SMART: PI3Ka domain annotation

PI3Ka Phosphoinositide 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 2.7.1.137) 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)].
Family alignment:	View or

There are 632 PI3Ka domains in 631 proteins in SMART's nrdb database.

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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)

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		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)
INTERPRO IPR001263