Schultz et al. (1998) Proc. Natl. Acad. Sci. USA 95, 5857-5864
Letunic et al. (2012) Nucleic Acids Res , doi:10.1093/nar/gkr931

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PI3Kc Phosphoinositide 3-kinase, catalytic domain

SMART accession number:	SM00146
Description:	Phosphoinositide 3-kinase isoforms participate in a variety of processes, including cell motility, the Ras pathway, vesicle trafficking and secretion, and apoptosis. These homologues may be either lipid kinases and/or protein kinases: the former phosphorylate the 3-position in the inositol ring of inositol phospholipids. The ataxia telangiectesia-mutated gene produced, the targets of rapamycin (TOR) and the DNA-dependent kinase have not been found to possess lipid kinase activity. Some of this family possess PI-4 kinase activities.
Interpro abstract (IPR000403):	Phosphatidylinositol 3-kinase (PI3-kinase) (EC 2.7.1.137) [(PUBMED:1322797)] is an enzyme that phosphorylates phosphoinositides on the 3-hydroxyl group of the inositol ring. The three products of PI3-kinase - PI-3-P, PI-3,4-P(2) and PI-3,4,5-P(3) function as secondary messengers in cell signalling. Phosphatidylinositol 4-kinase (PI4-kinase) (EC 2.7.1.67) [(PUBMED:8194527)] is an enzyme that acts on phosphatidylinositol (PI) in the first committed step in the production of the secondary messenger inositol-1'4'5'-trisphosphate. This domain is also present in a wide range of protein kinases, involved in diverse cellular functions, such as control of cell growth, regulation of cell cycle progression, a DNA damage checkpoint, recombination, and maintenance of telomere length. Despite significant homology to lipid kinases, no lipid kinase activity has been demonstrated for any of the PIK-related kinases [(PUBMED:12456783)]. The PI3- and PI4-kinases share a well conserved domain at their C-terminal section; this domain seems to be distantly related to the catalytic domain of protein kinases [(PUBMED:8387896), (PUBMED:12151228)]. The catalytic domain of PI3K has the typical bilobal structure that is seen in other ATP-dependent kinases, with a small N-terminal lobe and a large C-terminal lobe. The core of this domain is the most conserved region of the PI3Ks. The ATP cofactor binds in the crevice formed by the N-and C-terminal lobes, a loop between two strands provides a hydrophobic pocket for binding of the adenine moiety, and a lysine residue interacts with the alpha-phosphate. In contrast to protein kinases, the PI3K loop which interacts with the phosphates of the ATP and is known as the glycine-rich or P-loop, contains no glycine residues. Instead, contact with the ATP -phosphate is maintained through the side chain of a conserved serine residue.
GO function:	phosphotransferase activity, alcohol group as acceptor (GO:0016773)
Family alignment:	View or CHROMA formatCLUSTALW formatMSF formatFASTA formatPIR format

There are 1845 PI3Kc domains in 1845 proteins in SMART's nrdb database.

Click on the following links for more information.

• Evolution (species in which this domain is found)

• Click on to expand nodes. To display all proteins with a PI3Kc domain in a specific node, click on it.

  This tree shows only several representative species. The complete taxonomic breakdown of all proteins with PI3Kc domain is also avaliable.

  Useful shortcuts: Expand all nodes or Collapse tree
  Go to specific node: Anopheles gambiae, Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus, Saccharomyces cerevisiae, Takifugu rubripes

• Cellular role (predicted cellular role)

• Binding / catalysis: phosphoinositide-phosphorylation

• Literature (relevant references for this domain)

• Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

  • Anderson RA, Boronenkov IV, Doughman SD, Kunz J, Loijens JC
  • Phosphatidylinositol phosphate kinases, a multifaceted family of signaling enzymes.
  • J Biol Chem. 1999; 274: 9907-10

  • Walker EH, Perisic O, Ried C, Stephens L, Williams RL
  • Structural insights into phosphoinositide 3-kinase catalysis and signalling.
  • Nature. 1999; 402: 313-20
  • Display abstract

  • Phosphoinositide 3-kinases (PI3Ks) are ubiquitous lipid kinases that function both as signal transducers downstream of cell-surface receptors and in constitutive intracellular membrane and protein trafficking pathways. All PI3Ks are dual-specificity enzymes with a lipid kinase activity which phosphorylates phosphoinositides at the 3-hydroxyl, and a protein kinase activity. The products of PI3K-catalysed reactions, phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3), PtdIns(3,4)P2 and PtdIns(3)P, are second messengers in a variety of signal transduction pathways, including those essential to cell proliferation, adhesion, survival, cytoskeletal rearrangement and vesicle trafficking. Here we report the 2.2 A X-ray crystallographic structure of the catalytic subunit of PI3Kgamma, the class I enzyme that is activated by heterotrimeric G-protein betagamma subunits and Ras. PI3Kgamma has a modular organization centred around a helical-domain spine, with C2 and catalytic domains positioned to interact with phospholipid membranes, and a Ras-binding domain placed against the catalytic domain where it could drive allosteric activation of the enzyme.

