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Pathway Description
MAPK/p38
Homo sapiens
Category:
Metabolite Pathway
Sub-Category:
Signaling
Created: 2025-05-12
Last Updated: 2025-10-02
p38 kinases have been implicated to be involved in the cellular response to stress. They are proline-directed serine/threonine kinases of the mitogen-activated protein kinase (MAPK) family. This family is found in all eukaryotes for their roles in structure and regulation. The activation of p38 occurs through the dual phosphorylation of a region on the activation loop. This opening of the conformation allows for substrate recognition that makes the kinase highly active. They are activated by the MAPKK’s MKK3/MKK6 and MKK4, which are activated by MAPKKK’s.
References
MAPK/p38 References
Harrison, J. C., Zyla, T. R., Bardes, E. S. G., & Lew, D. J. (2004). Stress-specific activation mechanisms for the “cell integrity” MAPK pathway. Journal of Biological Chemistry, 279(4), 2616–2622. https://doi.org/10.1074/jbc.M306110200
Canovas, B., Nebreda, A.R. Diversity and versatility of p38 kinase signalling in health and disease. Nat Rev Mol Cell Biol 22, 346–366 (2021). https://doi.org/10.1038/s41580-020-00322-w
Martínez-Limón, A., Joaquin, M., Caballero, M., Posas, F., & de Nadal, E. (2020). The p38 Pathway: From Biology to Cancer Therapy. International journal of molecular sciences, 21(6), 1913. https://doi.org/10.3390/ijms21061913
Pearlman A, Loke J, Le Caignec C, White S, Chin L, Friedman A, Warr N, Willan J, Brauer D, Farmer C, Brooks E, Oddoux C, Riley B, Shajahan S, Camerino G, Homfray T, Crosby AH, Couper J, David A, Greenfield A, Sinclair A, Ostrer H: Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction pathway in human testis determination. Am J Hum Genet. 2010 Dec 10;87(6):898-904. doi: 10.1016/j.ajhg.2010.11.003.
Pubmed: 21129722
Schmutz J, Martin J, Terry A, Couronne O, Grimwood J, Lowry S, Gordon LA, Scott D, Xie G, Huang W, Hellsten U, Tran-Gyamfi M, She X, Prabhakar S, Aerts A, Altherr M, Bajorek E, Black S, Branscomb E, Caoile C, Challacombe JF, Chan YM, Denys M, Detter JC, Escobar J, Flowers D, Fotopulos D, Glavina T, Gomez M, Gonzales E, Goodstein D, Grigoriev I, Groza M, Hammon N, Hawkins T, Haydu L, Israni S, Jett J, Kadner K, Kimball H, Kobayashi A, Lopez F, Lou Y, Martinez D, Medina C, Morgan J, Nandkeshwar R, Noonan JP, Pitluck S, Pollard M, Predki P, Priest J, Ramirez L, Retterer J, Rodriguez A, Rogers S, Salamov A, Salazar A, Thayer N, Tice H, Tsai M, Ustaszewska A, Vo N, Wheeler J, Wu K, Yang J, Dickson M, Cheng JF, Eichler EE, Olsen A, Pennacchio LA, Rokhsar DS, Richardson P, Lucas SM, Myers RM, Rubin EM: The DNA sequence and comparative analysis of human chromosome 5. Nature. 2004 Sep 16;431(7006):268-74. doi: 10.1038/nature02919.
Pubmed: 15372022
Xia Y, Wu Z, Su B, Murray B, Karin M: JNKK1 organizes a MAP kinase module through specific and sequential interactions with upstream and downstream components mediated by its amino-terminal extension. Genes Dev. 1998 Nov 1;12(21):3369-81. doi: 10.1101/gad.12.21.3369.
Pubmed: 9808624
Derijard B, Raingeaud J, Barrett T, Wu IH, Han J, Ulevitch RJ, Davis RJ: Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science. 1995 Feb 3;267(5198):682-5. doi: 10.1126/science.7839144.
Pubmed: 7839144
Lin A, Minden A, Martinetto H, Claret FX, Lange-Carter C, Mercurio F, Johnson GL, Karin M: Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. Science. 1995 Apr 14;268(5208):286-90. doi: 10.1126/science.7716521.
Pubmed: 7716521
Su GH, Hilgers W, Shekher MC, Tang DJ, Yeo CJ, Hruban RH, Kern SE: Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene. Cancer Res. 1998 Jun 1;58(11):2339-42.
Pubmed: 9622070
Dorow DS, Devereux L, Tu GF, Price G, Nicholl JK, Sutherland GR, Simpson RJ: Complete nucleotide sequence, expression, and chromosomal localisation of human mixed-lineage kinase 2. Eur J Biochem. 1995 Dec 1;234(2):492-500. doi: 10.1111/j.1432-1033.1995.492_b.x.
