| Structural highlights
Disease
M3K20_HUMAN Split-foot malformation-mesoaxial polydactyly syndrome;Congenital fiber-type disproportion myopathy. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry.
Function
M3K20_HUMAN Stress-activated component of a protein kinase signal transduction cascade that promotes programmed cell death in response to various stress, such as ribosomal stress, osmotic shock and ionizing radiation (PubMed:10924358, PubMed:11836244, PubMed:12220515, PubMed:14521931, PubMed:15350844, PubMed:15737997, PubMed:18331592, PubMed:20559024, PubMed:26999302, PubMed:32289254, PubMed:32610081, PubMed:35857590). Acts by catalyzing phosphorylation of MAP kinase kinases, leading to activation of the JNK (MAPK8/JNK1, MAPK9/JNK2 and/or MAPK10/JNK3) and MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14) pathways (PubMed:11042189, PubMed:11836244, PubMed:12220515, PubMed:14521931, PubMed:15172994, PubMed:15737997, PubMed:32289254, PubMed:32610081, PubMed:35857590). Activates JNK through phosphorylation of MAP2K4/MKK4 and MAP2K7/MKK7, and MAP kinase p38 gamma (MAPK12) via phosphorylation of MAP2K3/MKK3 and MAP2K6/MKK6 (PubMed:11836244, PubMed:12220515). Involved in stress associated with adrenergic stimulation: contributes to cardiac decompensation during periods of acute cardiac stress (PubMed:15350844, PubMed:21224381, PubMed:27859413). May be involved in regulation of S and G2 cell cycle checkpoint by mediating phosphorylation of CHEK2 (PubMed:15342622).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] Key component of the stress-activated protein kinase signaling cascade in response to ribotoxic stress or UV-B irradiation (PubMed:32289254, PubMed:32610081, PubMed:35857590). Acts as the proximal sensor of ribosome collisions during the ribotoxic stress response (RSR): directly binds to the ribosome by inserting its flexible C-terminus into the ribosomal intersubunit space, thereby acting as a sentinel for colliding ribosomes (PubMed:32289254, PubMed:32610081). Upon ribosome collisions, activates either the stress-activated protein kinase signal transduction cascade or the integrated stress response (ISR), leading to programmed cell death or cell survival, respectively (PubMed:32610081). Dangerous levels of ribosome collisions trigger the autophosphorylation and activation of MAP3K20, which dissociates from colliding ribosomes and phosphorylates MAP kinase kinases, leading to activation of the JNK and MAP kinase p38 pathways that promote programmed cell death (PubMed:32289254, PubMed:32610081). Less dangerous levels of ribosome collisions trigger the integrated stress response (ISR): MAP3K20 activates EIF2AK4/GCN2 independently of its protein-kinase activity, promoting EIF2AK4/GCN2-mediated phosphorylation of EIF2S1/eIF-2-alpha (PubMed:32610081). Also part of the stress-activated protein kinase signaling cascade triggering the NLRP1 inflammasome in response to UV-B irradiation: ribosome collisions activate MAP3K20, which directly phosphorylates NLRP1, leading to activation of the NLRP1 inflammasome and subsequent pyroptosis (PubMed:35857590). NLRP1 is also phosphorylated by MAP kinase p38 downstream of MAP3K20 (PubMed:35857590). Also acts as a histone kinase by phosphorylating histone H3 at 'Ser-28' (H3S28ph) (PubMed:15684425).[18] [19] [20] [21] Isoform that lacks the C-terminal region that mediates ribosome-binding: does not act as a sensor of ribosome collisions in response to ribotoxic stress (PubMed:32289254, PubMed:32610081, PubMed:35857590). May act as an antagonist of isoform ZAKalpha: interacts with isoform ZAKalpha, leading to decrease the expression of isoform ZAKalpha (PubMed:27859413).[22] [23] [24] [25]
Publication Abstract from PubMed
Ribosome collisions activate the ribotoxic stress response mediated by the MAP3K ZAK, which in turn regulates cell-fate consequences through downstream phosphorylation of the MAPKs p38 and JNK(1). Despite the critical role of ZAK during cellular stress, a mechanistic and structural understanding of ZAK-ribosome interactions and how these lead to activation remain elusive. Here we combine biochemistry and cryo-electron microscopy to discover distinct ZAK-ribosome interactions required for constitutive recruitment and for activation. We find that upon induction of ribosome collisions, interactions between ZAK and the ribosomal protein RACK1 enable its activation by dimerization of its SAM domains at the collision interface. Furthermore, we discover how this process is negatively regulated by the ribosome-binding protein SERBP1 to prevent constitutive ZAK activation. Characterization of novel SAM variants as well as a known pathogenic variant of the SAM domain of ZAK supports a key role of the SAM domain in regulating kinase activity on and off the ribosome, with some mutants bypassing the ribosome requirement for ZAK activation. Collectively, our data provide a mechanistic blueprint of the kinase activity of ZAK at the collided ribosome interface.
