Ras/Raf/ERK signaling pathway (MAPK pathway)

The Ras/Raf/ERK signaling pathway, also known as the Mitogen-activated protein kinase (MAPK) cascade, is a fundamental signal transduction route that communicates signals from cell surface receptors to the nucleus [StatPearls, NBK557700; NIH/NCI, MAPK Pathway]. This pathway is typically initiated by the activation of receptor tyrosine kinases (RTKs) by growth factors, leading to the activation of the small GTPase Ras [UniProt, KRAS; StatPearls, NBK557700]. Active Ras then recruits and activates Raf kinases, which sequentially phosphorylate MEK and then ERK [Nature Reviews Drug Discovery, doi:10.1038/nrd.2017.230]. Once activated, ERK translocates to the nucleus to regulate transcription factors that control essential cellular processes such as proliferation, differentiation, and survival [StatPearls, NBK557700]. Dysregulation of this pathway, often through gain-of-function mutations in KRAS or BRAF, is a hallmark of many human cancers, including melanoma and pancreatic adenocarcinoma [NIH/NCI, MAPK Pathway; Nature Reviews Drug Discovery, doi:10.1038/nrd.2017.230]. Consequently, the pathway is a major focus of oncology drug development, with numerous approved inhibitors targeting specific mutated or overactive components to suppress tumor growth [PubChem, Vemurafenib; FDA, Drugs Approved for Melanoma].

Other names

Ras-Raf-MEK-ERK pathwayMAPK/ERK cascadeMitogen-activated protein kinase pathwayERK signaling pathway

Small molecule inhibition of specific kinases (Raf, MEK) or GTPases (Ras) within the cascade to block downstream phosphorylation of ERK and prevent nuclear translocation of transcription factors associated with cell growth [StatPearls, NBK557700; Nature Reviews Drug Discovery, doi:10.1038/nrd.2017.230].