  • Ren XD, Schwartz MA
  • Regulation of inositol lipid kinases by Rho and Rac.
  • Curr Opin Genet Dev. 1998; 8: 63-7
  • Display abstract

  • Rho and Rac small GTPases associate with type-I phosphatidylinositol 4-phosphate 5-kinase to regulate the production of phosphatidylinositol 4,5-bisphosphate. This lipid appears to mediate some of the effects of Rho and Rac on the actin cytoskeleton. The genes for several type-I phosphatidylinositol 4-phosphate 5-kinases have been cloned recently but it is not known which one interacts with Rho and/or Rac. Rho family GTPases also interact with phosphatidylinositol 3-kinase, though this kinase can be either upstream or downstream of the GTPases depending upon the system.

  • Domin J, Waterfield MD
  • Using structure to define the function of phosphoinositide 3-kinase family members.
  • FEBS Lett. 1997; 410: 91-5

  • Toker A, Cantley LC
  • Signalling through the lipid products of phosphoinositide-3-OH kinase.
  • Nature. 1997; 387: 673-6
  • Display abstract

  • When a stimulatory agonist molecule binds at the exterior of the cell membrane, a second messenger transduces the signal to the interior of the cell. Second messengers can be derived from phospholipids in the membrane by the action of the enzymes phospholipase C or phosphoinositide-3-OH kinase (PI(3)K). PI(3)K is a key player in many cellular responses, including the movement of organelle membranes, shape alteration through rearrangement of cytoskeletal actin, transformation and chemotaxis. But how PI(3)K mediates these responses is only now becoming clear.

  • Vanhaesebroeck B, Leevers SJ, Panayotou G, Waterfield MD
  • Phosphoinositide 3-kinases: a conserved family of signal transducers.
  • Trends Biochem Sci. 1997; 22: 267-72
  • Display abstract

  • Phosphoinositide 3-kinases (PI3Ks) generate lipids that are implicated in receptor-stimulated signalling and in the regulation of membrane traffic. Several distinct classes of PI3Ks have now been identified that have been conserved throughout eukaryotic evolution. Potential signalling pathways downstream of PI3Ks have been elucidated and PI3K function is now being characterised in several model organisms.

  • Carpenter CL, Cantley LC
  • Phosphoinositide kinases.
  • Curr Opin Cell Biol. 1996; 8: 153-8
  • Display abstract

  • Recently, a number of cDNA clones with homology to the catalytic subunit of phosphoinositide 3-kinase have been identified, and the sequence of the first cDNA clone encoding a phosphatidylinositol 4-phosphate 5-kinase has been published. Use of both dominant-negative mutants of phosphoinositide 3-kinase and the inhibitors wortmannin and LY294002 has identified a number of processes in which phosphoinositide 3-kinase participates, including cell motility, the Ras pathway, vesicle trafficking and secretion, and apoptosis. Several possible biochemical targets of phosphoinositides have been found.

  • Keith CT, Schreiber SL
  • PIK-related kinases: DNA repair, recombination, and cell cycle checkpoints.
  • Science. 1995; 270: 50-1

  • Lavin MF, Khanna KK, Beamish H, Spring K, Watters D, Shiloh Y
  • Relationship of the ataxia-telangiectasia protein ATM to phosphoinositide 3-kinase.
  • Trends Biochem Sci. 1995; 20: 382-3

  • Kapeller R, Cantley LC
  • Phosphatidylinositol 3-kinase.
  • Bioessays. 1994; 16: 565-76
  • Display abstract

  • Currently, a central question in biology is how signals from the cell surface modulate intracellular processes. In recent years phosphoinositides have been shown to play a key role in signal transduction. Two phosphoinositide pathways have been characterized, to date. In the canonical phosphoinositide turnover pathway, activation of phosphatidylinositol-specific phospholipase C results in the hydrolysis of phosphatidylinositol 4,5-bisphosphate and the generation of two second messengers, inositol 1,4,5-trisphosphate and diacylglycerol. The 3-phosphoinositide pathway involves protein-tyrosine kinase-mediated recruitment and activation of phosphatidylinositol 3-kinase, resulting in the production of phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. The 3-phosphoinositides are not substrates of any known phospholipase C, are not components of the canonical phosphoinositide turnover pathway, and may themselves act as intracellular mediators. The 3-phosphoinositide pathway has been implicated in growth factor-dependent mitogenesis, membrane ruffling and glucose uptake. Furthermore the homology of the yeast vps34 with the mammalian phosphatidylinositol 3-kinase has suggested a role for this pathway in vesicular trafficking. In this review the different mechanisms employed by protein-tyrosine kinases to activate phosphatidylinositol 3-kinase, and its involvement in the signaling cascade initiated by tyrosine phosphorylation, are examined.

• Disease (disease genes where sequence variants are found in this domain)

• SwissProt sequences and OMIM curated human diseases associated with missense mutations within the PI3Kc domain.

