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Gene Review

ZAK  -  sterile alpha motif and leucine zipper...

Homo sapiens

Synonyms: AZK, MLK7, MLT, MLTK, MRK, ...
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Disease relevance of ZAK

  • We, therefore, investigated the potential involvement of ZAK (which in cultured H9c2 cardiomyoblast cell is a positive mediator of cell hypertrophy) [1].
  • Overexpression of the ZAK gene induces the apoptosis of a hepatoma cell line [2].
  • Very importantly, MLTK-alpha-overexpressing cells formed fibrosarcomas when injected s.c. into athymic nude mice, whereas almost no tumor formation was observed in mice that received injections of mock or siRNA-MLTK-alpha stably transfected cells [3].
  • To assess whether t(11;18, q21;q21), which results in a chimeric transcript between the AP12 and MLT genes, predicts lymphoma resistance to antibiotic therapy, we screened for the fusion transcript with RT-PCR in ten responsive and 12 non-responsive gastric MALT lymphomas [4].
  • A cDNA encoding a beta-1,4-galactosyltransferase named beta-1,4-GalT II was cloned from a cDNA library of the human breast tumor cell line, MRK-nu-1 [5].

High impact information on ZAK

  • MAK and MRK require dual phosphorylation in a TDY motif catalyzed by an unidentified human threonine kinase and tyrosine autophosphorylation [6].
  • MRK preferentially phosphorylates R-P-X-S/T-P sites, with the preference for arginine at position -3 (P-3) being more stringent than for prolines at P-2 and P+1 [6].
  • Pgp expression and function were analyzed by flow cytometric analysis of MRK 16 binding and Rhodamine 123 retention, respectively [7].
  • Selective elimination of multidrug resistance-positive cells (LoVo/Dx) was obtained by using the monoclonal antibody MRK 16, which recognizes a surface epitope of the Mr 170,000 glycoprotein, and a sheep anti-mouse immunoglobulin antibody, conjugated to the ribosome-inactivating protein saporin 6 [8].
  • In cell suspensions composed of 90% normal bone marrow cells and 10% multidrug resistance-positive cells, the monoclonal antibody MRK 16 followed by the anti-mouse immunotoxin caused the elimination of 99% multidrug resistance-positive cells, as revealed by immunofluorescence and immunocytochemistry as well as by a clonal assay [8].

Chemical compound and disease context of ZAK

  • A monoclonal antibody (MAb), MRK 16, specific to Adriamycin-resistant human myelogenous leukemia cell line K562, was used to examine whether the antigen molecules (P-glycoprotein) recognized by the MAb are present in the adrenals [9].
  • Migraine MLT-down: an unusual presentation of migraine in patients with aspartame-triggered headaches [10].
  • A predominantly hospital-based outbreak of multiply-resistant Klebsiella pneumoniae capsular type K2 (MRK) expressing expanded spectrum betalactamase (ESBL) activity and fully sensitive only to the carbapenems and amikacin is described [11].
  • We have investigated the antiproliferative effects of a polyamine synthesis inhibitor, methylglyoxal bis(cyclopentylamidinohydrazone) (MCBCP), on human breast cancer MRK-nu-1 cells [12].
  • Apoptosis induction in human breast cancer MRK-nu-1 cells by a polyamine synthesis inhibitor, methylglyoxal bis(cyclopentylamidinohydrazone)(MGBCP) [12].

Biological context of ZAK

  • MRK, a mixed lineage kinase-related molecule that plays a role in gamma-radiation-induced cell cycle arrest [13].
  • The stress kinase MRK contributes to regulation of DNA damage checkpoints through a p38gamma-independent pathway [14].
  • MRK depletion by RNA interference resulted in defective S and G(2) checkpoints induced by IR that were accompanied by reduced Chk2 phosphorylation and delayed Cdc25A degradation [14].
  • Additionally, MLK7 altered fetal gene expression and increased protein synthesis in cardiac myocytes [15].
  • Our results showed that the expression of a wild-type form of ZAK induces the characteristic hypertrophic growth features, including increased cell size, elevated atrial natriuretic factor expression, and increased actin fiber organization [1].

Anatomical context of ZAK


Associations of ZAK with chemical compounds

  • The recombinant histidine tagged MLK7 expressed and purified from insect cells exhibited serine/threonine kinase activity in vitro with myelin basic protein as substrate [15].
  • Taken together, these data demonstrate that MLK7 is the MAPKKK required for modulation of the stress-activated MAPKs downstream of anisomycin and UV stimulation and that DHP-2 can be used to block MLK7 pathway activation in cells as well as in vivo [17].
  • It has been suggested that the indole hormone melatonin (N-acetyl-5-methoxytryptamine, MLT) is an important natural antioxidant and free radical scavenger [J. Pineal Res., 14:51; 1993] [21].
  • For this purpose, we characterized the free-radical scavenging potency of several compounds exhibiting various affinities for melatonin membrane receptors (MLT 1a and 1b) [22].
  • The level of P-gp detected by MRK 16 correlated with R123 accumulation [23].

