Crystal Structure of the P38α-MAPKAP Kinase 2 Heterodimer
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The p38 signaling pathway is activated in response to cell stress and induces production of proinflammatory cytokines. P38alpha is phosphorylated and activated in response to cell stress by MKK3 and MKK6 and in turn phosphorylates a number of substrates, including MAPKAP kinase 2 (MK2). We have determined the crystal structure of the unphosphorylated p38alpha-MK2 heterodimer. The C-terminal regulatory domain of MK2 binds in the docking groove of p38alpha, and the ATP-binding sites of both kinases are at the heterodimer interface. The conformation suggests an extra mechanism in addition to the regulation of the p38alpha and MK2 phosphorylation states that prevents phosphorylation of substrates in the absence of cell stress. Addition of constitutively active MKK6-DD results in rapid phosphorylation of the p38alpha-MK2 heterodimer.
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p38 is capable of binding KIM peptides bi-directionally, in a C-to-N versus the more common N-to-C direction.
“In addition, while the structure of p38 bound to its substrate, the MAPKAP-2 (MK2) kinase was the first structure to show that p38 is capable of binding KIM peptides bi-directionally 54,55 (that is, in a C-to-N, versus the more common N-to-C direction; Figs.2(A,B))”
From Molecular basis of MAP kinase regulation (2013) · cites this paper as [54]
ERK2-pepRSK1 and ERK2-pepMNK1 peptides bound in a reversed N- to C-terminal orientation compared with D-motif peptides, similar to pepMK2 binding to p38α.
“These peptides bound in a reversed N- to C-terminal orientation compared to D-motif peptides (Fig. 3B-D), similar to the binding of pepMK2 to p38α (31).”
From Specificity of Linear Motifs That Bind to a Common Mitogen-Activated Protein Kinase Docking Groove (2012) · cites this paper as [31]
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A protein kinase involved in the regulation of inflammatory cytokine biosynthesis
Lee, J. C., Laydon, J. T., McDonnell, P., Gallagher, T. F., Kumar, S., Green, D., McNulty, D. E., Blumenthal, M. J., Keys, J., vatter, S. W. L., et al. (1994) · Nature · doi:10.1038/372739a0 · Cited by 3,266 · see citing works
Cuenda, A., Rouse, J., Doza, Y. N., Meier, R., Cohen, P., Gallagher, T. F., Young, P. R., & Lee, J. C. (1995) · FEBS Letters · doi:10.1016/0014-5793(95)00357-f · Cited by 2,086 · see citing works
p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases
Kumar, S., Boehm, J. C., & Lee, J. C. (2003) · Nature Reviews Drug Discovery · doi:10.1038/nrd1177 · Cited by 1,199 · see citing works
A conserved docking motif in MAP kinases common to substrates, activators and regulators
Tanoue, T., Adachi, M., Moriguchi, T., & Nishida, E. (2000) · Nature Cell Biology · doi:10.1038/35000065 · Cited by 816 · see citing works
Winzen, R., Kracht, M., Ritter, B., Wilhelm, A., Chen, C. A., Shyu, A., Müller, M., Gaestel, M., Resch, K., & Holtmann, H. (1999) · The EMBO Journal · doi:10.1093/emboj/18.18.4969 · Cited by 770 · see citing works
Refinement of severely incomplete structures with maximum likelihood inBUSTER–TNT
Blanc, E., Roversi, P., Vonrhein, C., Flensburg, C., Lea, S. M., & Bricogne, G. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904016427 · Cited by 719 · see citing works
An approach to multi-copy search in molecular replacement
Vagin, A. A., & Teplyakov, A. (2000) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444900013780 · Cited by 702 · see citing works
FGF and stress regulate CREB and ATF‐1 via a pathway involving p38 MAP kinase and MAPKAP kinase‐2.
Tan, Y., Rouse, J. W., Zhang, A., Cariati, S., Cohen, P., & Comb, M. J. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00840.x · Cited by 634 · see citing works
Stokoe, D., Engel, K., Campbell, D. G., Cohen, P., & Gaestel, M. (1992) · FEBS Letters · doi:10.1016/0014-5793(92)81216-9 · Cited by 569 · see citing works
Kumar, S., McDonnell, P., Gum, R. J., Hand, A. T., Lee, J. C., & Young, P. R. (1997) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.6849 · Cited by 507 · see citing works
MAPKAP kinase‐2; a novel protein kinase activated by mitogen‐activated protein kinase.
