RAS Interaction with PI3K: More Than Just Another Effector Pathway

Abstract

RAS proteins are small GTPases known for their involvement in oncogenesis: around 25% of human tumors present mutations in a member of this family. RAS operates in a complex signaling network with multiple activators and effectors, which allows them to regulate many cellular functions such as cell proliferation, differentiation, apoptosis, and senescence. Phosphatidylinositol 3-kinase (PI3K) is one of the main effector pathways of RAS, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism. However, it is the involvement of this pathway in human tumors that has attracted most attention. PI3K has proven to be necessary for RAS-induced transformation in vitro, and more importantly, mice with mutations in the PI3K catalytic subunit p110α that block its ability to interact with RAS are highly resistant to endogenous oncogenic KRASinduced lung tumorigenesis and HRAS-induced skin carcinogenesis. These animals also have a delayed development of the lymphatic vasculature. Many PI3K inhibitors have been developed that are now in clinical trials. However, it is a complex pathway with many feedback loops, and interactions with other pathways make the results of its inhibition hard to predict. Combined therapy with another RAS-regulated pathway such as RAF/MEK/ ERK may be the most effective way to treat cancer, at least in animal models mimicking the human disease. In this review, we will summarize current knowledge about how RAS regulates one of its best-known effectors, PI3K.

Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease

“…10). Although challenging the signalling dogma holding that the GTPase-dependent stimulation of PI3Ka is mostly mediated by direct physical interactions with oncogenic Ras proteins 33 , these results are consistent with previous data indicating that the PI3Ka/Akt axis can be activated in Ras-independent manners in some Ras-transformed cells 16,24,[34][35][36][37] . Interestingly, the influence of R-Ras2 on the PI3K/Akt pathway is highly dependent on the experimental conditions used.…”

Block one, unleash a hundred. Mechanisms of DAB2IP inactivation in cancer

“…8,9 In addition, Ras proteins can also activate PI3K, mediating proliferative and survival signals. 10,11 The GAP domain of DAB2IP is homologous to other RasGAPs, such as GAP120 and neurofibromin (NF1), and can stimulate the GTPase activity of RAS proteins both in vitro and in cancer cell lines (Figure 2). [12][13][14][15] In prostate cancer cells, DAB2IP was shown to be recruited by the adaptor protein DAB2/DOC2 to promote Ras inactivation and inhibition of MAPK signaling upon receptor stimulation.…”

“…The GAP activity of DAB2IP can further enforce inhibition of the PI3K-AKT axis by reducing Ras-dependent activation of PI3K p110α subunit. 10,11 Interestingly, animal models showed that DAB2IP functions as endogenous inhibitor of adaptive angiogenesis in part by binding directly to VEGFR-2 and limiting PI3K activation ( Figure 4b). 4 GSK3β-β-catenin signaling.…”

ROCK2/rasHa co-operation induces malignant conversion via p53 loss, elevated NF-κB and tenascin C-associated rigidity, but p21 inhibits ROCK2/NF-κB-mediated progression

“…[4][5][6]13 This association with invasion and metastasis, plus the fact that ROCK proteins act as effectors downstream of ras signalling, make ROCK inhibition an attractive therapeutic target; 3,8 particularly since ras-specific inhibitors have proved unsuccessful. 14 However, few transgenic studies have directly explored activated ROCK2/ras Ha synergism. Classic DMBA/TPA skin carcinogenesis employing 4HT-inducible ROCK2 mice [K14.ROCK er ] 15 implicated synergism with ras Ha activation 16 as papilloma conversion rates increased; 5 but given the numerous mutations elicited by DMBA initiation 16 direct ROCK2/ras Ha cooperation remains unclear and potential synergism in earlier papillomatogenesis uncertain.…”