The RAS Signaling Network and Cancer

The RAS small GTPases (HRAS, KRAS, and NRAS) comprise the most frequently mutated oncogene family in human cancer. RAS proteins reside on the cytoplasmic face of the plasma membrane where they act as binary on-off switches that relay signals from extracellular signal-activated cell surface receptors to diverse cytoplasmic signaling networks. RAS signaling is dysregulated by diverse mechanisms in cancer. These include hyperactivating point mutations in RAS itself, aberrant activation of upstream components (e.g., receptor tyrosine kinases), loss of negative regulators (e.g., neurofibromin), and mutational activation of downstream components (e.g., RAF, PI3Kα). Aberrant RAS activation drives persistent activation of downstream effector signaling networks, primarily through the RAF-MEK-ERK mitogen-activated protein kinase (MAPK) cascade. Mutational activation of RAS-ERK signaling is also the defining feature of rare germline developmental disorders termed RASopathies. As the terminal node of the ERK MAPK pathway, ERK regulates a complex phosphoproteome and transcriptome, with the MYC transcription factor and oncoprotein a major component of ERK-driven cancer growth. In this review, we summarize key proximal and distal features of the RAS signaling network and highlight approaches for targeting RAS and the ERK MAPK signaling network for cancer treatment.