Extracellular signal-regulated kinase mitogen-activated protein kinase signaling pathway (ERK MAPK pathway)

The Extracellular signal-regulated kinase mitogen-activated protein kinase (ERK MAPK) signaling pathway is a fundamental intracellular cascade that communicates signals from cell surface receptors to the nucleus. This pathway is structured as a three-tiered kinase module where a MAP kinase kinase kinase (RAF) activates a MAP kinase kinase (MEK), which in turn activates the MAP kinase (ERK) through sequential phosphorylation [1]. Activation typically begins with the binding of extracellular ligands to receptor tyrosine kinases, triggering the activation of Ras GTPases [2]. Once activated, ERK translocates to the nucleus to regulate transcription factors that govern critical cellular processes such as proliferation, differentiation, and survival [3]. Hyperactivation of this pathway is a common driver in human cancers, often resulting from mutations in BRAF or RAS, making it a high-priority target for therapeutic intervention [4]. Clinical strategies currently involve the use of RAF and MEK inhibitors, with ERK inhibitors being developed to overcome resistance mechanisms [5]. Beyond oncology, mutations in this pathway are responsible for a group of developmental disorders known as RASopathies [1]. The pathway also plays roles in inflammatory responses and synaptic plasticity in the nervous system [2]. Therapeutic challenges include the rapid development of drug resistance through bypass signaling or compensatory mutations [4]. Monitoring pathway activity via phosphorylated ERK levels serves as a key biomarker for assessing drug efficacy in clinical settings [5].

Other names

Ras/Raf/MEK/ERK pathwayMAPK/ERK pathwayClassical MAPK pathwayMAP kinase cascadeMAPK1/3 signaling

Inhibition of the phosphorylation cascade by targeting specific kinase nodes (RAF, MEK, or ERK) through ATP-competitive or allosteric mechanisms to prevent downstream signaling.