Pseudokinase Explained

Pseudokinases are catalytically-deficient pseudoenzyme^[1] variants of protein kinases that are represented in all kinomes across the kingdoms of life. Pseudokinases have both physiological (signal transduction) and pathophysiological functions.^{[2] [3] [4] [5] [6] [7] [8]}

History

The phrase pseudokinase was first coined in 2002.^[9] They were subsequently sub-classified into different 'classes'.^{[10] [8] [11] [12] [13]} Several pseudokinase-containing families are found in the human kinome, including the Tribbles pseudokinases, which are at the interface between kinase and ubiquitin E3 ligase signalling.^{[14] [15] [16]}

The human pseudokinases (and their pseudophosphatase cousins) are implicated in a wide variety of diseases,^{[17] [18]} which has made them potential drug targets and antitargets).^{[19] [20] [21] [22]} Pseudokinases are made up of an evolutionary mixture of eukaryotic protein kinase (ePK) and non ePK-related pseudoenzyme proteins (e.g., FAM20A, which binds ATP^[23] and is pseudokinase due to a conserved glutamate to glutamine swap in the alpha-C helix.^[24] FAM20A is implicated in periodontal disease, and serves to control the catalytic activity of FAM20C, an important physiological casein kinase that controls phosphorylation of proteins in the Golgi apparatus that are destined for secretion,^[25] such as the milk protein casein.

A comprehensive evolutionary analysis confirms that pseudokinases group into multiple subfamilies, and these are found in the annotated kinome of organisms across the kingdoms of life, including prokaryotes, archaea and all eukaryotic lineages with an annotated proteome; this data is searchable in ProKino (http://vulcan.cs.uga.edu/prokino/about/browser). ^[26]

See also

• Kinase
• Pseudoenzyme
• Phosphatome
• Protein phosphatase

Further reading

• Eyers PA, Murphy JM . The evolving world of pseudoenzymes: proteins, prejudice and zombies . BMC Biology . 14 . 1 . 98 . November 2016 . 27835992 . 5106787 . 10.1186/s12915-016-0322-x . free .

External links

• Web site: Professor Patrick Eyers - University of Liverpool Kinome Assay and Screening Facility . Liverpool.ac.uk . 2017-01-16.
• Web site: Kinome details and access to KinBase . 2017-01-16.
• Web site: Prokino software to analyse kinase site conservation = . 2017-01-16.
• Web site: The human pseudokinome wiki . 2017-01-16.