Stokoe, D., Campbell, D. G., Nakielny, S., Hidaka, H., Leevers, S. J., Marshall, C. J., & Cohen, P. T. W. (1992) · The EMBO Journal · doi:10.1002/j.1460-2075.1992.tb05492.x · Cited by 467 · see citing works
Lasa, M., Mahtani, K. R., Finch, A. J., Brewer, G., Saklatvala, J., & Clark, A. R. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.12.4265-4274.2000 · Cited by 413 · see citing works
The p38 MAP kinase pathway as a therapeutic target in inflammatory disease
Saklatvala, J. (2004) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2004.03.009 · Cited by 408 · see citing works
Cuenda, A., Cohen, P., Buée‐Scherrer, V., & Goedert, M. (1997) · The EMBO Journal · doi:10.1093/emboj/16.2.295 · Cited by 362 · see citing works
Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2
Ben-Levy, R., Hooper, S., Wilson, R., Paterson, H. F., & Marshall, C. J. (1998) · Current Biology · doi:10.1016/s0960-9822(98)70442-7 · Cited by 338 · see citing works
Molecular recognitions in the MAP kinase cascades
Tanoue, T., & Nishida, E. (2003) · Cellular Signalling · doi:10.1016/s0898-6568(02)00112-2 · Cited by 318 · see citing works
Chang, C.-I., Xu, B.-E., Akella, R., Cobb, M. H., & Goldsmith, E. J. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00525-7 · Cited by 302 · see citing works
Protein phosphatase 2Cα inhibits the human stress‐responsive p38 and JNK MAPK pathways
Takekawa, M., Maeda, T., & Saito, H. (1998) · The EMBO Journal · doi:10.1093/emboj/17.16.4744 · Cited by 286 · see citing works
Tanoue, T., Maeda, R., Adachi, M., & Nishida, E. (2001) · The EMBO Journal · doi:10.1093/emboj/20.3.466 · Cited by 285 · see citing works
Leptomycin B‐sensitive nuclear export of MAPKAP kinase 2 is regulated by phosphorylation
Engel, K., Kotlyarov, A., & Gaestel, M. (1998) · The EMBO Journal · doi:10.1093/emboj/17.12.3363 · Cited by 267 · see citing works
Crystal Structure of p38 Mitogen-activated Protein Kinase
Wilson, K. P., Fitzgibbon, M. J., Caron, P. R., Griffith, J. P., Chen, W., McCaffrey, P. G., Chambers, S. P., & Su, M. S. S. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.44.27696 · Cited by 262 · see citing works
Distinct Cellular Functions of MK2
Kotlyarov, A., Yannoni, Y. M., Fritz, S., Laaß, K., Telliez, J., Pitman, D., Lin, L., & Gaestel, M. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.13.4827-4835.2002 · Cited by 230 · see citing works
Stokoe, D., Caudwell, B., Cohen, P., & Cohen, P. T. W. (1993) · Biochemical Journal · doi:10.1042/bj2960843 · Cited by 190 · see citing works
Fantz, D. A., Jacobs, D., Glossip, D., & Kornfeld, K. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m102512200 · Cited by 183 · see citing works
Bardwell, A. J., Flatauer, L. J., Matsukuma, K. E., Thorner, J. W., & Bardwell, L. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m010271200 · Cited by 177 · see citing works
A Novel MAPK Phosphatase MKP-7 Acts Preferentially on JNK/SAPK and p38α and β MAPKs
Tanoue, T., Yamamoto, T., Maeda, R., & Nishida, E. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m101981200 · Cited by 165 · see citing works
Huang, C., Zhan, L., Ai, Y., & Jongstra, J. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.1.17 · Cited by 161 · see citing works
In the Cellular Garden of Forking Paths: How p38 MAPKs Signal for Downstream Assistance
Shi, Y., & Gaestel, M. (2002) · Biological Chemistry · doi:10.1515/bc.2002.173 · Cited by 154 · see citing works
Docking interactions in the mitogen-activated protein kinase cascades
Tanoue, T., & Nishida, E. (2002) · Pharmacology & Therapeutics · doi:10.1016/s0163-7258(02)00188-2 · Cited by 134 · see citing works
Meng, W., Swenson, L. L., Fitzgibbon, M. J., Hayakawa, K., ter Haar, E., Behrens, A. E., Fulghum, J. R., & Lippke, J. A. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.c200418200 · Cited by 128 · see citing works
Self-citationInhibitors of Protein Kinase Signaling Pathways