Pubmed: 8536694
Katoh M, Hirai M, Sugimura T, Terada M: Cloning and characterization of MST, a novel (putative) serine/threonine kinase with SH3 domain. Oncogene. 1995 Apr 6;10(7):1447-51.
Pubmed: 7731697
Dorow DS, Devereux L, Dietzsch E, De Kretser T: Identification of a new family of human epithelial protein kinases containing two leucine/isoleucine-zipper domains. Eur J Biochem. 1993 Apr 15;213(2):701-10. doi: 10.1111/j.1432-1033.1993.tb17810.x.
Pubmed: 8477742
Gallo KA, Mark MR, Scadden DT, Wang Z, Gu Q, Godowski PJ: Identification and characterization of SPRK, a novel src-homology 3 domain-containing proline-rich kinase with serine/threonine kinase activity. J Biol Chem. 1994 May 27;269(21):15092-100.
Pubmed: 8195146
Ing YL, Leung IW, Heng HH, Tsui LC, Lassam NJ: MLK-3: identification of a widely-expressed protein kinase bearing an SH3 domain and a leucine zipper-basic region domain. Oncogene. 1994 Jun;9(6):1745-50.
Pubmed: 8183572
Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. doi: 10.1038/ng1285. Epub 2003 Dec 21.
Pubmed: 14702039
Wang XS, Diener K, Jannuzzi D, Trollinger D, Tan TH, Lichenstein H, Zukowski M, Yao Z: Molecular cloning and characterization of a novel protein kinase with a catalytic domain homologous to mitogen-activated protein kinase kinase kinase. J Biol Chem. 1996 Dec 6;271(49):31607-11. doi: 10.1074/jbc.271.49.31607.
Pubmed: 8940179
Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K, Gotoh Y: Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science. 1997 Jan 3;275(5296):90-4. doi: 10.1126/science.275.5296.90.
Pubmed: 8974401
Sakurai H, Shigemori N, Hasegawa K, Sugita T: TGF-beta-activated kinase 1 stimulates NF-kappa B activation by an NF-kappa B-inducing kinase-independent mechanism. Biochem Biophys Res Commun. 1998 Feb 13;243(2):545-9. doi: 10.1006/bbrc.1998.8124.
Pubmed: 9480845
Dempsey CE, Sakurai H, Sugita T, Guesdon F: Alternative splicing and gene structure of the transforming growth factor beta-activated kinase 1. Biochim Biophys Acta. 2000 Dec 15;1517(1):46-52. doi: 10.1016/s0167-4781(00)00258-x.
Pubmed: 11118615
Moriguchi T, Toyoshima F, Gotoh Y, Iwamatsu A, Irie K, Mori E, Kuroyanagi N, Hagiwara M, Matsumoto K, Nishida E: Purification and identification of a major activator for p38 from osmotically shocked cells. Activation of mitogen-activated protein kinase kinase 6 by osmotic shock, tumor necrosis factor-alpha, and H2O2. J Biol Chem. 1996 Oct 25;271(43):26981-8. doi: 10.1074/jbc.271.43.26981.
Pubmed: 8900184
Raingeaud J, Whitmarsh AJ, Barrett T, Derijard B, Davis RJ: MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Mol Cell Biol. 1996 Mar;16(3):1247-55. doi: 10.1128/mcb.16.3.1247.
Pubmed: 8622669
Stein B, Brady H, Yang MX, Young DB, Barbosa MS: Cloning and characterization of MEK6, a novel member of the mitogen-activated protein kinase kinase cascade. J Biol Chem. 1996 May 10;271(19):11427-33. doi: 10.1074/jbc.271.19.11427.
Pubmed: 8626699
Han J, Lee JD, Jiang Y, Li Z, Feng L, Ulevitch RJ: Characterization of the structure and function of a novel MAP kinase kinase (MKK6). J Biol Chem. 1996 Feb 9;271(6):2886-91. doi: 10.1074/jbc.271.6.2886.
Pubmed: 8621675
Lechner C, Zahalka MA, Giot JF, Moller NP, Ullrich A: ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation. Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4355-9. doi: 10.1073/pnas.93.9.4355.
Pubmed: 8633070
Goedert M, Hasegawa J, Craxton M, Leversha MA, Clegg S: Assignment of the human stress-activated protein kinase-3 gene (SAPK3) to chromosome 22q13.3 by fluorescence in situ hybridization. Genomics. 1997 May 1;41(3):501-2. doi: 10.1006/geno.1997.4633.
Pubmed: 9169156
Li Z, Jiang Y, Ulevitch RJ, Han J: The primary structure of p38 gamma: a new member of p38 group of MAP kinases. Biochem Biophys Res Commun. 1996 Nov 12;228(2):334-40. doi: 10.1006/bbrc.1996.1662.
Pubmed: 8920915
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