Notes and References

1. Murphy JM, Farhan H, Eyers PA . Bio-Zombie: the rise of pseudoenzymes in biology . Biochemical Society Transactions . 45 . 2 . 537–544 . April 2017 . 28408493 . 10.1042/BST20160400 .
2. Jacobsen AV, Murphy JM . The secret life of kinases: insights into non-catalytic signalling functions from pseudokinases . Biochemical Society Transactions . 45 . 3 . 665–681 . June 2017 . 28620028 . 10.1042/BST20160331 . free .
3. Murphy JM, Zhang Q, Young SN, Reese ML, Bailey FP, Eyers PA, Ungureanu D, Hammaren H, Silvennoinen O, Varghese LN, Chen K, Tripaydonis A, Jura N, Fukuda K, Qin J, Nimchuk Z, Mudgett MB, Elowe S, Gee CL, Liu L, Daly RJ, Manning G, Babon JJ, Lucet IS . A robust methodology to subclassify pseudokinases based on their nucleotide-binding properties . The Biochemical Journal . 457 . 2 . 323–34 . January 2014 . 24107129 . 5679212 . 10.1042/BJ20131174 .
4. Kannan N, Taylor SS . Rethinking pseudokinases . Cell . 133 . 2 . 204–5 . April 2008 . 18423189 . 10.1016/j.cell.2008.04.005 . 6226312 .
5. Mukherjee K, Sharma M, Urlaub H, Bourenkov GP, Jahn R, Südhof TC, Wahl MC . CASK Functions as a Mg2+-independent neurexin kinase . Cell . 133 . 2 . 328–39 . April 2008 . 18423203 . 3640377 . 10.1016/j.cell.2008.02.036 .
6. Bailey FP, Byrne DP, Oruganty K, Eyers CE, Novotny CJ, Shokat KM, Kannan N, Eyers PA . The Tribbles 2 (TRB2) pseudokinase binds to ATP and autophosphorylates in a metal-independent manner . The Biochemical Journal . 467 . 1 . 47–62 . April 2015 . 25583260 . 4844368 . 10.1042/BJ20141441 .
7. Shi F, Telesco SE, Liu Y, Radhakrishnan R, Lemmon MA . ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation . Proceedings of the National Academy of Sciences of the United States of America . 107 . 17 . 7692–7 . April 2010 . 20351256 . 2867849 . 10.1073/pnas.1002753107 . 2010PNAS..107.7692S . free .
8. Zeqiraj E, Filippi BM, Deak M, Alessi DR, van Aalten DM . Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation . Science . 326 . 5960 . 1707–11 . December 2009 . 19892943 . 3518268 . 10.1126/science.1178377 . 2009Sci...326.1707Z .
9. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S . The protein kinase complement of the human genome . Science . 298 . 5600 . 1912–34 . December 2002 . 12471243 . 10.1126/science.1075762 . 2002Sci...298.1912M . 26554314 .
10. Boudeau J, Miranda-Saavedra D, Barton GJ, Alessi DR . Emerging roles of pseudokinases . Trends in Cell Biology . 16 . 9 . 443–52 . September 2006 . 16879967 . 10.1016/j.tcb.2006.07.003 .
11. Zeqiraj E, van Aalten DM . Pseudokinases-remnants of evolution or key allosteric regulators? . Current Opinion in Structural Biology . 20 . 6 . 772–81 . December 2010 . 21074407 . 3014569 . 10.1016/j.sbi.2010.10.001 .
12. Scheeff ED, Eswaran J, Bunkoczi G, Knapp S, Manning G . Structure of the pseudokinase VRK3 reveals a degraded catalytic site, a highly conserved kinase fold, and a putative regulatory binding site . Structure . 17 . 1 . 128–38 . January 2009 . 19141289 . 2639636 . 10.1016/j.str.2008.10.018 .
13. Eyers PA, Murphy JM . Dawn of the dead: protein pseudokinases signal new adventures in cell biology . Biochemical Society Transactions . 41 . 4 . 969–74 . August 2013 . 23863165 . 10.1042/BST20130115 .
14. Eyers PA, Keeshan K, Kannan N . Tribbles in the 21st Century: The Evolving Roles of Tribbles Pseudokinases in Biology and Disease . Trends in Cell Biology . 27 . 4 . 284–298 . April 2017 . 27908682 . 5382568 . 10.1016/j.tcb.2016.11.002 .
15. Foulkes DM, Byrne DP, Yeung W, Shrestha S, Bailey FP, Ferries S, Eyers CE, Keeshan K, Wells C, Drewry DH, Zuercher WJ, Kannan N, Eyers PA . Covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2 (TRIB2) pseudokinase in cancer cells. . Science Signaling . 11 . 549 . September 2018 . eaat7951 . 30254057 . 10.1126/scisignal.aat7951 . 6553640 .
16. Jamieson SA, Ruan Z, Burgess AE, Curry JR, McMillan HD, Brewster JL, Dunbier AK, Axtman AD, Kannan N, Mace PD . Substrate binding allosterically relieves autoinhibition of the pseudokinase TRIB1 . Science Signaling . 11 . 549 . September 2018 . eaau0597 . 30254053 . 10.1126/scisignal.aau0597. 6553639 .
17. Reiterer V, Eyers PA, Farhan H . Day of the dead: pseudokinases and pseudophosphatases in physiology and disease . Trends in Cell Biology . 24 . 9 . 489–505 . September 2014 . 24818526 . 10.1016/j.tcb.2014.03.008 .
18. Chen MJ, Dixon JE, Manning G . Genomics and evolution of protein phosphatases . Science Signaling . 10 . 474 . eaag1796 . April 2017 . 28400531 . 10.1126/scisignal.aag1796 . 41041971 .
19. Byrne DP, Foulkes DM, Eyers PA . Pseudokinases: update on their functions and evaluation as new drug targets . . 9 . 2 . 245–265 . January 2017 . 28097887 . 10.4155/fmc-2016-0207 . free .
20. Bailey FP, Byrne DP, McSkimming D, Kannan N, Eyers PA . Going for broke: targeting the human cancer pseudokinome . The Biochemical Journal . 465 . 2 . 195–211 . January 2015 . 25559089 . 10.1042/BJ20141060 .
21. Cowan-Jacob SW, Jahnke W, Knapp S . Novel approaches for targeting kinases: allosteric inhibition, allosteric activation and pseudokinases . . 6 . 5 . 541–61 . April 2014 . 24649957 . 10.4155/fmc.13.216 .
22. Foulkes DM, Byrne DP, Bailey FP, Eyers PA . Tribbles pseudokinases: novel targets for chemical biology and drug discovery? . Biochemical Society Transactions . 43 . 5 . 1095–103 . October 2015 . 26517930 . 10.1042/BST20150109 .
23. Cui J, Zhu Q, Zhang H, Cianfrocco MA, Leschziner AE, Dixon JE, Xiao J . Structure of Fam20A reveals a pseudokinase featuring a unique disulfide pattern and inverted ATP-binding . eLife . 6 . April 2017 . 28432788 . 5413348 . 10.7554/eLife.23990 . free .
24. Cui J, Xiao J, Tagliabracci VS, Wen J, Rahdar M, Dixon JE . A secretory kinase complex regulates extracellular protein phosphorylation . eLife . 4 . e06120 . March 2015 . 25789606 . 4421793 . 10.7554/eLife.06120 . free .
25. Tagliabracci VS, Wiley SE, Guo X, Kinch LN, Durrant E, Wen J, Xiao J, Cui J, Nguyen KB, Engel JL, Coon JJ, Grishin N, Pinna LA, Pagliarini DJ, Dixon JE . A Single Kinase Generates the Majority of the Secreted Phosphoproteome . Cell . 161 . 7 . 1619–32 . June 2015 . 26091039 . 4963185 . 10.1016/j.cell.2015.05.028 .
26. Kwon A, Scott S, Taujale R, Yeung W, Kochut KJ, Eyers PA, Kannan N . Tracing the origin and evolution of pseudokinases across the tree of life . Science Signaling . 12 . 578 . April 2019 . eaav3810 . 31015289 . 10.1126/scisignal.aav3810 . 6997932 .