MAPKinasen

MAPkinasen, in the common English usage MAP kinases, are a family of protein kinases that regulate cellular responses to a wide range of stimuli. They transduce extracellular signals into intracellular responses by phosphorylating downstream targets, including transcription factors, thereby controlling gene expression, differentiation, proliferation, and survival.

MAP kinases operate within three-tiered phosphorylation cascades. A MAP kinase kinase kinase (MAP3K) activates a MAP kinase kinase (MAP2K), which then activates a MAP kinase (MAPK). MAP2Ks require dual phosphorylation on both threonine and tyrosine residues within the activation loop. The activation loop motif is typically Thr-X-Tyr (TXY). Upstream signals such as growth factors, cytokines, or stress trigger the cascade, amplifying the signal through sequential phosphorylation events.

The best-characterized MAPK subfamilies are ERK1/2 (MAPK1/3), JNKs (MAPK8-9-10), and p38 MAPKs (MAPK14 and related). ERK1/2 predominantly promote growth and differentiation, while JNK and p38 respond strongly to stress and inflammatory cues, influencing apoptosis, inflammation, and cytokine production. Other members include ERK5 (MAPK7). Specificity is achieved through scaffolding proteins, subcellular localization, and feedback mechanisms. Phosphatases such as MAP kinase phosphatases (MKPs) deactivate MAPKs to terminate signaling.

Dysregulation of MAPK signaling is linked to diseases, notably cancer, where activating mutations in upstream components drive pathway activity. Therapeutic targeting includes MEK inhibitors and RAF inhibitors, with ongoing research into resistance mechanisms and combination strategies. MAPK pathways are evolutionarily conserved across eukaryotes and play essential roles in development and adaptation.