  Protein	Disease
  Serine-protein kinase ATM (Q13315) (SMART)	OMIM:208900: Ataxia-telangiectasia ; T-cell prolymphocytic leukemia, sporadic ; Lymphoma, B-cell non-Hodgkin, somatic ; {Breast cancer, susceptibility to} ; Lymphoma, mantle cell

• Metabolism (metabolic pathways involving proteins which contain this domain)

• Click the image to view the interactive version of the map in iPath

  % proteins involved KEGG pathway ID Description 8.66 map04070 Phosphatidylinositol signaling system 7.50 map00562 Inositol phosphate metabolism 4.02 map05214 Glioma 4.02 map04910 Insulin signaling pathway 4.02 map05215 Prostate cancer 4.02 map04012 ErbB signaling pathway 4.02 map04150 mTOR signaling pathway 4.02 map05221 Acute myeloid leukemia 4.02 map04930 Type II diabetes mellitus 3.09 map04210 Apoptosis 2.40 map05222 Small cell lung cancer 2.40 map05213 Endometrial cancer 2.40 map04370 VEGF signaling pathway 2.40 map04662 B cell receptor signaling pathway 2.40 map04630 Jak-STAT signaling pathway 2.40 map05212 Pancreatic cancer 2.40 map05220 Chronic myeloid leukemia 2.40 map04670 Leukocyte transendothelial migration 2.40 map04810 Regulation of actin cytoskeleton 2.40 map05223 Non-small cell lung cancer 2.40 map04664 Fc epsilon RI signaling pathway 2.40 map05210 Colorectal cancer 2.40 map04620 Toll-like receptor signaling pathway 2.40 map04510 Focal adhesion 2.40 map04660 T cell receptor signaling pathway 2.40 map05211 Renal cell carcinoma 2.40 map05218 Melanoma 2.40 map04650 Natural killer cell mediated cytotoxicity 2.40 map04914 Progesterone-mediated oocyte maturation 2.09 map04140 Regulation of autophagy 1.86 map04110 Cell cycle 1.62 map04920 Adipocytokine signaling pathway 1.24 map04115 p53 signaling pathway 0.23 map04111 Cell cycle - yeast This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with PI3Kc domain which could be assigned to a KEGG orthologous group, and not all proteins containing PI3Kc domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

• Structure (3D structures containing this domain)

• 3D Structures of PI3Kc domains in PDB

  PDB code	Main view	Title
  1e7u		Structure determinants of phosphoinositide 3-kinase inhibition by wortmannin, ly294002, quercetin, myricetin and staurosporine
  1e7v		Structure determinants of phosphoinositide 3-kinase inhibition by wortmannin, ly294002, quercetin, myricetin and staurosporine
  1e8w		Structure determinants of phosphoinositide 3-kinase inhibition by wortmannin, ly294002, quercetin, myricetin and staurosporine
  1e8x		Structural insights into phoshoinositide 3-kinase enzymatic mechanism and signalling
  1e8y		Structure determinants of phosphoinositide 3-kinase inhibition by wortmannin, ly294002, quercetin, myricetin and staurosporine
  1e8z		Structure determinants of phosphoinositide 3-kinase inhibition by wortmannin, ly294002, quercetin, myricetin and staurosporine
  1e90		Structure determinants of phosphoinositide 3-kinase inhibition by wortmannin, ly294002, quercetin, myricetin and staurosporine
  1he8		Ras g12v - pi 3-kinase gamma complex
  2a4z		Crystal structure of human pi3kgamma complexed with as604850
  2a5u		Crystal structure of human pi3kgamma complexed with as605240
  2chw		A pharmacological map of the pi3-k family defines a role for p110 alpha in signaling: the structure of complex of phosphoinositide 3-kinase gamma with inhibitor pik-39
  2chx		A pharmacological map of the pi3-k family defines a role for p110alpha in signaling: the structure of complex of phosphoinositide 3-kinase gamma with inhibitor pik-90
  2chz		A pharmacological map of the pi3-k family defines a role for p110alpha in signaling: the structure of complex of phosphoinositide 3-kinase gamma with inhibitor pik-93
  2rd0		Structure of a human p110alpha/p85alpha complex
  2v4l		Complex of human phosphoinositide 3-kinase catalytic subunit gamma (p110 gamma) with pik-284
  3csf		Crystal structure of pi3k p110gamma catalytical domain in complex with organoruthenium inhibitor dw2
  3cst		Crystal structure of pi3k p110gamma catalytical domain in complex with organoruthenium inhibitor e5e2
  3dbs		Structure of pi3k gamma in complex with gdc0941
  3dpd		Achieving multi-isoform pi3k inhibition in a series of substituted 3,4-dihydro-2h-benzo[1,4]oxazines
  3ene		Complex of pi3k gamma with an inhibitor
  3hhm		Crystal structure of p110alpha h1047r mutant in complex with nish2 of p85alpha and the drug wortmannin
  3hiz		Crystal structure of p110alpha h1047r mutant in complex with nish2 of p85alpha
  3ibe		Crystal structure of a pyrazolopyrimidine inhibitor bound to pi3 kinase gamma
  3ihy		Human pik3c3 crystal structure

• Links (links to other resources describing this domain)

• BLOCKS	PI3_4_KINASE_1
  PFAM	PI3_PI4_kinase
  INTERPRO	IPR000403

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