Force, T. L., Kuida, K., Namchuk, M., Parang, K., & Kyriakis, J. M. (2004) · Circulation · doi:10.1161/01.cir.0000118538.21306.a9 · Cited by 128 · see citing works
Ho, D. T., Bardwell, A. J., Abdollahi, M., & Bardwell, L. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m304229200 · Cited by 108 · see citing works
BARDWELL, A. J., ABDOLLAHI, M., & BARDWELL, L. (2003) · Biochemical Journal · doi:10.1042/bj20021806 · Cited by 97 · see citing works
Inhibitors of p38 MAP Kinase: Therapeutic Intervention in Cytokine-Mediated Diseases
Salituro, F. G., Germann, U. A., Wilson, K. P., Bemis, G. W., Fox, T., & Su, M. S. S. (1999) · Current Medicinal Chemistry · doi:10.2174/092986730609220401150415 · Cited by 87 · see citing works
Modular Structure of a Docking Surface on MAPK Phosphatases
Tanoue, T., Yamamoto, T., & Nishida, E. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m202096200 · Cited by 78 · see citing works
Underwood, K. W., Parris, K. D., Federico, E., Mosyak, L., Czerwinski, R. M., Shane, T., Taylor, M., Svenson, K., Liu, Y., Hsiao, C.-L., et al. (2003) · Structure · doi:10.1016/s0969-2126(03)00092-3 · Cited by 62 · see citing works
FRET‐based detection of different conformations of MK2
Neininger, A., Thielemann, H., & Gaestel, M. (2001) · EMBO Reports · doi:10.1093/embo-reports/kve157 · Cited by 60 · see citing works
The Primary Structure of a Human Map Kinase Activated Protein Kinase 2
Zu, Y., Wu, F. Y., Gilchrist, A., Ai, Y. X., Labadia, M. E., & Huang, C. (1994) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1994.1566 · Cited by 58 · see citing works
Catalysis and Function of the p38α·MK2a Signaling Complex
Lukas, S., Kroe‐Barrett, R., Wildeson, J., Peet, G. W., Frego, L., Davidson, W. C., Ingraham, R. H., Pargellis, C. A., Labadia, M. E., & WERNEBURG, B. G. (2004) · Biochemistry · doi:10.1021/bi049508v · Cited by 51 · see citing works
Zu, Y., Ai, Y., & Huang, C. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.1.202 · Cited by 46 · see citing works
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Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases
Cargnello, M., & Roux, P. P. (2011) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00031-10 · Cited by 3,274 · see citing works
Mechanisms and functions of p38 MAPK signalling
Cuadrado, A., & Nebreda, Á. R. (2010) · Biochemical Journal · doi:10.1042/bj20100323 · Cited by 1,679 · see citing works
Smart, O. S., Womack, T. O., Flensburg, C., Keller, P., Paciorek, W., Sharff, A., Vonrhein, C., & Bricogne, G. (2012) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444911056058 · Cited by 612 · see citing works
Kinases that control the cell cycle in response to DNA damage: Chk1, Chk2, and MK2
Reinhardt, H. C., & Yaffe, M. B. (2009) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2009.01.018 · Cited by 494 · see citing works
Molecular basis of MAP kinase regulation
Peti, W., & Page, R. (2013) · Protein Science · doi:10.1002/pro.2374 · Cited by 302 · see citing works
Reinhardt, H. C., Hasskamp, P., Schmedding, I., Morandell, S., van Vugt, M. A. T. M., Wang, X., Linding, R., Ong, S., Weaver, D. T., Carr, S. A., et al. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.018 · Cited by 229 · see citing works
p38 Pathway Kinases as Anti-inflammatory Drug Targets
Schindler, J. F., Monahan, J. B., & Smith, W. G. (2007) · Journal of Dental Research · doi:10.1177/154405910708600902 · Cited by 228 · see citing works
Specificity of Linear Motifs That Bind to a Common Mitogen-Activated Protein Kinase Docking Groove
Garai, Á., Zeke, A., Gógl, G., Törő, I., Fördős, F., Blankenburg, H., Bárkai, T., Varga, J., Alexa, A., Emig, D., et al. (2012) · Science Signaling · doi:10.1126/scisignal.2003004 · Cited by 177 · see citing works
Bakan, A., Nevins, N., Lakdawala, A. S., & Bahar, İ. (2012) · Journal of Chemical Theory and Computation · doi:10.1021/ct300117j · Cited by 165 · see citing works
MAPK-Activated Protein Kinases: Servant or Partner?
