Mitogen-activated Protein Kinases (MAPKs) Overview

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 "Materials" 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 (M1891, M2016, M2295)	MBP (M1891, M2295)
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 (M1891, M2295)	Lef1 c-Myb
Activators	Not Known	EGF (E4127, E9644) Oxidative and osmotic stress	Not Known	wnt TGFβ (T7039, T2815)
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

Materials

Sorry, an unexpected error has occurred

Network error: Failed to fetch

References

1. Abe MK, Kuo W, Hershenson MB, Rosner MR. 1999. Extracellular Signal-Regulated Kinase 7 (ERK7), a Novel ERK with a C-Terminal Domain That Regulates Its Activity, Its Cellular Localization, and Cell Growth. Mol. Cell. Biol.. 19(2):1301-1312. https://doi.org/10.1128/mcb.19.2.1301

2. Cargnello M, Roux PP. 2011. Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases. Microbiology and Molecular Biology Reviews. 75(1):50-83. https://doi.org/10.1128/mmbr.00031-10

3. Robinson MJ, Cobb MH. 1997. Mitogen-activated protein kinase pathways. Current Opinion in Cell Biology. 9(2):180-186. https://doi.org/10.1016/s0955-0674(97)80061-0

4. COHEN P. 1997. The search for physiological substrates of MAP and SAP kinases in mammalian cells. Trends in Cell Biology. 7(9):353-361. https://doi.org/10.1016/s0962-8924(97)01105-7

5. Davis RJ. 2000. Signal Transduction by the JNK Group of MAP Kinases. Cell. 103(2):239-252. https://doi.org/10.1016/s0092-8674(00)00116-1

6. DAVIES SP, REDDY H, CAIVANO M, COHEN P. 2000. Specificity and mechanism of action of some commonly used protein kinase inhibitors. 351(1):95-105. https://doi.org/10.1042/bj3510095

7. del Barco Barrantes I, Nebreda A. 2012. Roles of p38 MAPKs in invasion and metastasis. 40(1):79-84. https://doi.org/10.1042/bst20110676

8. Haagenson KK, Wu GS. 2010. The role of MAP kinases and MAP kinase phosphatase-1 in resistance to breast cancer treatment. Cancer Metastasis Rev. 29(1):143-149. https://doi.org/10.1007/s10555-010-9208-5

9. Ichijo H. 1999. From receptors to stress-activated MAP kinases. Oncogene. 18(45):6087-6093. https://doi.org/10.1038/sj.onc.1203129

10. Kato Y, Chao T, Hayashi M. 2000. Role of BMK1 in regulation of growth factor-induced cellular responses.. Immunol Res. 21, 233–237.

11. Kim EK, Choi E. 2010. Pathological roles of MAPK signaling pathways in human diseases. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1802(4):396-405. https://doi.org/10.1016/j.bbadis.2009.12.009

12. Liu Y, Shepherd EG, Nelin LD. 2007. MAPK phosphatases ? regulating the immune response. Nat Rev Immunol. 7(3):202-212. https://doi.org/10.1038/nri2035

13. Ono K, Han J. 2000. The p38 signal transduction pathway Activation and function. Cellular Signalling. 12(1):1-13. https://doi.org/10.1016/s0898-6568(99)00071-6

14. J. Schnieders M, S. Kaoud T, Yan C, N. Dalby K, Ren P. 2012. Computational Insights for the Discovery of Non-ATP Competitive Inhibitors of MAP Kinases. curr drug metab. 18(9):1173-1185. https://doi.org/10.2174/138920012799362873

15. Seger R, Krebs EG. 1995. The MAPK signaling cascade. FASEB j.. 9(9):726-735. https://doi.org/10.1096/fasebj.9.9.7601337

16. Tanoue T, Nishida E. 2003. Molecular recognitions in the MAP kinase cascades. Cellular Signalling. 15(5):455-462. https://doi.org/10.1016/s0898-6568(02)00112-2

17. Tanoue T, Adachi M, Moriguchi T, Nishida E. 2000. A conserved docking motif in MAP kinases common to substrates, activators and regulators. Nat Cell Biol. 2(2):110-116. https://doi.org/10.1038/35000065

18. Tibbles LA, Woodgett JR. 1999. The stress-activated protein kinase pathways. Cellular and Molecular Life Sciences (CMLS). 55(10):1230-1254. https://doi.org/10.1007/s000180050369