ZAK activation at the collided ribosome.,Huso VL, Niu S, Catipovic MA, Saba JA, Denk T, Park E, Cheng J, Berninghausen O, Becker T, Green R, Beckmann R Nature. 2025 Nov 19. doi: 10.1038/s41586-025-09772-8. PMID:41261136[26]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Liu TC, Huang CJ, Chu YC, Wei CC, Chou CC, Chou MY, Chou CK, Yang JJ. Cloning and expression of ZAK, a mixed lineage kinase-like protein containing a leucine-zipper and a sterile-alpha motif. Biochem Biophys Res Commun. 2000 Aug 11;274(3):811-6. PMID:10924358 doi:http://dx.doi.org/10.1006/bbrc.2000.3236
- ↑ Gotoh I, Adachi M, Nishida E. Identification and characterization of a novel MAP kinase kinase kinase, MLTK. J Biol Chem. 2001 Feb 9;276(6):4276-86. Epub 2000 Oct 19. PMID:11042189 doi:http://dx.doi.org/10.1074/jbc.M008595200
- ↑ Gross EA, Callow MG, Waldbaum L, Thomas S, Ruggieri R. MRK, a mixed lineage kinase-related molecule that plays a role in gamma-radiation-induced cell cycle arrest. J Biol Chem. 2002 Apr 19;277(16):13873-82. Epub 2002 Feb 8. PMID:11836244 doi:http://dx.doi.org/10.1074/jbc.M111994200
- ↑ Yang JJ. Mixed lineage kinase ZAK utilizing MKK7 and not MKK4 to activate the c-Jun N-terminal kinase and playing a role in the cell arrest. Biochem Biophys Res Commun. 2002 Sep 13;297(1):105-10. PMID:12220515 doi:10.1016/s0006-291x(02)02123-x
- ↑ Yu X, Bloem LJ. Effect of C-terminal truncations on MLK7 catalytic activity and JNK activation. Biochem Biophys Res Commun. 2003 Oct 17;310(2):452-7. PMID:14521931 doi:10.1016/j.bbrc.2003.09.075
- ↑ Cho YY, Bode AM, Mizuno H, Choi BY, Choi HS, Dong Z. A novel role for mixed-lineage kinase-like mitogen-activated protein triple kinase alpha in neoplastic cell transformation and tumor development. Cancer Res. 2004 Jun 1;64(11):3855-64. PMID:15172994 doi:http://dx.doi.org/10.1158/0008-5472.CAN-04-0201
- ↑ Tosti E, Waldbaum L, Warshaw G, Gross EA, Ruggieri R. The stress kinase MRK contributes to regulation of DNA damage checkpoints through a p38gamma-independent pathway. J Biol Chem. 2004 Nov 12;279(46):47652-60. Epub 2004 Sep 1. PMID:15342622 doi:http://dx.doi.org/10.1074/jbc.M409961200
- ↑ Christe M, Jin N, Wang X, Gould KE, Iversen PW, Yu X, Lorenz JN, Kadambi V, Zuckerman SH, Bloem LJ. Transgenic mice with cardiac-specific over-expression of MLK7 have increased mortality when exposed to chronic beta-adrenergic stimulation. J Mol Cell Cardiol. 2004 Sep;37(3):705-15. PMID:15350844 doi:10.1016/j.yjmcc.2004.06.004