Ronkina, N., & Gaestel, M. (2022) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-081720-114505 · Cited by 162 · see citing works
Current status and future prospects of p38α/MAPK14 kinase and its inhibitors
Madkour, M. M., Anbar, H. S., & El–Gamal, M. I. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113216 · Cited by 122 · see citing works
Molecular basis of MAPK-activated protein kinase 2:p38 assembly
White, A., Pargellis, C. A., Studts, J. M., Werneburg, B. G., & Farmer, B. T. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0701679104 · Cited by 111 · see citing works
Wang, C., Hockerman, S. L., Jacobsen, E. J., Alippe, Y., Selness, S. R., Hope, H. R., Hirsch, J. L., Mnich, S. J., Saabye, M. J., Hood, W. F., et al. (2018) · The Journal of Experimental Medicine · doi:10.1084/jem.20172063 · Cited by 103 · see citing works
Potential of p38-MAPK inhibitors in the treatment of ischaemic heart disease
Clark, J., Sarafraz, N., & Marber, M. S. (2007) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2007.06.013 · Cited by 101 · see citing works
An updated patent review of p38 MAP kinase inhibitors (2014-2019)
Haller, V., Nahidino, P., Förster, M., & Laufer, S. (2020) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2020.1749263 · Cited by 82 · see citing works
Fiore, M., Forli, S., & Manetti, F. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01457 · Cited by 81 · see citing works
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Duraisamy, S., Bajpai, M., Bughani, U., Dastidar, S. G., Ray, A., & Chopra, P. (2008) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.12.8.921 · Cited by 73 · see citing works
MK2 and MK3 - a pair of isoenzymes?
Ronkina, N. (2008) · Frontiers in bioscience · doi:10.2741/3095 · Cited by 71 · see citing works
Bellou, S., Hink, M. A., Bagli, E., Panopoulou, E., Bastiaens, P. I. H., Murphy, C., & Fotsis, T. (2009) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00058.2009 · Cited by 69 · see citing works
Revisiting protein kinase–substrate interactions: Toward therapeutic development
de Oliveira, P. S. L., Ferraz, F. A. N., Pena, D. A., Pramio, D. T., Morais, F. A., & Schechtman, D. (2016) · Science Signaling · doi:10.1126/scisignal.aad4016 · Cited by 68 · see citing works
Zhang, Y.-Y., Wu, J.-W., & Wang, Z.-X. (2011) · Science Signaling · doi:10.1126/scisignal.2002241 · Cited by 52 · see citing works
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Zhang, T., Jiang, J.-H., Liu, J., Xu, L., Duan, S., Sun, L., Zhao, W., & Qian, F. (2020) · Frontiers in Medicine · doi:10.3389/fmed.2020.00207 · Cited by 51 · see citing works
Tokunaga, Y., Takeuchi, K., Takahashi, H. K., & Shimada, I. (2014) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2861 · Cited by 50 · see citing works
Architecture of the MKK6-p38α complex defines the basis of MAPK specificity and activation
Juyoux, P., Galdadas, I., Gobbo, D., von Velsen, J., Pelosse, M., Tully, M. D., Vadas, O., Gervasio, F. L., Pellegrini, E., & Bowler, M. W. (2023) · Science · doi:10.1126/science.add7859 · Cited by 49 · see citing works
Ou, X., Li, S., Xu, B., Wang, Z., Quan, S., Li, M., Zhang, Q.-H., Ouyang, Y., Schatten, H., Xing, F.-Q., et al. (2010) · Cell Cycle · doi:10.4161/cc.9.20.13389 · Cited by 49 · see citing works
Yang, Y., Liu, H., & Yao, X. (2012) · Molecular BioSystems · doi:10.1039/c2mb25042j · Cited by 48 · see citing works
Singh, R. K., Najmi, A. K., & Dastidar, S. G. (2017) · Pharmacological Reports · doi:10.1016/j.pharep.2017.03.023 · Cited by 47 · see citing works
Yoshizawa, T., Hammaker, D. R., Boyle, D. L., Corr, M., Flavell, R. A., Davis, R. J., Schett, G. A., & Firestein, G. S. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0900483 · Cited by 44 · see citing works
