The Ras-ERK and PI3K-mTOR pathways are crucial for controlling cell survival, differentiation, proliferation, metabolism, and motility in response to extracellular cues. These pathways were among the first to be discovered when scientists began cloning proto-oncogenes and purifying cellular kinase activities in the 1980s. Initially modeled as linear signaling conduits activated by different stimuli, these pathways were found to intersect and co-regulate downstream functions. The extent of this crosstalk and its significance in cancer therapeutics is now becoming clear. The Ras-ERK pathway involves the activation of ERK (extracellular signal-regulated kinase) by growth factors, polypeptide hormones, neurotransmitters, chemokines, and phorbol esters through their cognate RTKs (receptor tyrosine kinases) and GPCRs (G protein-coupled receptors), or by direct activation of PKC (protein kinase C). ERK phosphorylates cytoplasmic signaling proteins and transcription factors, such as RSK (p90 ribosomal S6 kinase) and TCF (Ternary Complex Factor), which induce the expression of genes involved in cell survival, division, and motility. The PI3K-mTOR pathway, on the other hand, responds to growth factors, energy status, amino acid levels, and cellular stress. Growth factors activate PI3K, which generates PP3 (phosphatidylinositol 3,4,5 tri-phosphate), which recruits AKT to the plasma membrane. AKT phosphorylates survival, proliferation, and motility factors, as well as the TSC2 (tuberous sclerosis complex 2) GAP (GTPase activating protein). AKT phosphorylation of TSC2 releases RHEB (Ras homolog enriched in brain), which directly activates mTORC1. mTORC1 consists of mTOR, RAPTOR (regulatory-associated protein of mTOR), and mLST8 (mammalian lethal with Sec13 protein 8). mTORC1 phosphorylates eIF4E-binding protein (4E-BP) and S6K (p70 ribosomal S6 Kinase), which modulate ribosome biogenesis and protein translation. The intensity and duration of pathway activation are regulated by the strength of the stimulus and by feedback loops. The Ras-ERK and PI3K-mTORC1 pathways can negatively regulate each other's activity through cross-inhibition, and they can also cross-activate each other. For example, ERK phosphorylates GAB1, which inhibits PI3K recruitment to the receptor, while PI3K activation can lead to mTORC1 activity through ERK and RSK signaling to the TSC complex. Co-inhibition of both pathways has been successful in reducing tumor growth in xenograft cancer models, highlighting the importance of understanding the mechanisms of these pathways forThe Ras-ERK and PI3K-mTOR pathways are crucial for controlling cell survival, differentiation, proliferation, metabolism, and motility in response to extracellular cues. These pathways were among the first to be discovered when scientists began cloning proto-oncogenes and purifying cellular kinase activities in the 1980s. Initially modeled as linear signaling conduits activated by different stimuli, these pathways were found to intersect and co-regulate downstream functions. The extent of this crosstalk and its significance in cancer therapeutics is now becoming clear. The Ras-ERK pathway involves the activation of ERK (extracellular signal-regulated kinase) by growth factors, polypeptide hormones, neurotransmitters, chemokines, and phorbol esters through their cognate RTKs (receptor tyrosine kinases) and GPCRs (G protein-coupled receptors), or by direct activation of PKC (protein kinase C). ERK phosphorylates cytoplasmic signaling proteins and transcription factors, such as RSK (p90 ribosomal S6 kinase) and TCF (Ternary Complex Factor), which induce the expression of genes involved in cell survival, division, and motility. The PI3K-mTOR pathway, on the other hand, responds to growth factors, energy status, amino acid levels, and cellular stress. Growth factors activate PI3K, which generates PP3 (phosphatidylinositol 3,4,5 tri-phosphate), which recruits AKT to the plasma membrane. AKT phosphorylates survival, proliferation, and motility factors, as well as the TSC2 (tuberous sclerosis complex 2) GAP (GTPase activating protein). AKT phosphorylation of TSC2 releases RHEB (Ras homolog enriched in brain), which directly activates mTORC1. mTORC1 consists of mTOR, RAPTOR (regulatory-associated protein of mTOR), and mLST8 (mammalian lethal with Sec13 protein 8). mTORC1 phosphorylates eIF4E-binding protein (4E-BP) and S6K (p70 ribosomal S6 Kinase), which modulate ribosome biogenesis and protein translation. The intensity and duration of pathway activation are regulated by the strength of the stimulus and by feedback loops. The Ras-ERK and PI3K-mTORC1 pathways can negatively regulate each other's activity through cross-inhibition, and they can also cross-activate each other. For example, ERK phosphorylates GAB1, which inhibits PI3K recruitment to the receptor, while PI3K activation can lead to mTORC1 activity through ERK and RSK signaling to the TSC complex. Co-inhibition of both pathways has been successful in reducing tumor growth in xenograft cancer models, highlighting the importance of understanding the mechanisms of these pathways for