- ↑ Wang X, Mader MM, Toth JE, Yu X, Jin N, Campbell RM, Smallwood JK, Christe ME, Chatterjee A, Goodson T Jr, Vlahos CJ, Matter WF, Bloem LJ. Complete inhibition of anisomycin and UV radiation but not cytokine induced JNK and p38 activation by an aryl-substituted dihydropyrrolopyrazole quinoline and mixed lineage kinase 7 small interfering RNA. J Biol Chem. 2005 May 13;280(19):19298-305. PMID:15737997 doi:10.1074/jbc.M413059200
- ↑ Jandhyala DM, Ahluwalia A, Obrig T, Thorpe CM. ZAK: a MAP3Kinase that transduces Shiga toxin cytokine expression. Cell Microbiol. 2008 Jul;10(7):1468-77. PMID:18331592 doi:10.1111/j.1462-5822.2008.01139.x
- ↑ Sauter KA, Magun EA, Iordanov MS, Magun BE. ZAK is required for doxorubicin, a novel ribotoxic stressor, to induce SAPK activation and apoptosis in HaCaT cells. Cancer Biol Ther. 2010 Aug 1;10(3):258-66. PMID:20559024 doi:10.4161/cbt.10.3.12367
- ↑ Cariolato L, Cavin S, Diviani D. A-kinase anchoring protein (AKAP)-Lbc anchors a PKN-based signaling complex involved in α1-adrenergic receptor-induced p38 activation. J Biol Chem. 2011 Mar 11;286(10):7925-7937. PMID:21224381 doi:10.1074/jbc.M110.185645
- ↑ Mathea S, Abdul Azeez KR, Salah E, Tallant C, Wolfreys F, Konietzny R, Fischer R, Lou HJ, Brennan PE, Schnapp G, Pautsch A, Kessler BM, Turk BE, Knapp S. Structure of the Human Protein Kinase ZAK in Complex with Vemurafenib. ACS Chem Biol. 2016 Mar 31. PMID:26999302 doi:http://dx.doi.org/10.1021/acschembio.6b00043
- ↑ Fu CY, Kuo WW, Ho TJ, Wen SY, Lin LC, Tseng YS, Hung HC, Viswanadha VP, Yang JJ, Huang CY. ZAKβ antagonizes and ameliorates the cardiac hypertrophic and apoptotic effects induced by ZAKα. Cell Biochem Funct. 2016 Dec;34(8):606-612. PMID:27859413 doi:10.1002/cbf.3234
- ↑ Vind AC, Snieckute G, Blasius M, Tiedje C, Krogh N, Bekker-Jensen DB, Andersen KL, Nordgaard C, Tollenaere MAX, Lund AH, Olsen JV, Nielsen H, Bekker-Jensen S. ZAKα Recognizes Stalled Ribosomes through Partially Redundant Sensor Domains. Mol Cell. 2020 May 21;78(4):700-713.e7. PMID:32289254 doi:10.1016/j.molcel.2020.03.021
- ↑ Wu CC, Peterson A, Zinshteyn B, Regot S, Green R. Ribosome Collisions Trigger General Stress Responses to Regulate Cell Fate. Cell. 2020 Jul 23;182(2):404-416.e14. PMID:32610081 doi:10.1016/j.cell.2020.06.006
- ↑ Robinson KS, Toh GA, Rozario P, Chua R, Bauernfried S, Sun Z, Firdaus MJ, Bayat S, Nadkarni R, Poh ZS, Tham KC, Harapas CR, Lim CK, Chu W, Tay CWS, Tan KY, Zhao T, Bonnard C, Sobota R, Connolly JE, Common J, Masters SL, Chen KW, Ho L, Wu B, Hornung V, Zhong FL. ZAKα-driven ribotoxic stress response activates the human NLRP1 inflammasome. Science. 2022 Jul 15;377(6603):328-335. PMID:35857590 doi:10.1126/science.abl6324
