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MAPKs

The mitogen-activated protein kinase (MAPK) family consists of both stress activated (SAPK) and mitogen-activated (MAPK) protein kinases. They form a network of signal transduction cascades that mediate cellular responses to a diverse range of stimuli, including growth factors, chemical or osmotic stress, irradiation, bacterial infection and proinflammatory cytokines. Most MAPKs are activated by dual phosphorylation on a Thr-Xaa-Tyr motif by upstream kinases, referred to as MAPK kinases or MKKs. MKKs are, in turn, activated by MKK kinases (MKKKs), over 30 of which have been described. However, the details of how they are activated or which MKKK really activates which MKK in vivo is still poorly understood. MAPK cascades frequently function as multi-protein complexes in which the different components are assembled on a scaffold protein and/or by specific protein-protein docking sites, thereby increasing the speed and specificity of the cascade. Nearly all MAPKs phosphorylate their substrates on serine or threonine residues that precede a proline, but their specificity in vivo is further enhanced by the presence of distinct docking sites that facilitate interaction with substrates.

Fourteen different MAPK family members have been identified in mammalian cells, and homologs are found in all eukaryotic cells. The most studied cascades in mammalian cells are the classical MAPK, p38 (SAPK2) and JNK (SAPK1) cascades. The classical MAPK cascade is activated by mitogens and growth factors, and plays an important role in the control of cell growth and differentiation. However, its inappropriate activation can be a major cause of cell transformation and cancer. It comprises two closely related MAPKs, termed extracellular signal regulated kinase 1 (ERK1) and ERK2. These kinases have many overlapping functions, but mouse knockouts have now revealed that they also have some distinct functions in vivo. Inhibitors which block the activation of MKK1/2 in cells, such as PD 98059, U0126 and PD 184352 and have been used extensively to investigate the functions of the classical MAPK cascade. Moreover, PD 184352 has been shown to strongly suppress the growth of human colon tumors implanted into mice. These three inhibitors were originally thought to be specific for the classical MAPK pathway, but are now known to also block the activation of MKK5, the activator of a distinct MAPK family member ERK5. ERK5 is activated by mitogens and has been suggested to be important for EGF-induced cell proliferation. Mouse knockouts have shown that ERK5 is required for embryonic development and endothelial cell survival.

The JNK cascade is activated by cellular stress, bacterial infection and proinflammatory cytokines, and results in the phosphorylation of AP1 transcription factors, such as c-Jun. There are three related isoforms of JNK each of which gives rise to several splice variants generating a total of ten different JNK variants. Mouse knockouts have shown that JNK1, 2 and 3 have distinct in vivo roles. The p38 cascade is activated by similar stimuli to JNK. Two of the p38 isoforms, α and β are inhibited by a class of anti-inflammatory drugs of which SB-203580 and SB-202190 are examples. These inhibitors have been used to identify many physiological substrates and to implicate the p38 isoforms in diverse cellular processes, including cytokine production and inflammatory responses. More potent p38 inhibitors are currently in clinical trials for the treatment of arthritis. Mouse knockouts have shown p38α is also essential for normal development. Less is known about the other p38 isoforms, γ and δ. P38γ is highly expressed in skeletal muscle, and has been shown to bind to, and co-localize with, α1-syntrophin by virtue of the interaction of its C-terminus with the PDZ domain of α1-syntrophin. P38δ appears to be expressed at low levels in most tissues and little is yet known about its function.

NLK (NEMO like kinase) has been extensively studied in development and can phosphorylate Tcf/Lef proteins and inhibit the DNA-binding ability of β-catenin/Tcf complexes, thereby blocking activation of Wnt targets.

ERK3 and ERK4 and ERK8 are more recently described MAPKs, whose functions are not yet understood. ERK8 appears to be constitutively phosphorylated on its Thr-Xaa-Tyr motif, however its substrates and activators are unknown. ERK3 is unusual in that the Thr-Xaa-Tyr phosphorylation motif is replaced by Ser-Xaa-Glu, and it appears to be rapidly turned over via the proteosome. ERK3 is also implicated in the activation of PRAK.

