vivo and required the RAC guanine nucleotide exchange factor DOCK180 and its adaptor ELMO1. Collectively, these findings show that the ubiquitous PI3K isoforms have different modes of regulation, which may have implications for the design and use of isoform-specific PI3K inhibitors in cancer therapy.

Fritsch R, de Krijger I, Fritsch K, George R, Reason B, Kumar MS, et al. RAS and RHO families of GTPases directly regulate distinct phosphoinositide 3-kinase isoforms. Cell 2013;153:1050–63.