- ↑ Choi HS, Choi BY, Cho YY, Zhu F, Bode AM, Dong Z. Phosphorylation of Ser28 in histone H3 mediated by mixed lineage kinase-like mitogen-activated protein triple kinase alpha. J Biol Chem. 2005 Apr 8;280(14):13545-53. Epub 2005 Jan 31. PMID:15684425 doi:http://dx.doi.org/M410521200
- ↑ Vind AC, Snieckute G, Blasius M, Tiedje C, Krogh N, Bekker-Jensen DB, Andersen KL, Nordgaard C, Tollenaere MAX, Lund AH, Olsen JV, Nielsen H, Bekker-Jensen S. ZAKα Recognizes Stalled Ribosomes through Partially Redundant Sensor Domains. Mol Cell. 2020 May 21;78(4):700-713.e7. PMID:32289254 doi:10.1016/j.molcel.2020.03.021
- ↑ Wu CC, Peterson A, Zinshteyn B, Regot S, Green R. Ribosome Collisions Trigger General Stress Responses to Regulate Cell Fate. Cell. 2020 Jul 23;182(2):404-416.e14. PMID:32610081 doi:10.1016/j.cell.2020.06.006
- ↑ Robinson KS, Toh GA, Rozario P, Chua R, Bauernfried S, Sun Z, Firdaus MJ, Bayat S, Nadkarni R, Poh ZS, Tham KC, Harapas CR, Lim CK, Chu W, Tay CWS, Tan KY, Zhao T, Bonnard C, Sobota R, Connolly JE, Common J, Masters SL, Chen KW, Ho L, Wu B, Hornung V, Zhong FL. ZAKα-driven ribotoxic stress response activates the human NLRP1 inflammasome. Science. 2022 Jul 15;377(6603):328-335. PMID:35857590 doi:10.1126/science.abl6324
- ↑ Fu CY, Kuo WW, Ho TJ, Wen SY, Lin LC, Tseng YS, Hung HC, Viswanadha VP, Yang JJ, Huang CY. ZAKβ antagonizes and ameliorates the cardiac hypertrophic and apoptotic effects induced by ZAKα. Cell Biochem Funct. 2016 Dec;34(8):606-612. PMID:27859413 doi:10.1002/cbf.3234
- ↑ Vind AC, Snieckute G, Blasius M, Tiedje C, Krogh N, Bekker-Jensen DB, Andersen KL, Nordgaard C, Tollenaere MAX, Lund AH, Olsen JV, Nielsen H, Bekker-Jensen S. ZAKα Recognizes Stalled Ribosomes through Partially Redundant Sensor Domains. Mol Cell. 2020 May 21;78(4):700-713.e7. PMID:32289254 doi:10.1016/j.molcel.2020.03.021
- ↑ Wu CC, Peterson A, Zinshteyn B, Regot S, Green R. Ribosome Collisions Trigger General Stress Responses to Regulate Cell Fate. Cell. 2020 Jul 23;182(2):404-416.e14. PMID:32610081 doi:10.1016/j.cell.2020.06.006
- ↑ Robinson KS, Toh GA, Rozario P, Chua R, Bauernfried S, Sun Z, Firdaus MJ, Bayat S, Nadkarni R, Poh ZS, Tham KC, Harapas CR, Lim CK, Chu W, Tay CWS, Tan KY, Zhao T, Bonnard C, Sobota R, Connolly JE, Common J, Masters SL, Chen KW, Ho L, Wu B, Hornung V, Zhong FL. ZAKα-driven ribotoxic stress response activates the human NLRP1 inflammasome. Science. 2022 Jul 15;377(6603):328-335. PMID:35857590 doi:10.1126/science.abl6324
- ↑ Huso VL, Niu S, Catipovic MA, Saba JA, Denk T, Park E, Cheng J, Berninghausen O, Becker T, Green R, Beckmann R. ZAK activation at the collided ribosome. Nature. 2025 Nov 19. PMID:41261136 doi:10.1038/s41586-025-09772-8
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