PI3KaPhosphoinositide 3-kinase family, accessory domain (PIK domain)
|SMART accession number:||SM00145|
|Description:||PIK domain is conserved in all PI3 and PI4-kinases. Its role is unclear but it has been suggested to be involved in substrate presentation.|
|Interpro abstract (IPR001263):|
Phosphatidylinositol 3-kinase (PI3-kinase) (EC 18.104.22.168) is an enzyme that phosphorylates phosphoinositides on the 3-hydroxyl group of the inositol ring. The role of the accessory domain of phosphoinositide 3-kinase (PI3-kinase) is unclear. It may be involved in substrate presentation [(PUBMED:8248783)].
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- Evolution (species in which this domain is found)
Click on to expand nodes. To display all proteins with a PI3Ka domain in a specific node, click on it.
This tree shows only several representative species. The complete taxonomic breakdown of all proteins with PI3Ka domain is also avaliable.
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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: unknown
- Literature (relevant references for this domain)
Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.
- 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.
- 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.
- 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.
- Flanagan CA, Schnieders EA, Emerick AW, Kunisawa R, Admon A, Thorner J
- Phosphatidylinositol 4-kinase: gene structure and requirement for yeast cell viability.
- Science. 1993; 262: 1444-8
- Display abstract
Phosphatidylinositol (PtdIns) 4-kinase catalyzes the first step in the biosynthesis of PtdIns-4,5-bisphosphate (PtdIns[4,5]P2). Hydrolysis of PtdIns[4,5]P2 in response to extracellular stimuli is thought to initiate intracellular signaling cascades that modulate cell proliferation and differentiation. The PIK1 gene encoding a PtdIns 4-kinase from the yeast Saccharomyces cerevisiae was isolated by polymerase chain reaction (PCR) with oligonucleotides based on the sequence of peptides derived from the purified enzyme. The sequence of the PIK1 gene product bears similarities to that of PtdIns 3-kinases from mammals (p110) and yeast (Vps34p). Expression of PIK1 from a multicopy plasmid elevated PtdIns 4-kinase activity and enhanced the response to mating pheromone. A pik1 null mutant was inviable, indicating that PtdIns4P and presumably PtdIns[4,5]P2 are indispensable phospholipids.
- Metabolism (metabolic pathways involving proteins which contain this domain)
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% proteins involved KEGG pathway ID Description 8.46 map04070 Phosphatidylinositol signaling system 6.98 map00562 Inositol phosphate metabolism 3.05 map05222 Small cell lung cancer 3.05 map04664 Fc epsilon RI signaling pathway 3.05 map05210 Colorectal cancer 3.05 map05213 Endometrial cancer 3.05 map04370 VEGF signaling pathway 3.05 map04620 Toll-like receptor signaling pathway 3.05 map04662 B cell receptor signaling pathway 3.05 map05212 Pancreatic cancer 3.05 map04630 Jak-STAT signaling pathway 3.05 map05220 Chronic myeloid leukemia 3.05 map04210 Apoptosis 3.05 map04510 Focal adhesion 3.05 map04670 Leukocyte transendothelial migration 3.05 map04910 Insulin signaling pathway 3.05 map05215 Prostate cancer 3.05 map05214 Glioma 3.05 map04012 ErbB signaling pathway 3.05 map04810 Regulation of actin cytoskeleton 3.05 map04150 mTOR signaling pathway 3.05 map04660 T cell receptor signaling pathway 3.05 map05211 Renal cell carcinoma 3.05 map05221 Acute myeloid leukemia 3.05 map04930 Type II diabetes mellitus 3.05 map05223 Non-small cell lung cancer 3.05 map05218 Melanoma 3.05 map04650 Natural killer cell mediated cytotoxicity 3.05 map04914 Progesterone-mediated oocyte maturation 2.26 map04140 Regulation of autophagy
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 PI3Ka domain which could be assigned to a KEGG orthologous group, and not all proteins containing PI3Ka 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 PI3Ka 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 1e8z 1e90 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)