Kinase Family PIK

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Kinase Classification: Group PKL: Family PIK

Related to PIKK, these phosphorylate phosphatidyl inositol on the 3' and 4' positions (PI3K, PI4K), and some have autokinase activity.

The PIK family has the following subfamilies:

Subfamily PI3K1

Includes human genes PIK3CA (p110a), PIK3CB (p110b), PIK3CG (p110g) and PIK3CD (p110 delta)

Subfamily PI3K2

includes human genes PIK3C2A, PIK3C2B, and PIK3C2G

Subfamily PI3K3

PI3K3 includes the human PIK3C3 and yeast vps34.

Subfamily PI4KA

Includes human PI4KA

PI4KB includes human PI4KB

Subfamily PI4K2

Is a highly divergent subfamily of PIK and includes human PI4K2A and PI4K2B.

Subfamily AFK (Actin Fragmin Kinase)

Is a protein kinase with remote similarity to PI4K2.


Domain Structure

Varied

Evolution

Protein Kinase Activity

Several reports indicate that multiple PIKs have autokinase (autophosphorylation) activity, in addition to their inositol kinase activities.

All four human PI3K1 (p110) proteins have been reported to autophosphorylate and to transphosphorylate their p85 regulatory partners [1, 2, 3, 4], and for all but PIK3CG, autophosphorylation inhibited kinase activity. Curiously, the phosphorylation site on the B form is the absolutely last amino acid, and that of G is second-to-last [2], while the D autophosphorylation is 6 AA from the end [3].

Phosphorylation on the p85 alpha subunit at Ser-608 inhibited kinase activity and p85-p110 association and was modulated in vivo []. Partially purified human PIK3CG could autophosphorylate on serine and phosphorylate its binding partner, p85a on Ser-608 [4]. Mutation of chemical inhibition both destroyed both the lipid and protein kinase activities, arguing that the activity is not due to a co-purifying kinase. The functional effect of the autophosphorylation is unknown, but the p85 phosphorylation is predicted to inhibit activity of PI3Kg. PIK3CA was also associated with a copurifying activity that could shown to phosphorylate both itself and p85 [1]. PIK3CD could also autophosphorylate and phosphorlyate p85, and autophosphorylateion was shown to inhibit activity [3].

Yeast Vps34 (PI3K3) was shown to autophosphorylate on serine [5], and the C. albicans Vps34 was mutated to abolish lipid kinase activity but retain autophosphorylation when expressed in E. coli [6].

Human PI4KB, expressed as an E. coli fusion protein was shown to autophosphorylate and this phosphorylation was inhibitory [7], and PI4KA may also have protein kinase activity: it associates with and causes hyperphosphorylation of Hepatitis C protein NS5A, and one report indicated preliminary observation of in vitro protein kinase activity [8]

References

  1. Carpenter CL, Auger KR, Duckworth BC, Hou WM, Schaffhausen B, and Cantley LC. A tightly associated serine/threonine protein kinase regulates phosphoinositide 3-kinase activity. Mol Cell Biol. 1993 Mar;13(3):1657-65. DOI:10.1128/mcb.13.3.1657-1665.1993 | PubMed ID:8382773 | HubMed [Carpenter]
  2. Czupalla C, Culo M, Müller EC, Brock C, Reusch HP, Spicher K, Krause E, and Nürnberg B. Identification and characterization of the autophosphorylation sites of phosphoinositide 3-kinase isoforms beta and gamma. J Biol Chem. 2003 Mar 28;278(13):11536-45. DOI:10.1074/jbc.M210351200 | PubMed ID:12502714 | HubMed [Czupalla]
  3. Vanhaesebroeck B, Higashi K, Raven C, Welham M, Anderson S, Brennan P, Ward SG, and Waterfield MD. Autophosphorylation of p110delta phosphoinositide 3-kinase: a new paradigm for the regulation of lipid kinases in vitro and in vivo. EMBO J. 1999 Mar 1;18(5):1292-302. DOI:10.1093/emboj/18.5.1292 | PubMed ID:10064595 | HubMed [Vanhaesebroeck]
  4. Stoyanova S, Bulgarelli-Leva G, Kirsch C, Hanck T, Klinger R, Wetzker R, and Wymann MP. Lipid kinase and protein kinase activities of G-protein-coupled phosphoinositide 3-kinase gamma: structure-activity analysis and interactions with wortmannin. Biochem J. 1997 Jun 1;324 ( Pt 2)(Pt 2):489-95. DOI:10.1042/bj3240489 | PubMed ID:9182708 | HubMed [Stoyanova]
  5. Stack JH and Emr SD. Vps34p required for yeast vacuolar protein sorting is a multiple specificity kinase that exhibits both protein kinase and phosphatidylinositol-specific PI 3-kinase activities. J Biol Chem. 1994 Dec 16;269(50):31552-62. PubMed ID:7989323 | HubMed [Stack]
  6. Günther J, Nguyen M, Härtl A, Künkel W, Zipfel PF, and Eck R. Generation and functional in vivo characterization of a lipid kinase defective phosphatidylinositol 3-kinase Vps34p of Candida albicans. Microbiology (Reading). 2005 Jan;151(Pt 1):81-89. DOI:10.1099/mic.0.27333-0 | PubMed ID:15632428 | HubMed [Gunther]
  7. Zhao XH, Bondeva T, and Balla T. Characterization of recombinant phosphatidylinositol 4-kinase beta reveals auto- and heterophosphorylation of the enzyme. J Biol Chem. 2000 May 12;275(19):14642-8. DOI:10.1074/jbc.275.19.14642 | PubMed ID:10799551 | HubMed [Zhao]
  8. Reiss S, Harak C, Romero-Brey I, Radujkovic D, Klein R, Ruggieri A, Rebhan I, Bartenschlager R, and Lohmann V. The lipid kinase phosphatidylinositol-4 kinase III alpha regulates the phosphorylation status of hepatitis C virus NS5A. PLoS Pathog. 2013 May;9(5):e1003359. DOI:10.1371/journal.ppat.1003359 | PubMed ID:23675303 | HubMed [Reiss]
  9. Foukas LC, Beeton CA, Jensen J, Phillips WA, and Shepherd PR. Regulation of phosphoinositide 3-kinase by its intrinsic serine kinase activity in vivo. Mol Cell Biol. 2004 Feb;24(3):966-75. DOI:10.1128/MCB.24.3.966-975.2004 | PubMed ID:14729945 | HubMed [Foukas]
  10. 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 | PubMed ID:10777481 | HubMed [Itoh]
All Medline abstracts: PubMed | HubMed