Pseudokinases-remnants of Evolution or Key Allosteric Regulators?

Overview

Journal Curr Opin Struct Biol

Date 2010 Nov 16

PMID 21074407

Citations 77

Authors

Elton Zeqiraj

Daan M F van Aalten

Affiliations

Soon will be listed here.

Abstract

Protein kinases provide a platform for the integration of signal transduction networks. A key feature of transmitting these cellular signals is the ability of protein kinases to activate one another by phosphorylation. A number of kinases are predicted by sequence homology to be incapable of phosphoryl group transfer due to degradation of their catalytic motifs. These are termed pseudokinases and because of the assumed lack of phosphoryltransfer activity their biological role in cellular transduction has been mysterious. Recent structure-function studies have uncovered the molecular determinants for protein kinase inactivity and have shed light to the biological functions and evolution of this enigmatic subset of the human kinome. Pseudokinases act as signal transducers by bringing together components of signalling networks, as well as allosteric activators of active protein kinases.

Citing Articles

Activation of CAMK2 by pseudokinase PEAK1 represents a targetable pathway in triple negative breast cancer.

Yang X, Ma X, Zhao T, Croucher D, Nguyen E, Clark K Nat Commun. 2025; 16(1):1871.

PMID: 39984440 PMC: 11845518. DOI: 10.1038/s41467-025-57046-8.

NRBP1 promotes malignant phenotypes of glioblastoma by regulating PI3K/Akt activation.

Zhang A, Peng S, Sun S, Ye S, Zhao Y, Wu Q Cancer Med. 2024; 13(16):e70100.

PMID: 39149873 PMC: 11327863. DOI: 10.1002/cam4.70100.

Trans-activating mutations of the pseudokinase ERBB3.

Koivu M, Chakroborty D, Airenne T, Johnson M, Kurppa K, Elenius K Oncogene. 2024; 43(29):2253-2265.

PMID: 38806620 PMC: 11245391. DOI: 10.1038/s41388-024-03070-9.

Illumination of understudied ciliary kinases.

Flax R, Rosston P, Rocha C, Anderson B, Capener J, Durcan T Front Mol Biosci. 2024; 11:1352781.

PMID: 38523660 PMC: 10958382. DOI: 10.3389/fmolb.2024.1352781.

Large-scale analysis of the N-terminal regulatory elements of the kinase domain in plant Receptor-like kinase family.

Fu Q, Liu Q, Zhang R, Chen J, Guo H, Ming Z BMC Plant Biol. 2024; 24(1):174.

PMID: 38443815 PMC: 10916322. DOI: 10.1186/s12870-024-04846-7.

References

Jura N, Endres N, Engel K, Deindl S, Das R, Lamers M . Mechanism for activation of the EGF receptor catalytic domain by the juxtamembrane segment. Cell. 2009; 137(7):1293-307. PMC: 2814540. DOI: 10.1016/j.cell.2009.04.025. View

Zhang X, Gureasko J, Shen K, Cole P, Kuriyan J . An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell. 2006; 125(6):1137-49. DOI: 10.1016/j.cell.2006.05.013. View

Villa F, Capasso P, Tortorici M, Forneris F, de Marco A, Mattevi A . Crystal structure of the catalytic domain of Haspin, an atypical kinase implicated in chromatin organization. Proc Natl Acad Sci U S A. 2009; 106(48):20204-9. PMC: 2777964. DOI: 10.1073/pnas.0908485106. View

Sharma R . Evolution of the membrane guanylate cyclase transduction system. Mol Cell Biochem. 2002; 230(1-2):3-30. View

Kolch W . Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol. 2005; 6(11):827-37. DOI: 10.1038/nrm1743. View

Boudeau J, Miranda-Saavedra D, Barton G, Alessi D . Emerging roles of pseudokinases. Trends Cell Biol. 2006; 16(9):443-52. DOI: 10.1016/j.tcb.2006.07.003. View

Kim C, Xuong N, Taylor S . Crystal structure of a complex between the catalytic and regulatory (RIalpha) subunits of PKA. Science. 2005; 307(5710):690-6. DOI: 10.1126/science.1104607. View

Zeqiraj E, Filippi B, Goldie S, Navratilova I, Boudeau J, Deak M . ATP and MO25alpha regulate the conformational state of the STRADalpha pseudokinase and activation of the LKB1 tumour suppressor. PLoS Biol. 2009; 7(6):e1000126. PMC: 2686265. DOI: 10.1371/journal.pbio.1000126. View

Good M, Tang G, Singleton J, Remenyi A, Lim W . The Ste5 scaffold directs mating signaling by catalytically unlocking the Fus3 MAP kinase for activation. Cell. 2009; 136(6):1085-97. PMC: 2777755. DOI: 10.1016/j.cell.2009.01.049. View

10.

Baxter E, Scott L, Campbell P, East C, Fourouclas N, Swanton S . Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005; 365(9464):1054-61. DOI: 10.1016/S0140-6736(05)71142-9. View

11.

Manning G, Whyte D, Martinez R, Hunter T, Sudarsanam S . The protein kinase complement of the human genome. Science. 2002; 298(5600):1912-34. DOI: 10.1126/science.1075762. View

12.

Kawagoe T, Sato S, Matsushita K, Kato H, Matsui K, Kumagai Y . Sequential control of Toll-like receptor-dependent responses by IRAK1 and IRAK2. Nat Immunol. 2008; 9(6):684-91. DOI: 10.1038/ni.1606. View

13.

James C, Ugo V, Le Couedic J, Staerk J, Delhommeau F, Lacout C . A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005; 434(7037):1144-8. DOI: 10.1038/nature03546. View

14.

Labesse G, Gelin M, Bessin Y, Lebrun M, Papoin J, Cerdan R . ROP2 from Toxoplasma gondii: a virulence factor with a protein-kinase fold and no enzymatic activity. Structure. 2009; 17(1):139-46. DOI: 10.1016/j.str.2008.11.005. View

15.

Kannan N, Taylor S, Zhai Y, Venter J, Manning G . Structural and functional diversity of the microbial kinome. PLoS Biol. 2007; 5(3):e17. PMC: 1821047. DOI: 10.1371/journal.pbio.0050017. View

16.

Jeffrey P, Russo A, Polyak K, Gibbs E, Hurwitz J, Massague J . Mechanism of CDK activation revealed by the structure of a cyclinA-CDK2 complex. Nature. 1995; 376(6538):313-20. DOI: 10.1038/376313a0. View

17.

Kornev A, Haste N, Taylor S, Ten Eyck L . Surface comparison of active and inactive protein kinases identifies a conserved activation mechanism. Proc Natl Acad Sci U S A. 2006; 103(47):17783-8. PMC: 1693824. DOI: 10.1073/pnas.0607656103. View

18.

Bhandari R, Srinivasan N, Mahaboobi M, Ghanekar Y, Suguna K, Visweswariah S . Functional inactivation of the human guanylyl cyclase C receptor: modeling and mutation of the protein kinase-like domain. Biochemistry. 2001; 40(31):9196-206. DOI: 10.1021/bi002595g. View

19.

Hanks S, Quinn A, Hunter T . The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science. 1988; 241(4861):42-52. DOI: 10.1126/science.3291115. View

20.

Scheeff E, 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. 2009; 17(1):128-38. PMC: 2639636. DOI: 10.1016/j.str.2008.10.018. View