The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation

Abstract

The Ras-ERK (extracellular signal-regulated kinase) and PI3K (phosphatidylinositol 3-kinase)-mTOR (mammalian target of rapamycin) signaling pathways are the cell’s chief mechanisms for controlling cell survival, differentiation, proliferation, metabolism, and motility in response to extracellular cues. Components of these pathways were among the first to be discovered when scientists began cloning proto-oncogenes and purifying cellular kinase activities in the 1980s. Ras-ERK and PI3K-mTOR were originally modeled as linear signaling conduits activated by different stimuli, yet even early experiments hinted that they might intersect to regulate each other and co-regulate downstream functions. The extent of this crosstalk and its significance in cancer therapeutics are now becoming clear.

mTOR signaling response to resistance exercise is altered by chronic resistance training and detraining in skeletal muscle

“…The ERK1/2 signaling pathway has the ability to regulate proteins involved in the initiation and elongation stages of mRNA translation in an mTOR-dependent and -independent manner (28,35,43,44). Recent studies indicated that ERK signaling is involved in later phase anabolic responses after resistance exercise (5,6,15).…”

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.…”

Translational regulation of the cell cycle: when, where, how and why?

“…Important signal-transduction pathways linking regulation of protein synthesis to nutrient sensing are mitogen-activated protein kinase and target of rapamycin signalling cascades. However, as the connection of these signalling pathways to translational regulation and cell growth has been extensively reviewed, they will not be further discussed here (for more information see reviews [11][12][13][14]). …”