Kinase Subfamily PKX

Kinase Classification: Group AGC: Family PKA: Subfamily PKX

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

Evolution

Clear PKX genes are found in all animal genomes studied. Outside of the animals, many eukaryotes have two PKA family proteins, with one more similar to metazoan PKA and the other more similar to PKX, though the orthology is not highly significant. 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, while 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. It 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.

Domain Structure

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

Functions

Drosophila PKA-C3 interacts with Swiss Cheese (SWS), which has homology to PKA regulatory subunits, and is an ER-tethered esterase involved in both neurogenesis and neurodegeneration []. PKA subfamily members do not have this interaction. The human ortholog of SWS, PNPLA6 is also regulated by PKA family inhibitors and agonists [2]

Cα and human PrKX differ by their selective holoenzyme formation in living cells, as PrKX is inhibited only by RIα, but not by RIIα (14, 15). Here, we have tested all four human R subunits for the first time side by side and show that this so far unique property of RI over RII preference with respect to autoinhibition appears to be an evolutionarily conserved feature of PrKX and at least four of its orthologs (Mus musculus Pkare, Drosophila melanogaster DC2, Trypanosoma brucei PKAC3, human PrKY), and possibly also Caenorhabditis elegans F47F2.1b

Human PRKX has been implicated in the development of tubular epithelia during kidney formation and angiogenesis [3], and is also highly expressed during stages of neurogenesis. PRKX may have an opposite effect to PKA during angiogenesis [4]. Several studies have shown a role in polycistic kidney disease and Polycistin-1 [5, 6]. PRKX is expressed during and required for macrophage diffenentiation [7, 8], where it phosphorylates the TGFb signaling adaptor, Smad6 [9]. PRKX is dynamically expressed during development, particularly in developing epithelia and brain [10, 11].

The worm ortholog, F47F2.1 was one of 122 genes shown to have a defect in myofilament formation in an RNAi screen [12]

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. pmid= 20380879
3. pmid= 6236808
4. 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 |
5. 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 |
6. 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 |
7. 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 |
8. 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 |
9. 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 |
10. 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 |
12. 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 |
13. 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 |