Kinase Subfamily ERK5

Kinase Classification: Group CMGC: Family MAPK: Subfamily ERK5

ERK5 (Extracellular signal Regulated Kinase) is a variant Erk-like MAPK found in most animals, and part of a variant MAPK cascade that includes the MEK5 MAP2K and the MEKK2 MAP3K. There is a single ERK5 in human, which is also known as MAPK7.

Evolution

ERK5 is found as a single copy. It is secondarily lost from most insects and nematodes, along with its upstream pathway members, MEK5 and MEKK2. It is also likely found in fungi (SLT2), several plant lineages and other protists, though their sequence similarity to animal ERK5 is a little ambiguous. A second homolog is found in fungi from the genus Saccharomyces, called KDX1, which is likely a pseudokinase, and in some species, a pseudogene.

Control of activity

Like most MAPK it is activated by dual phosphorylation of a TxY motif in the Activation loop by an upstream kinase ( MEK5). Activation also induces translocation to the nucleus.

Domain Structure

All animal ERK5 have a kinase domain close to the N-terminus, an L16 domain immediately afterwards that is shared with several other MAPK, and about 300-400 AA of unannotated C-terminal tail. Conservation profiling suggests that the tail includes some conserved motifs and a novel domain near the C-terminal tip. Fungal ERK5 lack most of the C-terminal tail, but do have a highly conserved ~13 AA motif at their C-terminus, which may have some similarity to the animal C-terminus. Other basal ERK5 have little or no conservation past the L16 domain.

Biological Function

Mammalian ERK5 activates the muscle transcription factors MEF2A, C, and D [1], downstream of EGF signaling. Yeast SLT2 activates the MEF ortholog, RLM1 [2] as part of the cell wall integrity (CWI) pathway. SKT2 also activates Swi, in a non-catalyic manner

Yeast SLT2 has many functions. The best studied is the cell wall integrity pathway, where the AGC kinase Pkc1 (a homolog of both PKC and PKN), which activates the MAP3K, Bck1, which then activates the MAP2Ks Mkk1 and Mkk2, that then activate Slt1, in a typical MAPK cascade. Bck1 is classified as STE11-Unclassified, but is arguably closer in sequence to MEKK2, the MEKK in the ERK5 pathway, than to others, while Mkk1 and Mkk2 are Ste7-Unclassified, but also almost as close to the ERK5 MEK, MEK5 as to others, suggesting that all three kinases are divergent members of the ERK5 signaling pathway.

Dictyostelium erkA (aka ERK1, but an ERK5 subfamily member) is required for chemotaxis and tip formation. MEK1 has a similar phenotype, and is a likely upstream MEK kinase, though it is closer to the MEK1 family than the MEK5 family. The sole Dicty MEKK, MEKKalpha, is similar to both MEKK15 and MEKK2, and includes the PB1 domain that is used to dimerize

References

1. Kato Y, Zhao M, Morikawa A, Sugiyama T, Chakravortty D, Koide N, Yoshida T, Tapping RI, Yang Y, Yokochi T, and Lee JD. Big mitogen-activated kinase regulates multiple members of the MEF2 protein family. J Biol Chem. 2000 Jun 16;275(24):18534-40. DOI:10.1074/jbc.M001573200 |
2. Levin DE. Cell wall integrity signaling in Saccharomyces cerevisiae. Microbiol Mol Biol Rev. 2005 Jun;69(2):262-91. DOI:10.1128/MMBR.69.2.262-291.2005 |