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Review
. 2004 Jun;68(2):320-44.
doi: 10.1128/MMBR.68.2.320-344.2004.

ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions

Philippe P Roux  1 , John Blenis
Affiliations
Review

ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions

Philippe P Roux et al. Microbiol Mol Biol Rev. 2004 Jun.

Abstract

Conserved signaling pathways that activate the mitogen-activated protein kinases (MAPKs) are involved in relaying extracellular stimulations to intracellular responses. The MAPKs coordinately regulate cell proliferation, differentiation, motility, and survival, which are functions also known to be mediated by members of a growing family of MAPK-activated protein kinases (MKs; formerly known as MAPKAP kinases). The MKs are related serine/threonine kinases that respond to mitogenic and stress stimuli through proline-directed phosphorylation and activation of the kinase domain by extracellular signal-regulated kinases 1 and 2 and p38 MAPKs. There are currently 11 vertebrate MKs in five subfamilies based on primary sequence homology: the ribosomal S6 kinases, the mitogen- and stress-activated kinases, the MAPK-interacting kinases, MAPK-activated protein kinases 2 and 3, and MK5. In the last 5 years, several MK substrates have been identified, which has helped tremendously to identify the biological role of the members of this family. Together with data from the study of MK-knockout mice, the identities of the MK substrates indicate that they play important roles in diverse biological processes, including mRNA translation, cell proliferation and survival, and the nuclear genomic response to mitogens and cellular stresses. In this article, we review the existing data on the MKs and discuss their physiological functions based on recent discoveries.

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Figures

FIG. 1.
FIG. 1.
Signaling cascades leading to activation of the MKs. Mitogens and cellular stresses lead to activation of the ERK1/2 and p38 cascades, which in turn phosphorylate and activate the five subgroups of MKs.
FIG. 2.
FIG. 2.
Amino acid alignments of D domains found in MKs. The ERK1/2 and p38 kinase binding regions, termed D domains, are found in most MKs and are required for efficient activation of the MKs by mitogens and cellular stresses. The D domains, shown in boldface, are characterized by a stretch of positively charged residues surrounded by hydrophobic residues. Some D domains mediate specific interaction with ERK1/2 or p38, while others are necessary for interaction with both upstream activators. In some MKs, the D domain region overlaps an NLS sequence (underlined).
FIG. 3.
FIG. 3.
Schematic representation of the overall structure of the MKs. While RSK1, -2, -3, and -4 and MSK1 and -2 are composed of two nonidentical kinase domains, the MNKs and MK2, -3, and -5 are single-kinase-domain proteins that display homology to the CTKD of RSKs and MSKs. The NTKDs of the RSKs and MSKs are members of the AGC family of kinases, which also require sequences known as the turn and hydrophobic motif for activity. Also necessary for activation of all MKs are the phosphorylation sites indicated by a black circle. The amino acid composition of each MK and its alternatively spliced variants refers to the human protein. The MK5A isoform has been omitted from this figure because it differs from MK5B only by the lack of two residues.
FIG. 4.
FIG. 4.
Alignment of the amino acid sequences of the single-kinase domain MKs (MNK1 and -2, MK2 and -3 and MK5) and the CTKDs of RSK1 and MSK1. The sequences comprising the kinase domain and its subregions are boxed and reveal the region of highest homology. The conserved activation loop threonine residue within the sequence Leu-Xaa-Thr-Pro is shown by an arrow, and the D domain region is identified by a line.
FIG. 5.
FIG. 5.
Phylogenetic tree of MK family members. The root of the tree is marked with a circle. All sequences used for the construction of this tree were human, and alternatively spliced isoforms of MNK2, MK2, and MK5 were also included in the analysis. The relative similarities between all MKs reflected by this tree suggest that the MKs comprise five groups, the RSK, MSK, MNK, MK2 and -3, and MK5 subfamilies. The Clustal X program was used to generate the multiple alignment on which the tree was based.
FIG. 6.
FIG. 6.
Signaling cascades leading to activation of RSKs and MSKs. RSK1, -2, -3, and -4 are activated by two inputs originating from the ERK1/2 and PDK1 enzymes. Similarly, MSK1 and -2 are activated by ERK1/2 but also by stimuli that activate the p38 kinases. Despite their relatively high homology, the RSKs and MSKs appear to have different biological functions.
FIG. 7.
FIG. 7.
Schematic representation of RSK1 compared to the related MSK1. The known phosphorylation sites on RSK1 and MSK1 are indicated by solid (essential site) and open (nonessential site) circles. The amino acid alignment and phosphorylated residues of RSK1 and MSK1 refer to the human proteins. While the kinases responsible for the phosphorylation of most sites within RSK1 and MSK1 are known, the identity of the kinase(s) responsible for the phosphorylation of several other essential sites remains unknown.
FIG. 8.
FIG. 8.
Substrates of the MKs. Upon activation, the RSKs, MSKs, MNKs, and MK2, -3, and -5 phosphorylate several substrates and regulate many biological responses, including mRNA translation, cell proliferation and survival, and the nuclear response to stress and mitogen stimulation. The list of substrates indicated in this figure is not exhaustive but emphasizes the many important substrates identified to date.
FIG. 9.
FIG. 9.
Signaling cascades leading to activation of the MNKs. MNK1 is activated by two inputs originating from the ERK1/2 and p38 kinases, but MNK2 is only stimulated by ERK1/2. The limited number of substrates identified for the MNKs suggests that they play roles in mRNA translation.
FIG. 10.
FIG. 10.
Signaling cascades leading to activation of MK2 and -3 and MK5. MK2 and -3 have been shown to be activated by p38. Conversely, MK5 was initially shown to be regulated by p38, but recent data have not been able to confirm these results. While no bona fide substrates of MK5 have been identified to date, MK2 and -3 have been found to regulate mRNA stability and actin reorganization.
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