Ras-Mitogen-Activated Protein Kinase signaling pathway proteins (Ras-MAPK)

The Ras-Mitogen-Activated Protein Kinase (Ras-MAPK) signaling pathway, also known as the ERK pathway, is a central signal transduction axis that translates extracellular growth stimuli into fundamental cellular responses. The core cascade consists of the small GTPase Ras and a three-tiered kinase hierarchy comprising Raf (MAP3K), MEK (MAP2K), and ERK (MAPK), which propagate signals through sequential phosphorylation events [1, 11]. This pathway is a master regulator of essential biological processes, including cell proliferation, differentiation, survival, and apoptosis, making it one of the most critical pathways in human physiology and development [7, 22]. Aberrant activation of the Ras-MAPK pathway, primarily driven by gain-of-function mutations in KRAS, NRAS, or BRAF, is a hallmark of over 30% of all human cancers, including pancreatic, colorectal, and non-small cell lung cancers [1, 10]. Additionally, germline mutations in this pathway underlie a group of developmental disorders known as RASopathies, such as Noonan syndrome and Costello syndrome [5, 20]. While historically considered undruggable, the therapeutic landscape has been transformed by the approval of mutation-specific inhibitors like sotorasib (targeting KRAS G12C) and various Raf/MEK inhibitors [1, 9]. However, the clinical utility of these drugs is often challenged by complex feedback loops and the rapid emergence of acquired resistance, frequently necessitating the use of combination therapies to achieve durable responses [11, 14, 23].

Other names

MAPK/ERK pathwayRas-Raf-MEK-ERK signaling cascadeClassical MAPK pathwayMitogen-activated protein kinase signaling pathway

Inhibition of GTPase activation (Ras), competitive or allosteric inhibition of ATP binding/kinase catalytic activity (Raf, MEK, ERK), and disruption of signal propagation within the phosphorylation cascade.