MAPKKKs

MAPKKK, short for mitogen-activated protein kinase kinase kinase, is a family of serine/threonine kinases that sit at the apex of mitogen-activated protein kinase (MAPK) signaling cascades. They phosphorylate and activate MAPKKs (MAP kinase kinases), which in turn activate MAPKs (MAP kinases). Through this three-tier cascade, cells translate diverse signals into responses such as proliferation, differentiation, stress responses, and apoptosis. MAPKKKs respond to stimuli including growth factors, cytokines, osmotic and oxidative stress, and developmental cues, and they are activated by recruitment to membranes and by small GTPases such as Ras and Rho family members.

Most MAPKKKs contain a kinase domain and regulatory regions; many are activated by phosphorylation or by interaction with adaptor or scaffold proteins. Membrane recruitment by Ras or Rac and upstream adaptors often positions them to phosphorylate their cognate MAPKKs. The downstream MAPKKs then activate specific MAPKs by phosphorylating activation loop residues on Thr and Tyr.

Common mammalian MAPKKKs include the RAF kinases (ARAF, BRAF, RAF1), which initiate ERK signaling; the MEKK family (MAP3K1/2/3) that activates MEKs leading to ERK, JNK, or p38 outputs; ASK1 (MAP3K5) and TAK1 (MAP3K7) that primarily activate the JNK and p38 pathways; and the mixed-lineage kinase (MLK) family that links various stress and inflammatory signals to JNK/p38. Plant and invertebrate species also possess MAPKKKs with conserved roles.

In physiology and disease, MAPKKKs influence cell growth, differentiation, inflammation, and survival. Dysregulation or mutation of MAPKKKs is associated with cancer and inflammatory disorders, making components of MAPK cascades targets for pharmacological intervention and research.