Regulatory relationships of ZAK

  • The model proposed here is that ZAK might play a role as an upstream signal to suppress the ZZaPK function and decrease E2F expression [24].

Other interactions of ZAK

  • We also showed that Chk2 is a substrate for MRK in vitro and is phosphorylated at Thr(68) by active MRK in cells [14].
  • Western blot analysis shows that the decreased cyclin E level correlated strongly with the low proliferative capacity of ZAK-expressed cells [16].
  • The expression of ZAK in mammalian cells specifically leads to the activation of the JNK/SAPK pathway as well as the activation of transcription factor, NF-kappaB [2].
  • This cloned cDNA encodes a novel protein with Krüppel-type zinc fingers designed as ZZaPK (zinc finger and ZAK associated protein with KRAB domain) and is widely expressed [24].
  • Cloning and expression of ZAK, a mixed lineage kinase-like protein containing a leucine-zipper and a sterile-alpha motif [2].

Analytical, diagnostic and therapeutic context of ZAK

  • Northern blot analysis revealed that the expression of this ZAK gene is found in various parts of human tissues [2].
  • MRK phosphorylates Scythe at T1080 in vitro as determined by site-directed mutagenesis and mass spectrometry, supporting the consensus and suggesting Scythe as a physiological substrate for MRK [6].
  • These observations allowed us to work out a highly sensitive diagnostic test for the API2-MLT fusion on an ABI Prism 7700 sequence detector that confirmed the results of our initial approach [18].
  • MLT was given orally at a daily dose of 50 mg at 8.00 p.m., starting 7 days before IL-2, which was given subcutaneously at a dose of 3 million IU/day at 8.00 p.m. for 6 days/week for 4 weeks, corresponding to one cycle of immunotherapy [20].
  • Ten patients in the pediatric intensive care unit (ICU) at a hospital in Madrid were colonized by or infected with MRKP from October 1997 to April 1998 [25].


