Mitogen-activated protein kinase

Most MAPKs have a number of shared characteristics, such as the activation dependent on two phosphorylation events, a three-tiered pathway architecture and similar substrate recognition sites.

But there are also some ancient outliers from the group as sketched above, that do not have dual phosphorylation sites, only form two-tiered pathways, and lack the features required by other MAPKs for substrate binding.

[citation needed] In comparison to the three-tiered classical MAPK pathways, some atypical MAP kinases appear to have a more ancient, two-tiered system.

[6] In contrast to the classical MAP kinases, these atypical MAPKs require only a single residue in their activation loops to be phosphorylated.

[citation needed] As mentioned above, MAPKs typically form multi-tiered pathways, receiving input several levels above the actual MAP kinase.

This commonly (but not always) happens at the cell membrane, where most of their activators are bound (note that small G-proteins are constitutively membrane-associated due to prenylation).

Recently determined complex structures reveal that the dimers are formed in an orientation that leaves both their substrate-binding regions free.

The most important upstream activators of this pathway are the Raf proteins (A-Raf, B-Raf or c-Raf), the key mediators of response to growth factors (EGF, FGF, PDGF, etc.

)[citation needed] In contrast to the relatively well-insulated ERK1/2 pathway, mammalian p38 and JNK kinases have most of their activators shared at the MAP3K level (MEKK1, MEKK4, ASK1, TAK1, MLK3, TAOK1, etc.).

[14] The PB1 domain of MKK5 also contributes to the ERK5-MKK5 interaction: it provides a special interface (in addition to the D-motif found in MKK5) through which MKK5 can specifically recognize its substrate ERK5.

While also implicated in brain development, the embryonic lethality of ERK5 inactivation due to cardiac abnormalities underlines its central role in mammalian vasculogenesis.

While Fus3 and Kss1 are closely related ERK-type kinases, yeast cells can still activate them separately, with the help of a scaffold protein Ste5 that is selectively recruited by the G-proteins of the mating pathway.

The trick is that Ste5 can associate with and "unlock" Fus3 for Ste7 as a substrate in a tertiary complex, while it does not do the same for Kss1, leaving the filamentous growth pathway to be activated only in the absence of Ste5 recruitment.

Terrestrial plants contain four groups of classical MAPKs (MAPK-A, MAPK-B, MAPK-C and MAPK-D) that are involved in response to myriads of abiotic stresses.

This lineage has been deleted in protostomes, together with its upstream pathway components (MEKK2/3, MKK5), although they are clearly present in cnidarians, sponges and even in certain unicellular organisms (e.g. the choanoflagellate Monosiga brevicollis) closely related to the origins of multicellular animals.

This is suggested not just by the high divergence between extant genes, but also recent discoveries of atypical MAPKs in primitive, basal eukaryotes.

The presence of an FxFP motif in the KSR1 scaffold protein also serves to make it an ERK1/2 substrate, providing a negative feedback mechanism to set the correct strength of ERK1/2 activation.

[citation needed] Since the discovery of Ste5 in yeast, scientists were on the hunt to discover similar non-enzymatic scaffolding pathway elements in mammals.

While Ste5 actually forms a ternary complex with Ste7 and Fus3 to promote phosphorylation of the latter, known mammalian scaffold proteins appear to work by very different mechanisms.

[38] JIPs on the other hand, are apparently transport proteins, responsible for enrichment of MAPK signaling components in certain compartments of polarized cells.

[39] In this context, JNK-dependent phosphorylation of JIP1 (and possibly JIP2) provides a signal for JIPs to release the JIP-bound and inactive upstream pathway components, thus driving a strong local positive feedback loop.

[40] This sophisticated mechanism couples kinesin-dependent transport to local JNK activation, not only in mammals, but also in the fruitfly Drosophila melanogaster.

[41] Since the ERK signaling pathway is involved in both physiological and pathological cell proliferation, it is natural that ERK1/2 inhibitors would represent a desirable class of antineoplastic agents.

Indeed, many of the proto-oncogenic "driver" mutations are tied to ERK1/2 signaling, such as constitutively active (mutant) receptor tyrosine kinases, Ras or Raf proteins.

[42][43] MEK inhibitor cobimetinib has been investigated in pre-clinical lung cancer models in combination with inhibition of the PI3K pathway, where the two drugs lead to a synergistic response.

[44][45] JNK kinases are implicated in the development of insulin resistance in obese individuals[46] as well as neurotransmitter excitotoxicity after ischaemic conditions.

Mice that were genetically engineered to lack a functional JNK3 gene - the major isoform in brain – display enhanced ischemic tolerance and stroke recovery.

Yet the failure of more than a dozen chemically different compounds in the clinical phase suggests that p38 kinases might be poor therapeutic targets in autoimmune diseases.

X-ray structure of the ERK2 MAP kinase in its active form. Phosphorylated residues are displayed in red. Rendering based on pdb entry 2ERK.
Example for the inner workings of a MAP3 kinase: the activation cycle of mammalian Raf proteins (greatly simplified overview) [ 8 ] [ 9 ]
A simplified overview of MAPK pathways in mammals, organised into three main signaling modules (ERK1/2, JNK/p38 and ERK5)
Overview of MAPK pathways in yeast. Non-canonical components of the five known modules (mating, filamentation, hyperosmosis, cell wall integrity, sporulation pathways) are colored in blue.
The evolutionary origins of human mitogen-activated protein kinases (MAPKs) [ 15 ] [ 24 ]
The overview of the D-motif dependent MAPK interactions and substrate recognition. [ 31 ] All cited examples refer to the interactions of the mammalian ERK2 protein.