[Skip to Content](https://www.sigmaaldrich.com#main-content) [](https://www.sigmaaldrich.com/US/en) Products Cart0 USEN Products ProductsApplicationsServicesResourcesSupport [Login / Register](https://www.sigmaaldrich.com/oidc-sign-in) [Order Lookup](https://www.sigmaaldrich.com/US/en/order-lookup) [Quick Order](https://www.sigmaaldrich.com/US/en/quick-order) Cart0 [Home](https://www.sigmaaldrich.com/US/en)[Protein Expression](https://www.sigmaaldrich.com/US/en/applications/protein-biology/protein-expression)Mitogen-activated Protein Kinases (MAPKs) # 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)JNKp38α/β p38γ/δ __Other Names__p42/44 MAPKSAPK1SAPK2SAPK3 SAPK4 __Molecular Weight__ __(kDa)__42 – 44 kDa48 – 52 kDa41 kDa43 kDa __Isoforms__ERK1 ERK2 ([M3172](https://www.sigmaaldrich.com/US/en/product/sigma/M3172), [M9426](https://www.sigmaaldrich.com/US/en/product/sigma/M9426))JNK1 JNK2 JNK3p38α p38βp38γ p38δ __Species__Eukaryotes*C. elegans* *Drosophila* vertebratesEukaryotesVertebrates __Domain__ __Organization__1 kinase domain1 kinase domain1 kinase domain1 kinase domain __Phosphorylation__ __Sites__ERK1: Thr202, Tyr204 ERK2: Thr185, Tyr187JNK1a: Thr183, Tyr185 JNK2a: Thr183, Tyr185 JNK3a: Thr221, Tyr223Thr180 Tyr182p38γ: Thr184, Tyr186 p38δ: Thr180, Tyr18 __Tissue__ __Distribution__UbiquitousUbiquitous SAPK1b: brain, heart and testisUbiquitousLow expression in most tissues p38γ high in skeletal muscle p38δ highest in adrenal, pituitary __Subcellular__ __Localization__Cytosolic NuclearCytosolic NuclearCytosolic NuclearCytosolic __Binding Partners/__ __Associated Proteins__KSR MP1 β-arrestinJIPNot KnownNot Known __Upstream__ __Activators__MKK1 MKK2MKK4 MKK7MKK3 MKK6 ([M5814](https://www.sigmaaldrich.com/US/en/product/sigma/M5814))MKK6 ([M5814](https://www.sigmaaldrich.com/US/en/product/sigma/M5814)) __Downstream__ __Activation__MAPKAP-K1 MNK MSK MBP ([M1891](https://www.sigmaaldrich.com/US/en/product/sigma/M1891), [M2295](https://www.sigmaaldrich.com/US/en/product/sigma/M2295))c-Jun ([C5859](https://www.sigmaaldrich.com/US/en/product/sigma/C5859)) ATF2MAPKAP-K2/3 PRAK ([P0240](https://www.sigmaaldrich.com/US/en/product/sigma/P0240)) MNK MSK MBP ([M1891](https://www.sigmaaldrich.com/US/en/product/sigma/M1891), M2016, [M2295](https://www.sigmaaldrich.com/US/en/product/sigma/M2295)) MBP ([M1891](https://www.sigmaaldrich.com/US/en/product/sigma/M1891), [M2295](https://www.sigmaaldrich.com/US/en/product/sigma/M2295)) __Activators__Mitogens CytokinesCellular stress Cytokines Some mitogensCellular stress CytokinesCellular stress __Inhibitors__PD 98059 ([P215](https://www.sigmaaldrich.com/US/en/product/sigma/P215))* U0126 ([U120](https://www.sigmaaldrich.com/US/en/product/sigma/U120))* PD 184352 ([PZ0181](https://www.sigmaaldrich.com/US/en/product/sigma/PZ0181))\*TAT-JBD peptideSB-203580 ([S8307](https://www.sigmaaldrich.com/US/en/product/sigma/S8307)) SB-202190 ([S7067](https://www.sigmaaldrich.com/US/en/product/sigma/S7067)) BIRB8796Not Known __Selective__ __Activators__Not KnownNot KnownNot KnownNot Known __Physiological__ __Function__Immune function Neuronal signaling Differentiation Cell survivalImmune function Differentiation ApoptosisImmune function Differentiation ApoptosisNot Known __Disease__ __Relevance__CancerInflammationInflammationNot Known __Family Members__ERK3ERK5ERK8/ ERK7NLK __Other Names__ BMK   __Molecular Weight__ __(kDa)__83 kDa89 kDa60 kDa57 kDa __Isoforms__ERK3 ERK3 relatedNot KnownNot KnownNot Known __Species__VertebratesVertebrates Possible homologs in yeast Possible homologs in *C. elegans* Vertebrates*C. elegans* *Drosophila* Vertebrates __Domain__ __Organization__1 kinase domain1 kinase domain1 kinase domain1 kinase domain __Phosphorylation__ __Sites__Ser189Thr219 Tyr221Not KnownNot Known __Tissue__ __Distribution__UbiquitousUbiquitousLow expression in most tissues High levels in testisPlacenta Uterus __Subcellular__ __Localization__NuclearCytosolic NuclearCytosolic NuclearNuclear __Binding Partners/__ __Associated Proteins__Not KnownNot KnownNot KnownNot Known __Upstream__ __Activators__Not KnownMKK5Not KnownHIPK2 __Downstream__ __Activation__Not KnownMBP ([M1891](https://www.sigmaaldrich.com/US/en/product/sigma/M1891), [M2295](https://www.sigmaaldrich.com/US/en/product/sigma/M2295))MBP ([M1891](https://www.sigmaaldrich.com/US/en/product/sigma/M1891), [M2295](https://www.sigmaaldrich.com/US/en/product/sigma/M2295))Lef1 c-Myb __Activators__Not KnownEGF ([E4127](https://www.sigmaaldrich.com/US/en/product/sigma/E4127), [E9644](https://www.sigmaaldrich.com/US/en/product/sigma/e9644)) Oxidative and osmotic stressNot Knownwnt TGFβ ([T7039](https://www.sigmaaldrich.com/US/en/product/sigma/T7039), [T2815](https://www.sigmaaldrich.com/US/en/product/sigma/T2815)[](https://www.sigmaaldrich.com/ProductLookup.html?ProdNo=T2926&Brand=SIGMA)) __Inhibitors__Not KnownPD 98059 ([P215](https://www.sigmaaldrich.com/US/en/product/sigma/P215))* U0126 ([U120](https://www.sigmaaldrich.com/US/en/product/sigma/U120))* PD 184352 ([PZ0181](https://www.sigmaaldrich.com/US/en/product/sigma/PZ0181))* Not KnownNot Known __Selective__ __Activators__Not KnownNot KnownNot KnownNot Known __Physiological__ __Function__Not KnownRequired for endothelial cell survivalNot KnownEmbryogenesis Mesoderm formation __Disease__ __Relevance__Not KnownCancerNot KnownNot 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 Response not successful: Received status code 500 ### 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](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](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](https://doi.org/10.1016/s0955-0674%2897%2980061-0) 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](https://doi.org/10.1016/s0962-8924%2897%2901105-7) 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](https://doi.org/10.1016/s0092-8674%2800%2900116-1) 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](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](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](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](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](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](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](https://doi.org/10.1016/s0898-6568%2899%2900071-6) 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](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](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](https://doi.org/10.1016/s0898-6568%2802%2900112-2) 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](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. 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