polkuERKMAPK

polkuERKMAPK, also known as the ERK/MAPK signaling pathway, is a highly conserved signal transduction cascade that transmits stimuli from the cell surface to the nucleus to regulate gene expression and cellular behavior. The core cascade comprises a sequential kinase module: a small GTPase of the Ras family relays signals to Raf kinases, which activate MEK1/2, which in turn activate ERK1/2 by phosphorylation. ERK1/2 then migrate to the nucleus and phosphorylate transcription factors such as ELK1 and components of AP-1, leading to changes in transcription and, consequently, cell fate decisions. Activation is commonly initiated by receptor tyrosine kinases or certain GPCRs that promote Ras-GTP formation.

The pathway is tightly regulated; MEK1/2 phosphorylate ERK on a TEY motif; scaffold proteins like KSR1/2 organize components to ensure efficient signaling; negative feedback and phosphatases from the MKP/DUSP family dephosphorylate ERK. Crosstalk with other pathways, including PI3K/AKT and JNK, shapes the overall output and localization defines specificity (cytoplasmic vs nuclear).

ERK signaling influences cell proliferation, differentiation, survival, migration, metabolism, and synaptic plasticity, playing essential roles in development and tissue homeostasis. Dysregulation, often through mutations in Ras or Raf family members (notably BRAF), contributes to oncogenesis and therapy resistance. Pharmacological targeting includes MEK inhibitors (e.g., trametinib, selumetinib) and emerging ERK inhibitors; these agents are used in some cancers and remain an area of active research, with attention to feedback-mediated resistance and toxicity.