MAPKAPs

Several protein kinases are activated by the MAPK family members p38α (SAPK2a) and ERKs 1 and 2. The MAPKAP kinases can be subdivided into two groups; those comprising two kinase domains in a single polypeptide, and those with a single kinase domain. Both groups contain a C-terminal docking site that interacts with the activator, thereby permitting phosphorylation and activation of the MAPKAP kinases.

The two kinase domain enzymes are RSK (also called p90 Rsk), and mitogen and stress activated protein kinase (MSK). The N-terminal kinase domain of these proteins belongs to the AGC family, while the C-terminal domain is more closely related to the calmodulin dependent protein kinase family. The activation of RSK is complex and requires activation of the C-terminal kinase domain by ERK1/ERK2, which then phosphorylates a residue in the linker region between the two kinase domains. This phosphorylation event, together with the ERK1/ERK2-catalyzed phosphorylation of another site in the linker region, then activates the N-terminal domain, provided that a further site in the activation loop of the N-terminal domain has been phosphorylated by 3-phosphoinositide-dependent protein kinase-1 (PDK1). The N-terminal kinase domain then catalyzes the phosphorylation of exogenous substrates.

There are four mammalian homologs of RSK, which are activated by ERK1/ERK2. RSK is implicated in the regulation of several processes including cell survival, gene transcription and the control of meiosis. Mutations in the human RSK2 isoform is linked to Coffin Lowry syndrome, a disease associated with mental retardation and growth defects.

As implied by its name, MSK can be activated by either ERK1/ERK2 in response to mitogens and growth factors or by p38α following exposure to cellular stresses or proinflammatory cytokines. Its N-terminal kinase domain is 54% identical and its C-terminal kinase domain is 44% identical to the corresponding domains of RSK. All the phosphorylation sites in RSK are conserved in MSK, suggesting an analogous mechanism of activation. However, in contrast to RSK, PDK1 is not required for the activation of MSK, and phosphorylation of the activation loop of the N-terminal kinase domain is catalyzed by the C-terminal kinase domain of MSK. There are two isoforms of MSK in mammalian cells, termed MSK1 and MSK2. The MSKs are localized to the nucleus and their substrates include the transcription factors CREB and ATF1 and the chromatin proteins histone H3 and HMG-14. The Drosophila kinase JIL-1, an MSK1 homolog, has been localized to decondensed regions of chromosomes, suggesting a role in transcriptional regulation.

The MAPKAP kinases comprising a single kinase domain are members of the calmodulin dependent protein kinase family and are MAPKAP-K2, MAPKAP-K3, PRAK (also called MAPKAP-K5) and MAPK-integrating kinase (MNK). MAPKAP-K2 and MAPKAP-K3 are activated by p38α in vivo and their physiological substrates include heat shock protein (HSP) 27 and hnRNPA0. The phosphorylation of HSP27 stimulates actin polymerization and is thought to help repair the actin microfilament network that becomes disrupted when cells are stressed, thereby aiding cell survival. MAPKAP-K2 is also involved in controlling production of the proinflammatory cytokines, tumor necrosis factor, interleukin 6 and interferon γ, at a post-transcriptional level. This may result from the ability of MAPKAP-K2 to regulate the stability and/or translation of the mRNAs containing AU rich regions via the phosphorylation of RNA binding proteins such as hnRNPA0. MAPKAP-K2 knockout mice show decreases in TNF and IL-6 production and increases in survival in models of endotoxic shock. PRAK is also activated in vitro by p38α, however in vivo it is most likely activated by ERK3. The physiological role of PRAK is still unclear.

Two isoforms of MNK (MNK1 and MNK2) have been found in mammalian cells. Like the MSK isoforms, MNK1 can be activated by either ERK1/ERK2 or p38α. However, MNK2 appears to be activated preferentially by ERK1/ERK2. One substrate of MNK1 is the eukaryotic translation initiation factor 4E (eIF4E). Phosphorylation of this protein increases its affinity for the 5’ cap of the mRNA, thereby promoting translation. MNKs may also be involved in the production of TNF in the immune system.

