MAPKKKs

Mitogen-activated protein kinase (MAPK) signaling pathways mediate cellular responses to many stimuli including growth factors, hormones, cytokines and environmental stresses. MAPK pathways can be divided into those that predominantly respond to mitogens and those that predominantly respond to stress. The extracellular signal regulated kinase (ERK1 and ERK2) pathways are activated by mitogens and play an important role in controlling cell growth and differentiation. The stress-activated MAPK pathways include the c-Jun N-terminal kinase (JNK) and p38 pathways that are implicated in apoptosis and the immune response. The ERK5 MAPK pathway responds to both growth signals and certain stresses. All MAPK pathways feature a three-kinase cascade whereby MAPKs are activated by phosphorylation by a MAPK kinase (MKK or MEK) and MKKs are activated by serine/threonine phosphorylation by MAPK kinase kinases (MAPKKK or MAP3K).

The MAP3K group consists of a large diverse group of protein kinases with overlapping specificities for MKKs. They include members of the RAF, MEKK (MEK kinase), MLK (mixed lineage kinase), and TAO (thousand and one amino acid) families and the protein kinases MOS, ASK1 (apoptosis signal-regulating kinase-1), TAK1 (TGFβ-activated kinase-1) and TPL2 (tumor progression locus-2). The activities of MAP3Ks can be regulated by a number of mechanisms including phosphorylation, interaction with small GTPases, proteolysis, and binding to regulatory or scaffold proteins.

The RAF family are components of ERK signaling pathways and phosphorylate the highly related MEK1 and MEK2. RAF proteins are activated by their recruitment to Ras GTPase at membranes and by phosphorylation at regulatory sites. Mutations in RAF, particularly B-RAF, are associated with human cancers. A second MAP3K that is specific for the ERK pathway is MOS which is primarily expressed in germline cells and is implicated in oocyte maturation. The TPL2 MAP3K activates the ERK pathway and plays an important role in the innate immune response.

The MEKK and MLK families of MAP3Ks and the less well characterized TAO family are components of stress-activated MAPK pathways. The MEKK and MLK families can be activated by Rho-family GTPases and STE20-like protein kinases. MEKK1 can also be activated by proteolysis following apoptotic stimuli. Caspases cleave MEKK1 to release the catalytically active C-terminus that is highly pro-apoptotic. While predominantly involved in stress-signaling some members of these families can function as regulators of ERK pathways. For example, MEKK2 and MEKK3 are components of the ERK5 cascade, MEKK1 can function as a ubiquitin ligase and cause degradation of ERK1/2, and MLK3 has been suggested to be required for B-RAF signaling to ERK1/2.

Additional MAP3Ks that are components of JNK and p38 signaling pathways include ASK1 and TAK1. These MAP3Ks have distinct mechanisms of activation. ASK1 mediates apoptosis induced by oxidative stress and is activated by dissociation from a redox-sensitive inhibitory protein, thioredoxin. TAK1 is activated by TGFβ and cytokines via a mechanism dependent on the ubiquitination of an associated protein, TRAF6.

In addition to their central roles in MAPK signaling some MAP3Ks are components of other signaling pathways. For example C-RAF, MEKKs and TAK1 can activate the NF-kB signaling pathway independently of MAPKs. Also, a MAP3K related kinase NIK (NF-kB inducing kinase) is a component of NF-kB signalling pathways but has no reported role in MAPK signalling.

The large body of literature on MAPK pathways suggests that there is a high level of promiscuity at the level of MAP3Ks. However it is clear from gene-deletion studies in mice and lower eukaryotes that individual MAP3Ks have distinct cellular roles. One important regulatory mechanism for achieving specificity is by scaffold proteins linking particular MAP3Ks to particular MAPK modules in response to a stimulus.

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.