ERKpolku

ERKpolku, commonly referred to as the ERK/MAPK pathway, is a conserved signaling cascade that relays extracellular signals from cell surface receptors to the nucleus to regulate processes such as proliferation, differentiation, and survival. The core module is a three-kinase cascade: Ras activates Raf (MAPKKK), Raf activates MEK (MAPKK), and MEK activates ERK (MAPK). ERK1 and ERK2 are the principal kinases in vertebrates.

Upon receptor stimulation, such as by growth factors, Ras binds GTP and recruits Raf to the membrane, initiating the phosphorylation cascade. Activated ERK translocates to the nucleus and phosphorylates transcription factors (for example ELK1 and c-Fos) as well as cytosolic targets, leading to changes in gene expression and cellular responses.

Regulation of ERK signaling is tight and multifaceted. Negative feedback and phosphatases of the DUSP family inactivate ERK; scaffold proteins such as KSR1/2 and SHOC2 organize signaling complexes to modulate output; and proteins like Sprouty provide further negative regulation. The pathway interacts with other signaling networks, notably the PI3K-Akt pathway, to modulate response strength and duration and to influence spatial aspects of the signal within the cell.

Clinical relevance lies in the pathway’s role in development and disease. Aberrant ERK signaling is associated with cancer, often due to mutations in RAS or BRAF that cause constitutive activation. Therapeutic approaches include BRAF inhibitors (e.g., vemurafenib) and MEK inhibitors (e.g., trametinib), though resistance via pathway rewiring is a common challenge.

The ERK polku/ERK/MAPK pathway was characterized as part of the mitogen-activated protein kinase family, with ERK1/ERK2 encoded by MAPK3 and MAPK1, respectively, and studied across yeast, Drosophila, and mammalian systems.