 

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

 

Family Members RSK MSK MAPKAP-K2 MAPKAP-K3 MAPKAP-K5 MNK
Other Names MAPKAP-K1
p90Rsk
RSK-B MK2 3pK PRAK  
Molecular Weight
(approx)
83 kDa 87-90 kDa 42 kDa 42 kDa 54 kDa 46-48 kDa
Isoforms RSK1 (MAPKAP-K1a)
RSK2 (MAPKAP-K1b)
RSK3 (MAPKAP-K1c)
RSK4 (MAPKAP-K1d)
MSK1
MSK2
Not Known Not Known Not Known MNK1
MNK2
Species Drosophila
C. elegans
Vertebrates
Vertebrates C. elegans
Drosophila
Vertebrates
Vertebrates Vertebrates Vertebrates
Domain
Organization
2 kinase domains 2 kinase domains 1 kinase domain 1 kinase domain 1 kinase domain 1 kinase domain
Phosphorylation
Sites
RSK1
Ser221
Thr369
Ser363
Ser380
Thr573
Ser749
RSK2
Ser227
Thr365
Ser369
Ser386
Thr577
RSK3
Ser218
Ser356
Ser360
Ser386
Thr570
RSK4
Ser232
Thr368
Ser372
Ser389
Thr581
MSK1
Ser212
Ser360
Ser376
Ser381
Thr581
Ser752
Ser758
MSK2
Ser196
Ser343
Ser347
Ser360
Thr568
Thr25
Thr222
Ser272
Thr334
Thr338
Thr201
Ser251
Thr313
Thr317
Thr182 MNK1
Thr197
Thr202
MNK2
Thr197
Thr202
Ser27
Ser384
Ser387
Ser399
Thr403
Tissue
Distribution
Ubiquitous Ubiquitous Ubiquitous Ubiquitous Ubiquitous Ubiquitous
Subcellular
Localization
Cytosolic
Nuclear
Nuclear Cytosolic
Nuclear
Cytosolic
Nuclear
Cytosolic
Nuclear
Cytosolic
Binding Partners/
Associated Proteins
CBP
ERK1/2
Not Known p38 p38 ERK3 Not Known
Upstream
Activators
ERK1/2 ERK1/2
p38
p38 p38 ERK3 ERK1/2
p38 (MNK1)
Downstream
Activation
GSK3 (G1663)
BAD (B1682)
LKB1
Nur77
c-fos
SRF
CREB
ATF1
histone H3
HMG-14
HSP27 (H8158)
Tyrosine hydroxylase
hnRNPA0
E47  
HSP27 (H8158) Not Known eIF4E
Activators Mitogens
Cytokines
Mitocellular stress genes
Cytokines
Cellular stress
Cellular stress
Cytokines
Cellular stress
Cytokines
Not Known Mitogens
Cytokines
Inhibitors Ro 31-8220 (R136)
H89
Ro 31-8220 (R136)
H89
Not Known Not Known Not Known Not Known
Selective
Activators
Not Known Not Known Not Known Not Known Not Known Not Known
Physiological
Function
Transcription regulation
Cell survival
Transcription regulation
Regulation of RNA stability
Transcription regulation Not Known Not Known Regulation of translation
Disease
Relevance
Coffin-Lowry syndrome Not Known Inflammation Not Known Not Known Not Known

 

Footnotes

*These are well described functions for these kinases, however they may have other physiological functions in addition to these.

 

Abbreviations

BAD: Bc12-Associated death promoter
CREB: cAMP Responsive element binding protein
ERK: Extracellular signal-related kinase
GSK 3: Glycogen synthase kinase-3
HSP 27: Heat shock protein
LKB1: Peutz-Jeghers gene
MAPK: Mitogen activated protein kinase
MAPKAP: MAPK-activated protein
MNK: MAPK-integrating kinase
MSK: Mitogen and stress activated protein kinase
PRAK: p38-Regulated activated kinase
RSK: Ribosomal S6 kinase
SAPK: Stress activated protein kinase
SRF: Serum response factor

 

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References