Morgan, D., Berggren, K. L., Spiess, C., Smith, H. M., Tejwani, A., Weir, S. J., Lominska, C. E., Thomas, S. M., & Gan, G. N. (2021) · Molecular Carcinogenesis · doi:10.1002/mc.23348 · Cited by 42 · see citing works
Seisenbacher, G., Hafen, E., & Stocker, H. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002168 · Cited by 41 · see citing works
Specificity of signaling from MAPKs to MAPKAPKs: Kinases' Tango Nuevo
Gaestel, M. (2008) · Frontiers in bioscience · doi:10.2741/3136 · Cited by 40 · see citing works
Qian, F., Deng, J., Wang, G., Ye, R. D., & Christman, J. W. (2016) · Current Protein and Peptide Science · doi:10.2174/1389203716666150629121324 · Cited by 40 · see citing works
Shah, N. G., Tulapurkar, M. E., Ramarathnam, A., Brophy, A., Martinez, R., Hom, K., Hodges, T., Samadani, R., Singh, I. S., MacKerell, A. D., et al. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1602059 · Cited by 40 · see citing works
Sun, L., Wu, Q., Nie, Y., Cheng, N., Wang, R., Wang, G., Zhang, D., He, H., Ye, R. D., & Qian, F. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02610 · Cited by 40 · see citing works
Getlik, M., Grütter, C., Simard, J. R., Nguyen, H. D., Robubi, A., Aust, B., van Otterlo, W. A. L., & Rauh, D. (2011) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2011.11.019 · Cited by 40 · see citing works
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Alexa, A., Gógl, G., Glatz, G., Garai, Á., Zeke, A., Varga, J. M., Dudás, E. F., Jeszenői, N., Bodor, A., Hetényi, C., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1417571112 · Cited by 39 · see citing works
Bouças, J., Riabinska, A., Jokić, M., Herter-Sprie, G. S., Chen, S., Höpker, K., & Reinhardt, H. C. (2012) · Frontiers in Genetics · doi:10.3389/fgene.2012.00159 · Cited by 38 · see citing works
Sours, K. M., Kwok, S. C., Rachidi, T., Lee, T., Ring, A. Y., Hoofnagle, A. N., Resing, K. A., & Ahn, N. G. (2008) · Journal of Molecular Biology · doi:10.1016/j.jmb.2008.04.044 · Cited by 38 · see citing works
Du, J., Liu, P., Zhu, Y., Wang, G., Xing, S., Liu, T., Xia, J., Dong, S., Lv, N., & Li, Z. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114956 · Cited by 37 · see citing works
Patel, S. B., Cameron, P. M., O’Keefe, S. J., Frantz, B., Thompson, J., O’Neill, E. A., Tennis, T., Liu, L., Becker, J. W., & Scapin, G. (2009) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s090744490901600x · Cited by 37 · see citing works
Kliche, J., & Ivarsson, Y. (2022) · Biochemical Journal · doi:10.1042/bcj20200714 · Cited by 34 · see citing works
Suárez-López, L., Kong, Y. W., Sriram, G., Patterson, J. C., Rosenberg, S., Morandell, S., Haigis, K. M., & Yaffe, M. B. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.607891 · Cited by 33 · see citing works
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Li, Q., Zhang, N., Zhang, D., Wang, Y., Lin, T., Wang, Y., Zhou, H., Ye, Z., Zhang, F. P. Y., Lin, S., et al. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m709682200 · Cited by 33 · see citing works
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Schlapbach, A., & Huppertz, C. (2009) · Future Medicinal Chemistry · doi:10.4155/fmc.09.98 · Cited by 33 · see citing works
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Khattabi, I. E., & Sharma, A. J. (2013) · Molecular Endocrinology · doi:10.1210/me.2012-1346 · Cited by 29 · see citing works
Chen, Q., Che, C., Yang, S., Ding, P., Si, M., & Yang, G. H. (2022) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-022-04508-y · Cited by 29 · see citing works
Mujaibel, L. M., & Kilarkaje, N. (2013) · Environmental Toxicology · doi:10.1002/tox.21928 · Cited by 28 · see citing works
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Hill, Z. B., Perera, B. G. K., Andrews, S., & Maly, D. J. (2011) · ACS Chemical Biology · doi:10.1021/cb200387g · Cited by 27 · see citing works
