Kinase Subfamily ZAK

Kinase Classification: Group TKL: Family MLK: : Subfamily ZAK

ZAK is an animal-specific MAP kinase kinase kinase implicated in stress responses and control of cell proliferation and survival.

Evolution

ZAK is found in most metazoans, though lost in insects and some other arthropods. Mammals have a single copy, ZAK (aka MLTK, MLK, AZK, MLT, MRK).

Domain Structure

ZAK proteins have an N-terminal kinase domain followed by a leucine zipper region and a SAM domain which is absent from one of two major human splice isoforms.

Functions

ZAK is a MAP kinase kinase kinase, and is known in humans to activate MKK3/MKK6 and their downstream target p38g as well as MKK4/MKK7 and their downstream target Jnks [1]. Other studies have also shown activation of Erk and Erk5 signaling [2]. ZAK has both pro-proliferative and pro-apoptotic functions, and may influence cell cycle checkpoints [3, 4][]. The long form of ZAK is unregulated in cancer [5], and its splicing is controlled by the oncogenic splicing factor PRPF6 [6].

ZAK is activated by a number of stresses, including gamma radiation [1], osmotic shock [2] and UV radiation [7].

ZAK binds and likely activates the MSK1 kinase [8]. ZAK also binds the GTPases RhoA and RhoC and knockdown of ZAK phenocopied knockdown of RhoC [9]. The rho-dependent kinase PKN also binds and activates ZAK [10], and may act as a scaffold for ZAK, MKK6 and p38g.

Braf inhibitors have off-target effects on Zak, including inhibition of apoptosis [7, 11], and inhibition of ZAK has been shown to reduce pro-inflammatory gene expression that mediates toxic side-effects of doxorubicin [12].

References

1. Gross EA, Callow MG, Waldbaum L, Thomas S, and 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. DOI:10.1074/jbc.M111994200 |
2. Gotoh I, Adachi M, and Nishida E. Identification and characterization of a novel MAP kinase kinase kinase, MLTK. J Biol Chem. 2001 Feb 9;276(6):4276-86. DOI:10.1074/jbc.M008595200 |
3. Tosti E, Waldbaum L, Warshaw G, Gross EA, and 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. DOI:10.1074/jbc.M409961200 |
5. Liu J, McCleland M, Stawiski EW, Gnad F, Mayba O, Haverty PM, Durinck S, Chen YJ, Klijn C, Jhunjhunwala S, Lawrence M, Liu H, Wan Y, Chopra V, Yaylaoglu MB, Yuan W, Ha C, Gilbert HN, Reeder J, Pau G, Stinson J, Stern HM, Manning G, Wu TD, Neve RM, de Sauvage FJ, Modrusan Z, Seshagiri S, Firestein R, and Zhang Z. Integrated exome and transcriptome sequencing reveals ZAK isoform usage in gastric cancer. Nat Commun. 2014 May 8;5:3830. DOI:10.1038/ncomms4830 |
6. Adler AS, McCleland ML, Yee S, Yaylaoglu M, Hussain S, Cosino E, Quinones G, Modrusan Z, Seshagiri S, Torres E, Chopra VS, Haley B, Zhang Z, Blackwood EM, Singh M, Junttila M, Stephan JP, Liu J, Pau G, Fearon ER, Jiang Z, and Firestein R. An integrative analysis of colon cancer identifies an essential function for PRPF6 in tumor growth. Genes Dev. 2014 May 15;28(10):1068-84. DOI:10.1101/gad.237206.113 |
7. Vin H, Ching G, Ojeda SS, Adelmann CH, Chitsazzadeh V, Dwyer DW, Ma H, Ehrenreiter K, Baccarini M, Ruggieri R, Curry JL, Ciurea AM, Duvic M, Busaidy NL, Tannir NM, and Tsai KY. Sorafenib suppresses JNK-dependent apoptosis through inhibition of ZAK. Mol Cancer Ther. 2014 Jan;13(1):221-9. DOI:10.1158/1535-7163.MCT-13-0561 |
8. Wang W, Han G, Ye M, Shi H, Zou H, and Huo K. Mapping of phosphorylation sites in human MSK1 activated by a novel interaction with MRK-beta. Electrophoresis. 2010 Apr;31(8):1283-93. DOI:10.1002/elps.200900637 |
9. Korkina O, Dong Z, Marullo A, Warshaw G, Symons M, and Ruggieri R. The MLK-related kinase (MRK) is a novel RhoC effector that mediates lysophosphatidic acid (LPA)-stimulated tumor cell invasion. J Biol Chem. 2013 Feb 22;288(8):5364-73. DOI:10.1074/jbc.M112.414060 |
10. Takahashi M, Gotoh Y, Isagawa T, Nishimura T, Goyama E, Kim HS, Mukai H, and Ono Y. Regulation of a mitogen-activated protein kinase kinase kinase, MLTK by PKN. J Biochem. 2003 Feb;133(2):181-7. DOI:10.1093/jb/mvg022 |
11. Vin H, Ojeda SS, Ching G, Leung ML, Chitsazzadeh V, Dwyer DW, Adelmann CH, Restrepo M, Richards KN, Stewart LR, Du L, Ferguson SB, Chakravarti D, Ehrenreiter K, Baccarini M, Ruggieri R, Curry JL, Kim KB, Ciurea AM, Duvic M, Prieto VG, Ullrich SE, Dalby KN, Flores ER, and Tsai KY. BRAF inhibitors suppress apoptosis through off-target inhibition of JNK signaling. Elife. 2013 Nov 5;2:e00969. DOI:10.7554/eLife.00969 |
12. Wong J, Smith LB, Magun EA, Engstrom T, Kelley-Howard K, Jandhyala DM, Thorpe CM, Magun BE, and Wood LJ. Small molecule kinase inhibitors block the ZAK-dependent inflammatory effects of doxorubicin. Cancer Biol Ther. 2013 Jan;14(1):56-63. DOI:10.4161/cbt.22628 |
13. 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. DOI:10.1016/s0006-291x(02)02123-x |