TheRas-ERKandPI3K-mTORpathways: cross-talk and compensation (2011)

The Ras-extracellular signal-regulated kinase (Ras-ERK)and phosphatidylinositol 3-kinase-mammalian target ofrapamycin (PI3K-mTOR) signaling pathways are thechief mechanisms for controlling cell survival, differen-tiation, proliferation, metabolism, and motility in re-sponse to extracellular cues. Components of thesepathways were among the ﬁrst to be discovered whenscientists began cloning proto-oncogenes and purifyingcellular kinase activities in the 1980s. Ras-ERK and PI3K-mTOR were originally modeled as linear signaling con-duitsactivatedbydifferentstimuli,yetevenearlyexperi-ments hinted that they might intersect to regulate eachotherandco-regulatedownstreamfunctions.Theextentof this cross-talk and its signiﬁcance in cancer therapeu-tics are now becoming clear.Core componentsThe Ras-ERK pathwayExtracellular signal-regulated kinase (ERK) is a mitogen-activated protein kinase (MAPK) that functions as themajor effector of the Ras oncoprotein. MAPK pathwaysconsist of an initial GTPase-regulated kinase (MAPKKK)that phosphorylates and activates an intermediate kinase(MAPKK) that, in turn, phosphorylates and activates aneffector kinase (MAPK; Box 1). In the ERK-MAPK path-way,thesecomponentsaretheRasGTPaseandtheproteinkinases Raf, MEK andERK (Figure 1a). Ras andthe ERK-MAPK pathway are activated by growth factors, polypep-tide hormones, neurotransmitters, chemokines, and phor-bol esters, which signal through their cognate receptortyrosine kinases (RTKs) and G protein-coupled receptors(GPCRs), or by direct activation of protein kinase C (PKC)(Figure 1a) [1,2].Activated ERK phosphorylates cytoplasmic signalingproteins, including p90 ribosomal S6 kinase (RSK), andend-point effectors such as transcription factors. RSK sim-ilarlyphosphorylatesseveralcytoplasmictargetsandtran-scriptional regulators. ERK nuclear targets include theternary complex factor (TCF) transcription factors, whichplay a major role in inducing expression of the immediateearly genes (IEGs). The IEG products, such as c-Fos and c-Myc,inducelate-responsegenesthatpromotecellsurvival,cell division, and cell motility [3,4]. Confoundingly, non-physiological hyperactivation of Ras-ERK signaling caninduce the expression of cyclin-dependent kinase (CDK)inhibitors and trigger cell cycle arrest [5].The target speciﬁcity of active ERK is controlled bysubstrate availability (cell type, cell cycle phase, and ex-tracellular environment), by ERK scaffolding, and by sub-cellular localization. Scaffolding proteins tether MEK andERK to speciﬁc substrates and subcellular locales, and arerequired for ERK phosphorylation of the correspondingbound or local substrates [1].The PI3K-mTOR pathwayThe other key mechanism for controlling cell survival,division, and metabolism is the phosphatidylinositol 3-kinase (PI3K)-mammalian target of rapamycin (mTOR)pathway.mTORcomplex1(mTORC1)respondstogrowthfactors, energy status, amino acid levels, and cellularstress. Growth factors activate the lipid kinase PI3Kthrough either direct PI3K recruitment to the growthfactor receptors or indirect recruitment involving thedocking proteins insulin receptor substrate (IRS) orGRB2-associatedbinder(GAB).PI3K generatesphospha-tidylinositol 3,4,5 triphosphate (PIP3), which recruits theprotein kinase AKT to the plasma membrane where it isactivated by 3-phosphoinositide-dependent kinase 1(PDK1) and the second mTOR complex, mTORC2 (seebelow).AKTphosphorylatesmanysurvival,proliferation,and motility factors as well as the tuberous sclerosiscomplex 2 (TSC2) GTPase activating protein (GAP).AKT phosphorylation of TSC2 releases TSC inhibitionof the GTPase Ras homolog enriched in brain (RHEB).RHEB-GTP directly activates mTORC1 (Figure 1b) [6].mTORC1 consists of the Ser/Thr kinase mTOR, thescaffolding protein regulatory-associated protein ofmTOR (RAPTOR) and mammalian lethal with Sec13protein 8 (mLST8). This complex phosphorylates eukary-otic initiation factor 4E (eIF4E)-binding protein (4E-BP)and p70 ribosomal S6 kinase (S6K), events that promoteribosome biogenesis and the translation of cell growthand division proteins, such as c-Myc and cyclin D(Figure 1b). Notably, phosphorylation inhibits the abilityof 4E-BP to bind and sequester the eIF4E mRNA cap-binding protein, thereby permitting the assembly of thecap-binding complex and translation initiation. S6K, bycontrast, is activated by mTORC1 phosphorylation. S6Kacts on many substrates, including transcription factors,the ribosomal protein S6, RNA helicases, and other pro-tein substrates involved in translation initiation andelongation [6].Amino acid availability, energy status, and oxygenlevels feed into this core PI3K-mTORC1 pathway. Amino