Nguyen, T., Ruan, Z., Oruganty, K., & Kannan, N. (2015) · PLoS ONE · doi:10.1371/journal.pone.0119636 · Cited by 26 · see citing works
Lee, S., Warthaka, M., Yan, C., Kaoud, T. S., Piserchio, A., Ghose, R., Ren, P., & Dalby, K. N. (2011) · PLoS ONE · doi:10.1371/journal.pone.0018594 · Cited by 26 · see citing works
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Kinetic Mechanism and Inhibitor Characterization for c-jun-N-Terminal Kinase 3α1
Ember, B., Kamenecka, T., & LoGrasso, P. (2008) · Biochemistry · doi:10.1021/bi701852z · Cited by 22 · see citing works
DNA damage-inducible transcript 3 positively regulates RIPK1-mediated necroptosis
Ni, R., Cao, T., Ji, X., Peng, A., Zhang, Z., Fan, G., Stathopulos, P. B., Chakrabarti, S., Su, Z., & Peng, T. (2024) · Cell Death and Differentiation · doi:10.1038/s41418-024-01385-4 · Cited by 20 · see citing works
p38α MAP Kinase Dimers with Swapped Activation Segments and a Novel Catalytic Loop Conformation
Rothweiler, U., Åberg, E., Johnson, K. A., Hansen, T. E., Jørgensen, J. B., & Engh, R. A. (2011) · Journal of Molecular Biology · doi:10.1016/j.jmb.2011.06.013 · Cited by 20 · see citing works
Norrby, M., & Tågerud, S. (2010) · Journal of Cellular Physiology · doi:10.1002/jcp.22023 · Cited by 19 · see citing works
Docking Interactions of Hematopoietic Tyrosine Phosphatase with MAP Kinases ERK2 and p38α
Piserchio, A., Francis, D. M., Koveal, D., Dalby, K. N., Page, R., Peti, W., & Ghose, R. (2012) · Biochemistry · doi:10.1021/bi3012725 · Cited by 19 · see citing works
Peterson, L. B., Yaffe, M. B., & Imperiali, B. (2014) · Biochemistry · doi:10.1021/bi500862c · Cited by 19 · see citing works
Identification of a Novel Inhibitory Allosteric Site in p38α
Gómez‐Gutierrez, P., Campos, P. M., Vega, M., & Pérez, J. J. (2016) · PLoS ONE · doi:10.1371/journal.pone.0167379 · Cited by 19 · see citing works
MAP Kinase Mediated Activation of RSK1 and MK2 Substrate Kinases
Sok, P., Gógl, G., Kumar, G. S., Alexa, A., Singh, N., Kirsch, K., Sebő, A., Drahos, L., Gáspári, Z., Peti, W., et al. (2020) · Structure · doi:10.1016/j.str.2020.06.007 · Cited by 20 · see citing works
Proteome-wide screening for mitogen-activated protein kinase docking motifs and interactors
Shi, G., Song, C. D., Robles, J. T., Salichos, L., Lou, H. J., Lam, T. T., Gerstein, M., & Turk, B. E. (2023) · Science Signaling · doi:10.1126/scisignal.abm5518 · Cited by 19 · see citing works
High‐resolution crystal structure of human Mapkap kinase 3 in complex with a high affinity ligand
Cheng, R., Felicetti, B., Palan, S., Toogood‐Johnson, I., Scheich, C., Barker, J. J., Whittaker, M. A., & Hesterkamp, T. (2009) · Protein Science · doi:10.1002/pro.294 · Cited by 18 · see citing works
Kumar, G. S., Zettl, H., Page, R., & Peti, W. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.499178 · Cited by 12 · see citing works
Identification of Potential Small Molecule Binding Pockets in p38α MAP Kinase
Gómez‐Gutierrez, P., Rubio, J., & Pérez, J. J. (2017) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.7b00439 · Cited by 14 · see citing works
Deredge, D. J., Wintrode, P. L., Tulapurkar, M. E., Nagarsekar, A., Zhang, Y., Weber, D. J., Shapiro, P. S., & Hasday, J. D. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.007525 · Cited by 14 · see citing works
Discovery of a Potent Dihydrooxadiazole Series of Non-ATP-Competitive MK2 (MAPKAPK2) Inhibitors
Qin, J., Dhondi, P., Huang, X., Aslanian, R. G., Fossetta, J. D., Tian, F., Lundell, D. J., & Palani, A. (2011) · ACS Medicinal Chemistry Letters · doi:10.1021/ml200238g · Cited by 14 · see citing works
Rousseau, S. (2011) · AfCS-Nature Molecule Pages · doi:10.1038/mp.a001717.01 · Cited by 13 · see citing works
