ERks

ERKs, or extracellular signal-regulated kinases, are a subgroup of the mitogen-activated protein kinase (MAPK) family, primarily represented by two closely related serine/threonine kinases, ERK1 and ERK2 (encoded by MAPK3 and MAPK1). They act as key nodes in signaling networks that transduce extracellular cues into cellular responses such as proliferation, differentiation, and survival.

Activation occurs through a conserved kinase cascade. Receptor tyrosine kinases or other receptors detect stimuli and activate Ras, which then engages RAF kinases (ARAF, BRAF, or CRAF). RAF phosphorylates and activates MEK1/2, which, in turn, phosphorylates ERK1/2 on a threonine–tyrosine activation loop (the TEY motif). Phosphorylated ERK1/2 translocates to the nucleus and also acts in the cytosol, phosphorylating a wide range of substrates, including transcription factors such as ELK1, c-Fos, and c-Myc, as well as components involved in mRNA stability and translation. Specificity is shaped by docking interactions with scaffold proteins and substrates.

Functions of ERKs are diverse. They regulate cell cycle progression, particularly the G1/S transition, influence differentiation and development, and modulate metabolism and synaptic plasticity in the nervous system. In addition to nuclear effects, ERKs impact cytoskeletal organization, vesicle trafficking, and protein synthesis, enabling cells to adapt to external signals.

Regulation of ERK signaling is tightly controlled by dual specificity phosphatases (DUSPs/MKPs) and feedback loops that dampen or redirect signaling. Dysregulation of ERK signaling is linked to diseases, especially cancer, where constitutive pathway activation can arise from mutations in upstream components such as RAS or BRAF.

Therapeutically, components of the ERK pathway are targets of cancer drugs, including MEK inhibitors (e.g., trametinib, selumetinib) and ERK inhibitors (e.g., ulixertinib). Resistance and compensatory signaling remain challenges, motivating ongoing research into pathway dynamics and combination therapies.