 

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

 

Family Members MAPK
(M3172, M9426)
JNK p38α/β
p38γ/δ
Other Names p42/44 MAPK SAPK1 SAPK2 SAPK3
SAPK4
Molecular Weight
(kDa)
42 – 44 kDa 48 – 52 kDa 41 kDa 43 kDa
Isoforms ERK1
ERK2 (M3172, M9426)
JNK1
JNK2
JNK3
p38α
p38β
p38γ
p38δ
Species Eukaryotes C. elegans
Drosophila vertebrates
Eukaryotes Vertebrates
Domain
Organization
1 kinase domain 1 kinase domain 1 kinase domain 1 kinase domain
Phosphorylation
Sites
ERK1: Thr202, Tyr204
ERK2: Thr185, Tyr187
JNK1a: Thr183, Tyr185
JNK2a: Thr183, Tyr185
JNK3a: Thr221, Tyr223
Thr180
Tyr182
p38γ: Thr184, Tyr186
p38δ: Thr180, Tyr18
Tissue
Distribution
Ubiquitous Ubiquitous
SAPK1b: brain, heart and testis
Ubiquitous Low expression in most tissues
p38γ high in skeletal muscle
p38δ highest in adrenal, pituitary
Subcellular
Localization
Cytosolic
Nuclear
Cytosolic
Nuclear
Cytosolic
Nuclear
Cytosolic
Binding Partners/
Associated Proteins
KSR
MP1
β-arrestin
JIP Not Known Not Known
Upstream
Activators
MKK1
MKK2
MKK4
MKK7
MKK3
MKK6 (M5814)
MKK6 (M5814)
Downstream
Activation
MAPKAP-K1
MNK
MSK
MBP (M1891, M2295)
c-Jun (C5859)
ATF2
MAPKAP-K2/3
PRAK (P0240)
MNK
MSK
MBP (M1891M2016M2295)
MBP (M1891M2295)
Activators Mitogens
Cytokines
Cellular stress
Cytokines
Some mitogens
Cellular stress
Cytokines
Cellular stress
Inhibitors PD 98059 (P215)*
U0126 (U120)*
PD 184352 (PZ0181)*
TAT-JBD peptide SB-203580 (S8307)
SB-202190 (S7067)
BIRB8796
Not Known
Selective
Activators
Not Known Not Known Not Known Not Known
Physiological
Function
Immune function
Neuronal signaling
Differentiation
Cell survival
Immune function
Differentiation
Apoptosis
Immune function
Differentiation
Apoptosis
Not Known
Disease
Relevance
Cancer Inflammation Inflammation Not Known

 

 

Family Members ERK3 ERK5 ERK8/ ERK7 NLK
Other Names   BMK    
Molecular Weight
(kDa)
83 kDa 89 kDa 60 kDa 57 kDa
Isoforms ERK3
ERK3 related
Not Known Not Known Not Known
Species Vertebrates Vertebrates
Possible homologs in yeast
Possible homologs in C. elegans
Vertebrates C. elegans
Drosophila
Vertebrates
Domain
Organization
1 kinase domain 1 kinase domain 1 kinase domain 1 kinase domain
Phosphorylation
Sites
Ser189 Thr219
Tyr221
Not Known Not Known
Tissue
Distribution
Ubiquitous Ubiquitous Low expression in most tissues
High levels in testis
Placenta
Uterus
Subcellular
Localization
Nuclear Cytosolic
Nuclear
Cytosolic
Nuclear
Nuclear
Binding Partners/
Associated Proteins
Not Known Not Known Not Known Not Known
Upstream
Activators
Not Known MKK5 Not Known HIPK2
Downstream
Activation
Not Known MBP (M1891, M2295) MBP (M1891M2295) Lef1
c-Myb
Activators Not Known EGF (E4127, E9644)
Oxidative and osmotic stress
Not Known wnt
TGFβ (T7039T2815)
Inhibitors Not Known PD 98059 (P215)*
U0126 (U120)*
PD 184352 (PZ0181)*
Not Known Not Known
Selective
Activators
Not Known Not Known Not Known Not Known
Physiological
Function
Not Known Required for endothelial cell survival Not Known Embryogenesis
Mesoderm formation
Disease
Relevance
Not Known Cancer Not Known Not Known

 

Footnotes

* Inhibits upstream activator

 

Abbreviations

ERK: Extracellular signal-related kinase
JNK: c-Jun NH(2)-terminal protein kinase
MAPKAP: MAPK-activated protein
MBP: Myelin basic protein
MNK: MAPK-integrating kinase
MSK: Mitogen and stress activated protein kinase
PD 98059: 2-(2-Amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
PD 184352: 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
PRAK: p38-Regulated activated kinase
RSK: Ribosomal S6 kinase
SAPK: Stress activated protein kinase
SB-203580: 4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole
SB-202190: 4-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole
U0126: 1,4-Diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)butadien

 

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References