Suárez-López, L., Shui, B., Brubaker, D. K., Hill, M., Bergendorf, A. M., Changelian, P. S., Laguna, A., Starchenko, A., Lauffenburger, D. A., & Haigis, K. M. (2021) · iScience · doi:10.1016/j.isci.2021.103406 · Cited by 13 · see citing works
NMR Spectroscopy to Study MAP Kinase Binding to MAP Kinase Phosphatases
Peti, W., & Page, R. (2016) · Methods in molecular biology · doi:10.1007/978-1-4939-3746-2_11 · Cited by 13 · see citing works
Tran, Q. T. N., Gan, P. X. L., Liao, W., Mok, Y., Chai, C. L. L., & Wong, W. S. F. (2023) · Pharmacological Research · doi:10.1016/j.phrs.2023.106861 · Cited by 12 · see citing works
Rational mutagenesis to support structure-based drug design: MAPKAP kinase 2 as a case study
Argiriadi, M. A., Sousa, S., Banach, D. L., Marcotte, D. J., Xiang, T., Tomlinson, M. J., Demers, M. D., Harris, C., Kwak, S., Hardman, J., et al. (2009) · BMC Structural Biology · doi:10.1186/1472-6807-9-16 · Cited by 11 · see citing works
Malakhova, M. L., D’Angelo, I., Kim, H. G., Kurinov, I. V., Bode, A. M., & Dong, Z. (2010) · Journal of Molecular Biology · doi:10.1016/j.jmb.2010.03.064 · Cited by 11 · see citing works
The diterpenoid alkaloid noroxoaconitine is a Mapkap kinase 5 (MK5/PRAK) inhibitor
Kostenko, S., Khan, M. T. H., Sylte, I., & Moens, U. L. (2010) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0452-1 · Cited by 11 · see citing works
Umifenovir effectively inhibits IL-10 dependent persistent Coxsackie B4 virus infection
Zhang, S., Zhi, C., Li, H., Huang, D., Fan, Q., Cui, J., & Liang, C. (2017) · Antiviral Research · doi:10.1016/j.antiviral.2017.02.018 · Cited by 11 · see citing works
Monitoring Native p38α:MK2/3 Complexes via Trans Delivery of an ATP Acyl Phosphate Probe
Okerberg, E. S., Brown, H. E., Minimo, L., Alemayehu, S., Rosenblum, J. S., Patricelli, M. P., Nomanbhoy, T. K., & Kozarich, J. W. (2014) · Journal of the American Chemical Society · doi:10.1021/ja4129907 · Cited by 8 · see citing works
Cumming, J. G., Debreczeni, J. E., Edfeldt, F., Evertsson, E., Harrison, M., Holdgate, G. A., James, M. J., Lamont, S. G., Oldham, K., Sullivan, J. E., et al. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm501038s · Cited by 8 · see citing works
Bhole, R. P., Kadam, N., Karwa, P. N., Labhade, S., Kapare, H. S., & Gurav, S. S. (2025) · Molecular Diversity · doi:10.1007/s11030-025-11291-7 · Cited by 7 · see citing works
p38α MAPK inhibits stretch-induced JNK activation in cardiac myocytes through MKP-1
Feng, H., Gerilechaogetu, F., Golden, H. B., Nizamutdinov, D., Foster, D. M., Glaser, S. S., & Dostal, D. E. (2015) · International Journal of Cardiology · doi:10.1016/j.ijcard.2015.10.109 · Cited by 7 · see citing works
Ou, X., Li, S., Xu, B., Chen, L.-N., Jiang, M., Chen, S.-Q., & Chen, N.-Q. (2015) · Reproduction Fertility and Development · doi:10.1071/rd15150 · Cited by 7 · see citing works
Abouleisa, R., Miller, J. M., Gebreil, A., Salama, A. B. M., Dwenger, M. M., Abdelhafez, H., Wahid, R. M., Adewumi, A. T., Soliman, M. E. S., Abo-Dya, N. E., et al. (2023) · British Journal of Pharmacology · doi:10.1111/bph.16209 · Cited by 5 · see citing works
Label Transfer Reagents to Probe p38 MAPK Binding Partners
Andrews, S., Hill, Z. B., Perera, B. G. K., & Maly, D. J. (2013) · ChemBioChem · doi:10.1002/cbic.201200673 · Cited by 6 · see citing works
FRANCO, B. B., AGILANDESWARI, P., & Lakshminarayanan, K. (2024) · International Journal of Current Pharmaceutical Research · doi:10.22159/ijcpr.2024v16i6.6023 · Cited by 5 · see citing works
Owen, G. R., Stoychev, S., Achilonu, I., & Dirr, H. W. (2014) · Journal of Molecular Biology · doi:10.1016/j.jmb.2014.08.019 · Cited by 5 · see citing works
MK2 nonenzymatically promotes nuclear translocation of caspase-3 and resultant apoptosis
