Kinase Family PIPK

Kinase Classification: Group Atypical: Family PIP5K

PIP5K contains a number of different inositol kinases, some of which have reported to have protein kinase activity.

Kinase Domain

The PIP5K kinase domain is related both to the PKL kinases as well as to the ATP-Grasp fold of ATP-driven enzymes [1]. These kinases may share most of the active site residues of PKL kinases.

Subfamilies

There are three major subfamilies:

PIP5K1 includes human PIP5K1A, B, C (or alpha/beta/gamma)

PIP4K2 includes human PIP4K2A, B, C (or alpha/beta/gamma)

PIP5K3 includes a single human gene, PIKFYVE

Protein Kinase Activity

All four human PIP5K1 proteins showed autophosphorylation on Ser/Thr [2]. PIP5K1B produced in E. coli retained activity (suggesting that the activity was not due to a copurifying protein), and a mutant of PIP5K1A that had lost lipid kinase activity also failed to autophosphorylate. This autophosphorylation inhibited the lipid kinase activity. The same report saw phosphorylation of all three human PIP4K2 when isolated from COS-7 cells, but saw no activity when purified from E. coli, suggesting that this activity might be due to a copurifying protein kinase. The PIP4K2-associated activity may be from PKD1, which associates with both PIP5K1 and PIP4K2 [3].

PIKFYVE has also been reported to autophosphorylate and transphosphorylate [4], when immunoprecipitated from mammalian cells. A lipid-kinase-dead point mutant also abolished protein kinase activity. As with other PI5K, autophosphorylation inhibited lipid kinase activity.

Domain Structure

TBA

Evolution

All three subfamilies are found in most eukaryotes. PIP5K1 is absent from plants and PIP4K2 may be lacking in fungi, with PIP5K3 absent from both [5].

References

1. Grishin NV. Phosphatidylinositol phosphate kinase: a link between protein kinase and glutathione synthase folds. J Mol Biol. 1999 Aug 13;291(2):239-47. DOI:10.1006/jmbi.1999.2973 |
2. Itoh T, Ishihara H, Shibasaki Y, Oka Y, and Takenawa T. Autophosphorylation of type I phosphatidylinositol phosphate kinase regulates its lipid kinase activity. J Biol Chem. 2000 Jun 23;275(25):19389-94. DOI:10.1074/jbc.M000426200 |
3. Nishikawa K, Toker A, Wong K, Marignani PA, Johannes FJ, and Cantley LC. Association of protein kinase Cmu with type II phosphatidylinositol 4-kinase and type I phosphatidylinositol-4-phosphate 5-kinase. J Biol Chem. 1998 Sep 4;273(36):23126-33. DOI:10.1074/jbc.273.36.23126 |
4. Sbrissa D, Ikonomov OC, and Shisheva A. PIKfyve lipid kinase is a protein kinase: downregulation of 5'-phosphoinositide product formation by autophosphorylation. Biochemistry. 2000 Dec 26;39(51):15980-9. DOI:10.1021/bi001897f |
5. Brown JR and Auger KR. Phylogenomics of phosphoinositide lipid kinases: perspectives on the evolution of second messenger signaling and drug discovery. BMC Evol Biol. 2011 Jan 5;11:4. DOI:10.1186/1471-2148-11-4 |