Kinase Subfamily PKX

Kinase Classification: Group AGC: Family PKA: Subfamily PKX

PKX is a distinct subfamily of PKA, the cAMP-regulated protein kinase.

Evolution

PKX is found in all animal genomes studied. Outside of the animals, many eukaryotes have two PKA family proteins, with one weakly more similar to animal PKA and the other more similar to PKX. A single residue in the catalytic region clearly distinguishes these two extended subfamilies, and has been shown to mediate interaction between PKA subfamily members and the R2 (pseudosubstrate) regulatory subunits, (PKX members interact only with the R1 subunit) [1]. Most vertebrates have a single PKX, on the X chromosome, but humans have a duplication to make PRKY, on the Y chromosome. PRKY has a stop codon before the end of the kinase domain and is a likely pseudogene. Possible PRKY genes have been seen in other primate genomes and mapped to the Y chromosome of dog [2].

Domain Structure

Like other PKA, PKX genes have a kinase domain followed by a Pkinase_C C-terminal extension, and an unannotated N-terminal region.

Functions

Drosophila PKA-C3 interacts with Swiss Cheese (SWS), an ER-tethered esterase involved in both neurogenesis and neurodegeneration [3]. SWS has sequence similarity to PKA regulatory subunits in both the kinase-interacting region and in having cNMP-binding domains. PKA subfamily members do not interact with SWS. The human ortholog of SWS, PNPLA6 is also regulated by PKA family inhibitors and agonists [4] .

PKX has a weakly-described but conserved link to muscle development: The PKA-C3 promoter was found to bind the myogenic transcription factor Dmef2 [5], while the worm PKX, F47F2.1 was one of 122 genes shown to have a defect in myofilament formation in an RNAi screen [6]

Human PRKX has been implicated in the development of tubular epithelia during kidney formation and angiogenesis [7], and is also highly expressed during stages of neurogenesis. PRKX may have an opposite effect to PKA during angiogenesis [8]. Several studies have shown a role in polycistic kidney disease by interacting with Polycistin-1 [9, 10]. PRKX is expressed during and required for macrophage differentiation [11, 12], where it phosphorylates the TGFb signaling adaptor, Smad6 [13]. PRKX is dynamically expressed during development, particularly in developing epithelia and brain [14, 15].

References

1. Diskar M, Zenn HM, Kaupisch A, Kaufholz M, Brockmeyer S, Sohmen D, Berrera M, Zaccolo M, Boshart M, Herberg FW, and Prinz A. Regulation of cAMP-dependent protein kinases: the human protein kinase X (PrKX) reveals the role of the catalytic subunit alphaH-alphaI loop. J Biol Chem. 2010 Nov 12;285(46):35910-8. DOI:10.1074/jbc.M110.155150 |
2. Toder R, Gläser B, Schiebel K, Wilcox SA, Rappold G, Graves JA, and Schempp W. Genes located in and near the human pseudoautosomal region are located in the X-Y pairing region in dog and sheep. Chromosome Res. 1997 Aug;5(5):301-6. DOI:10.1023/B:CHRO.0000038760.84605.0d |
3. Bettencourt da Cruz A, Wentzell J, and Kretzschmar D. Swiss Cheese, a protein involved in progressive neurodegeneration, acts as a noncanonical regulatory subunit for PKA-C3. J Neurosci. 2008 Oct 22;28(43):10885-92. DOI:10.1523/JNEUROSCI.3015-08.2008 |
4. Chen JX, Long DX, Hou WY, Li W, and Wu YJ. Regulation of neuropathy target esterase by the cAMP/protein kinase A signal. Pharmacol Res. 2010 Sep;62(3):259-64. DOI:10.1016/j.phrs.2010.03.006 |
5. Junion G, Jagla T, Duplant S, Tapin R, Da Ponte JP, and Jagla K. Mapping Dmef2-binding regulatory modules by using a ChIP-enriched in silico targets approach. Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18479-84. DOI:10.1073/pnas.0507030102 |
6. Meissner B, Warner A, Wong K, Dube N, Lorch A, McKay SJ, Khattra J, Rogalski T, Somasiri A, Chaudhry I, Fox RM, Miller DM 3rd, Baillie DL, Holt RA, Jones SJ, Marra MA, and Moerman DG. An integrated strategy to study muscle development and myofilament structure in Caenorhabditis elegans. PLoS Genet. 2009 Jun;5(6):e1000537. DOI:10.1371/journal.pgen.1000537 |
7. Tu SI, Nagahashi G, and Sliwinski BJ. Regulatory effects of adenosine diphosphate on the activity of the plasma membrane ATPase of corn roots. Biochem Biophys Res Commun. 1984 Aug 16;122(3):1367-73. DOI:10.1016/0006-291x(84)91242-7 |
8. Li X, Iomini C, Hyink D, and Wilson PD. PRKX critically regulates endothelial cell proliferation, migration, and vascular-like structure formation. Dev Biol. 2011 Aug 15;356(2):475-85. DOI:10.1016/j.ydbio.2011.05.673 |
9. Li X, Hyink DP, Radbill B, Sudol M, Zhang H, Zheleznova NN, and Wilson PD. Protein kinase-X interacts with Pin-1 and Polycystin-1 during mouse kidney development. Kidney Int. 2009 Jul;76(1):54-62. DOI:10.1038/ki.2009.95 |
10. Li X, Burrow CR, Polgar K, Hyink DP, Gusella GL, and Wilson PD. Protein kinase X (PRKX) can rescue the effects of polycystic kidney disease-1 gene (PKD1) deficiency. Biochim Biophys Acta. 2008 Jan;1782(1):1-9. DOI:10.1016/j.bbadis.2007.09.003 |
11. Junttila I, Bourette RP, Rohrschneider LR, and Silvennoinen O. M-CSF induced differentiation of myeloid precursor cells involves activation of PKC-delta and expression of Pkare. J Leukoc Biol. 2003 Feb;73(2):281-8. DOI:10.1189/jlb.0702359 |
12. Semizarov D, Glesne D, Laouar A, Schiebel K, and Huberman E. A lineage-specific protein kinase crucial for myeloid maturation. Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15412-7. DOI:10.1073/pnas.95.26.15412 |
13. Glesne D and Huberman E. Smad6 is a protein kinase X phosphorylation substrate and is required for HL-60 cell differentiation. Oncogene. 2006 Jul 6;25(29):4086-98. DOI:10.1038/sj.onc.1209436 |
14. Li W, Yu ZX, and Kotin RM. Profiles of PrKX expression in developmental mouse embryo and human tissues. J Histochem Cytochem. 2005 Aug;53(8):1003-9. DOI:10.1369/jhc.4A6568.2005 |
16. Blaschke RJ, Monaghan AP, Bock D, and Rappold GA. A novel murine PKA-related protein kinase involved in neuronal differentiation. Genomics. 2000 Mar 1;64(2):187-94. DOI:10.1006/geno.2000.6116 |