Rosario, O. L. D., Suresh, K. S., Kallem, M., Singh, G., Shah, A., Zheng, L., Yun, X., Philip, N. M., Putcha, N., McClure, M. B., et al. (2023) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00340.2022 · Cited by 5 · see citing works
Prevention of Melanoma Extravasation as a New Treatment Option Exemplified by p38/MK2 Inhibition
Petzelbauer, P. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218344 · Cited by 4 · see citing works
Hu, M., Li, A. Z., Fleming, P., Gralla, J., Terón, K. I. N., Zhou, Y., Miller, E. J., Beyett, T. S., Wen, Z., Du, Y., et al. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c01425 · Cited by 3 · see citing works
Nagao, H., Kitagawa, D., Nakajima, F., Sawa, M., & Kinoshita, T. (2021) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2021.128056 · Cited by 3 · see citing works
MAPKAP Kinase 2 (MK2) as a Target for Anti-inflammatory Drug Discovery
Edmunds, J. J., & Talanian, R. V. (2012) · Royal Society of Chemistry eBooks · doi:10.1039/9781849735346-00158 · Cited by 3 · see citing works
Macrophage-associated kinase signaling in atherosclerosis – a systematic review
Müller, J. S., & van der Vorst, E. P. C. (2026) · Cell Communication and Signaling · doi:10.1186/s12964-026-02829-9 · Cited by 2 · see citing works
Xu, G., Zhang, W., Du, J., Cong, J., Wang, P., Li, X., Si, X., & Wei, B. (2025) · SAR and QSAR in environmental research · doi:10.1080/1062936x.2025.2475407 · Cited by 2 · see citing works
Protein Kinase Interactions with Regulatory and Effector Proteins
Defnet, A. E., Martinez, R., & Shapiro, P. (2020) · Springer eBooks · doi:10.1007/978-3-030-48283-1_4 · Cited by 2 · see citing works
Tao, L., Tian, W., Li, P., Chen, Y., & Liu, J. (2025) · Inflammation · doi:10.1007/s10753-025-02346-w · Cited by 1 · see citing works
MAPKAPK2 (mitogen-activated protein kinase-activated protein kinase 2)
Felix, R., Alves, V. A. F., Vettore, A. L., & Colleoni, G. W. B. (2011) · Atlas of Genetics and Cytogenetics in Oncology and Haematology · doi:10.4267/2042/44932
Protein engineering of p38 MAP kinase for substrate identification
Yasovich, N. (2012) · York University Digital Library (York University)
de Jong, D. (2018) · theses.fr (ABES) · doi:10.70675/27595e3bzbf8ez4196zb9b4z036b359e6b5c
Botterbusch, S., Huso, V. L., Weingartner, K. A., Tryggvason, G., Tripp, K. W., Green, R., & Kavran, J. M. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.05.22.726961 · Cited by 1 · see citing works
Zhang, Y., Pei, C.-J., Luo, Z., Zhu, Z., Wu, J., & Wang, Z. (2026) · Communications Biology · doi:10.1038/s42003-026-10502-7
Atypical p38 kinase signaling and pathological impact on human health
Royer, F. T., Schulz, L., Young, A., Burns, J., Owusu, E., Jadhav, Y., Hanner, K., & Grimsey, N. J. (2026) · Biochemical Journal · doi:10.1042/bcj20250269
- Authors
- Haar, E. T., Prabakhar, P., Liu, X., & Lepre, C.
- Affiliations
- Vertex Pharmaceuticals (United States) (US)
- Corresponding author
- Haar, Ernst ter
- ORCID
- Liu, Xun
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-03
- Volume
- 282
- Issue
- 13
- Pages
- 9733-9739
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2117941384
- Cited by
- 100
- References
- 40
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 2 · 2023: 6 · 2022: 4 · 2021: 6 · 2020: 5 · 2019: 2 · 2018: 3 · 2017: 4 · 2016: 4 · 2015: 5 · 2014: 5 · 2013: 6 · 2012: 8
- FWCI
- 2.91
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- p38α MAPK, MAPKAPK2, heterodimer, crystal structure, MKK3, MKK6, phosphorylation regulation, ATP binding site, inflammatory cytokines
- MeSH terms
- MAP-Kinase-Activated Kinase 2, Adenosine Triphosphate, Binding Sites, Humans, Protein Serine-Threonine Kinases, Protein Structure, Tertiary, Crystallography, X-Ray, Dimerization, Intracellular Signaling Peptides and Proteins, Mitogen-Activated Protein Kinase 14
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