Kinase Family PIPK
Kinase Classification: Group PKL: Family PIPK
PIPK phosphorylate already-phosphorylated phosphatidyl inositols, and some have reported protein kinase activity. They generally transform phosphatidyl insositol phosphate into phosphatidyl inositol bisphosphates, which regulate secretion, vesicular trafficking, membrane translocation, cell adhesion, chemotaxis, cell cycle and DNA synthesis. PIPKs have a variety of substrates, of which the primary ones are listed here.
Kinase Domain
The PIPK kinase domain is related both to the PKL kinases as well as to the ATP-Grasp fold of ATP-driven enzymes [1, 2]. These kinases may share most of the active site residues of PKL kinases. For that reason, they are included here within the PKL group, though other systems such as SCOP classify them in as a distinct fold.
Subfamilies
The PIPK family has three major subfamilies:
Subfamily PIP5K1
(Type I phosphatidylinositol-4-phosphate 5-kinase) includes human PIP5K1A, B, C (or alpha/beta/gamma), transforms PI4P to PI(4,5)P2
Subfamily PIP4K2
(Type II phosphatidylinositol-5-phosphate 4-kinase)includes human PIP4K2A, B, C (or alpha/beta/gamma), transforms PI5P to PI(4,5)P2
Subfamily PIP5K3
(Type III phosphatidylinositol-4-phosphate 5-kinase) includes a single human gene, PIKFYVE, transofrms PI to PI(3,5)P2
Protein Kinase Activity
All three human PIP5K1 proteins showed autophosphorylation on Ser/Thr [3]. 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 [4].
PIKFYVE has also been reported to autophosphorylate and transphosphorylate [5], when immunoprecipitated from mammalian cells. A lipid-kinase-dead point mutant also abolished protein kinase activity. As with other PIPK, autophosphorylation inhibited lipid kinase activity.
Is the protein kinase activity real or relevant?
The protein kinase activities of PIPK is not surprising, since they are already known to be kinase enzymes, but their protein kinase activity is not absolutely certain to exist or to be biologically relevant. For both PIP4K1 and PIKFYVE, the initial reports of protein kinase activity do not seem to have been replicated, and the activity associated with PIP4K2 was not found in bacterially-produced protein.
Other Functions
Phosphatidylinositol phosphate kinases (PIPK) catalyze the phosphorylation of phosphatidylinositol phosphate on the fourth or fifth hydroxyl of the inositol ring, to form phosphatidylinositol bisphosphates. These products regulate secretion, vesicular trafficking, membrane translocation, cell adhesion, chemotaxis, cell cycle and DNA synthesis.
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 [6].
References
- 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 |
- Scheeff ED and Bourne PE. Structural evolution of the protein kinase-like superfamily. PLoS Comput Biol. 2005 Oct;1(5):e49. DOI:10.1371/journal.pcbi.0010049 |
- 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 |
- 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 |
- 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 |
- 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 |
