MAPKcascade

MAPK cascade refers to a highly conserved three-tiered kinase signaling module that transduces extracellular cues into intracellular responses. The core consists of a MAP kinase kinase kinase (MAPKKK), which activates a MAP kinase kinase (MAPKK), which in turn activates a MAP kinase (MAPK). Activation is achieved by sequential phosphorylation, creating a phosphorylation cascade that regulates transcription factors, cytoskeletal dynamics, metabolism, and other processes.

In animals, the best-characterized cascades include the ERK1/2 pathway (Ras–Raf–MEK–ERK), the JNK pathway, and the p38 pathway. ERK signaling is typically associated with growth factor–driven proliferation and differentiation; JNK and p38 respond to stress stimuli and inflammation and can influence apoptosis, cytokine production, and senescence, depending on cell type and context.

Upstream inputs include receptor tyrosine kinases and G protein–coupled receptors. Small GTPases such as Ras recruit and activate MAPKKKs, which then phosphorylate MAPKKs and ultimately MAPKs. Scaffold proteins (for example, KSR or Shoc2) organize components to enhance specificity and speed, while feedback loops and cross-talk regulate signal strength and duration.

MAPK cascades are evolutionarily conserved, extending from yeast to humans. In yeast, Fus3 and Kss1 execute mating and filamentation responses; in plants, MPK cascades govern development and stress responses. Dysregulation of MAPK signaling is linked to cancer, inflammatory diseases, and developmental disorders.

Therapeutic strategies aim to modulate MAPK signaling, including MEK inhibitors (such as trametinib and binimetinib) and ERK inhibitors, with ongoing research to overcome resistance and toxicity. Understanding the precise wiring and context-dependent outputs of MAPK cascades remains essential for exploiting them in medicine.