  1. ZAK re-programs atrial natriuretic factor expression and induces hypertrophic growth in H9c2 cardiomyoblast cells. Huang, C.Y., Chueh, P.J., Tseng, C.T., Liu, K.Y., Tsai, H.Y., Kuo, W.W., Chou, M.Y., Yang, J.J. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  2. Cloning and expression of ZAK, a mixed lineage kinase-like protein containing a leucine-zipper and a sterile-alpha motif. Liu, T.C., Huang, C.J., Chu, Y.C., Wei, C.C., Chou, C.C., Chou, M.Y., Chou, C.K., Yang, J.J. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  3. A novel role for mixed-lineage kinase-like mitogen-activated protein triple kinase alpha in neoplastic cell transformation and tumor development. Cho, Y.Y., Bode, A.M., Mizuno, H., Choi, B.Y., Choi, H.S., Dong, Z. Cancer Res. (2004) [Pubmed]
  4. Resistance of t(11;18) positive gastric mucosa-associated lymphoid tissue lymphoma to Helicobacter pylori eradication therapy. Liu, H., Ruskon-Fourmestraux, A., Lavergne-Slove, A., Ye, H., Molina, T., Bouhnik, Y., Hamoudi, R.A., Diss, T.C., Dogan, A., Megraud, F., Rambaud, J.C., Du, M.Q., Isaacson, P.G. Lancet (2001) [Pubmed]
  5. Molecular cloning of a human cDNA encoding beta-1,4-galactosyltransferase with 37% identity to mammalian UDP-Gal:GlcNAc beta-1,4-galactosyltransferase. Sato, T., Furukawa, K., Bakker, H., Van den Eijnden, D.H., Van Die, I. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  6. Identification of Yin-Yang Regulators and a Phosphorylation Consensus for Male Germ Cell-Associated Kinase (MAK)-Related Kinase. Fu, Z., Larson, K.A., Chitta, R.K., Parker, S.A., Turk, B.E., Lawrence, M.W., Kaldis, P., Galaktionov, K., Cohn, S.M., Shabanowitz, J., Hunt, D.F., Sturgill, T.W. Mol. Cell. Biol. (2006) [Pubmed]
  7. Altered multidrug resistance phenotype caused by anthracycline analogues and cytosine arabinoside in myeloid leukemia. Hu, X.F., Slater, A., Kantharidis, P., Rischin, D., Juneja, S., Rossi, R., Lee, G., Parkin, J.D., Zalcberg, J.R. Blood (1999) [Pubmed]
  8. In vitro bone marrow purging of multidrug-resistant cells with a mouse monoclonal antibody directed against Mr 170,000 glycoprotein and a saporin-conjugated anti-mouse antibody. Dinota, A., Tazzari, P.L., Michieli, M., Visani, G., Gobbi, M., Bontadini, A., Tassi, C., Fanin, R., Damiani, D., Grandi, M. Cancer Res. (1990) [Pubmed]
  9. Apparent stronger expression in the human adrenal cortex than in the human adrenal medulla of Mr 170,000-180,000 P-glycoprotein. Sugawara, I., Nakahama, M., Hamada, H., Tsuruo, T., Mori, S. Cancer Res. (1988) [Pubmed]
  10. Migraine MLT-down: an unusual presentation of migraine in patients with aspartame-triggered headaches. Newman, L.C., Lipton, R.B. Headache. (2001) [Pubmed]
  11. An outbreak of multiply-resistant Klebsiella pneumoniae in the Grampian region of Scotland. Hobson, R.P., MacKenzie, F.M., Gould, I.M. J. Hosp. Infect. (1996) [Pubmed]
  12. Apoptosis induction in human breast cancer MRK-nu-1 cells by a polyamine synthesis inhibitor, methylglyoxal bis(cyclopentylamidinohydrazone)(MGBCP). Kaneko, H., Hibasami, H., Mori, K., Kawarada, Y., Nakashima, K. Anticancer Res. (1998) [Pubmed]
  13. MRK, a mixed lineage kinase-related molecule that plays a role in gamma-radiation-induced cell cycle arrest. Gross, E.A., Callow, M.G., Waldbaum, L., Thomas, S., Ruggieri, R. J. Biol. Chem. (2002) [Pubmed]
  14. The stress kinase MRK contributes to regulation of DNA damage checkpoints through a p38gamma-independent pathway. Tosti, E., Waldbaum, L., Warshaw, G., Gross, E.A., Ruggieri, R. J. Biol. Chem. (2004) [Pubmed]
  15. Tissue distribution and functional expression of a cDNA encoding a novel mixed lineage kinase. Bloem, L.J., Pickard, T.R., Acton, S., Donoghue, M., Beavis, R.C., Knierman, M.D., Wang, X. J. Mol. Cell. Cardiol. (2001) [Pubmed]
  16. 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. Yang, J.J. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  17. 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. Wang, X., Mader, M.M., Toth, J.E., Yu, X., Jin, N., Campbell, R.M., Smallwood, J.K., Christe, M.E., Chatterjee, A., Goodson, T., Vlahos, C.J., Matter, W.F., Bloem, L.J. J. Biol. Chem. (2005) [Pubmed]
  18. The product of the t(11;18), an API2-MLT fusion, marks nearly half of gastric MALT type lymphomas without large cell proliferation. Baens, M., Maes, B., Steyls, A., Geboes, K., Marynen, P., De Wolf-Peeters, C. Am. J. Pathol. (2000) [Pubmed]
  19. High-level expression of MRK 16 and MRK 20 murine monoclonal antibody-define proteins (170,000-180,000 P-glycoprotein and 85,000 protein) in leukaemias and malignant lymphomas. Sugawara, I., Kodo, H., Ohkochi, E., Hamada, H., Tsuruo, T., Mori, S. Br. J. Cancer (1989) [Pubmed]
  20. Immunotherapy with subcutaneous low-dose interleukin-2 and the pineal indole melatonin as a new effective therapy in advanced cancers of the digestive tract. Lissoni, P., Barni, S., Tancini, G., Ardizzoia, A., Rovelli, F., Cazzaniga, M., Brivio, F., Piperno, A., Aldeghi, R., Fossati, D. Br. J. Cancer (1993) [Pubmed]
  21. Reaction of melatonin and related indoles with hydroxyl radicals: EPR and spin trapping investigations. Matuszak, Z., Reszka, K., Chignell, C.F. Free Radic. Biol. Med. (1997) [Pubmed]
  22. The neuroprotective activities of melatonin against the Alzheimer beta-protein are not mediated by melatonin membrane receptors. Pappolla, M.A., Simovich, M.J., Bryant-Thomas, T., Chyan, Y.J., Poeggeler, B., Dubocovich, M., Bick, R., Perry, G., Cruz-Sanchez, F., Smith, M.A. J. Pineal Res. (2002) [Pubmed]
  23. Regulation of P-glycoprotein 1 and 2 gene expression and protein activity in two MCF-7/Dox cell line subclones. Davies, R., Budworth, J., Riley, J., Snowden, R., Gescher, A., Gant, T.W. Br. J. Cancer (1996) [Pubmed]
  24. A novel zinc finger protein, ZZaPK, interacts with ZAK and stimulates the ZAK-expressing cells re-entering the cell cycle. Yang, J.J. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  25. Outbreak of a multiresistant Klebsiella pneumoniae strain in an intensive care unit: antibiotic use as risk factor for colonization and infection. Asensio, A., Oliver, A., González-Diego, P., Baquero, F., Pérez-Díaz, J.C., Ros, P., Cobo, J., Palacios, M., Lasheras, D., Cantón, R. Clin. Infect. Dis. (2000) [Pubmed]
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