| SMART accession number: | SM00144
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| Description: |
Certain members of the PI3K family possess Ras-binding domains in their N-termini. These regions show some similarity (although not highly significant similarity) to Ras-binding RA domains (unpublished observation). |
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| Interpro abstract (IPR000341): |
Phosphatidylinositol 3-kinase (PI3K) (EC 2.7.1.137) is an enzyme that phosphorylates phosphoinositides on the 3-hydroxyl group of the inositol ring. A subset of PI3Ks has the capacity to bind and be activated by the GTP-bound small GTPase p21Ras (Ras). PI3Ks are recognized as one of the principal effectors of Ras signalling to the cell-cycle control machinery. In the structure of the RasPI3K gamma complex, contacts between the two molecules are made primarily via the so-called switch I region of Ras and the PI3K RBD. The RBD fold comprises a five-stranded mixed beta-sheet, flanked by two alpha-helices. Interaction between Ras and the PI3K RBD is primarily polar in character and, as characterised by kinetic measurements, is reversible and transient (PUBMED:12151228).
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| GO component: | phosphoinositide 3-kinase complex (GO:0005942) |
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| GO function: | 1-phosphatidylinositol-3-kinase activity (GO:0016303) |
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| Family alignment: |
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Click on the following links for more information.
- Evolution (species in which this domain is found)
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- Cellular role (predicted cellular role)
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Binding / catalysis: protein-binding, Ras-binding
- Literature (relevant references for this domain)
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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.
- Rodriguez-Viciana P, Warne PH, Vanhaesebroeck B, Waterfield MD, Downward J
- Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation.
- EMBO J. 1996; 15: 2442-51
- Display abstract
We have reported previously that Ras interacts with the catalytic subunit of phosphoinositide 3-kinase (PI 3-kinase) in a GTP-dependent manner. The affinity of the interaction of Ras-GTP with p85alpha/p110alpha is shown here to be approximately 150 nM. The site of interaction on the p110alpha and beta isoforms of PI 3-kinase lies between amino acid residues 133 and 314. A point mutation in this region, K227E, blocks the GTP-dependent interaction of PI 3-kinase p110alpha with Ras in vitro and the ability of Ras to activate PI 3-kinase in intact cells. In addition, this mutation elevates the basal activity of PI 3-kinase in intact cells, suggesting a direct influence of the Ras binding site on the catalytic activity of PI 3-kinase. Using an in vitro reconstitution assay, it is shown that the interaction of Ras-GTP, but not Ras-GDP, with PI 3-kinase leads to an increase in its enzymatic activity. This stimulation is synergistic with the effect of tyrosine phosphopeptide binding to p85, particularly at suboptimal peptide concentrations. These data show that PI 3-kinase is regulated by a number of mechanisms, and that Ras contributes to the activation of this lipid kinase synergistically with tyrosine kinases.
- Kodaki T, Woscholski R, Hallberg B, Rodriguez-Viciana P, Downward J, Parker PJ
- The activation of phosphatidylinositol 3-kinase by Ras.
- Curr Biol. 1994; 4: 798-806
- Display abstract
BACKGROUND: Activation of the mammalian phosphatidylinositol 3-kinase complex can play a critical role in transducing growth factor responses. The lipid kinase complex, which is made up of p85 alpha and p110 alpha regulatory and catalytic subunits, becomes associated with a number of activated receptor protein tyrosine kinases, but the mechanism of its activation has not yet been defined. Recent evidence indicates that Ras can bind to the p85 alpha/p110 alpha complex. We describe here the functional regulation of the mammalian phosphatidylinositol 3-kinase complex by Ras. RESULTS: Expression of p110 alpha, the catalytic subunit of phosphatidylinositol 3-kinase, in the fission yeast, Schizosaccharomyces pombe, has been used to demonstrate an inhibitory effect of p85 alpha on p110 alpha activity in intact cells; inhibition did not result from a decrease in p110 alpha expression. In this cellular context, we have investigated the effect of a constitutively active mutant of Ras, v-Ras, either on p85 alpha or p110 alpha-alone, or on the p85 alpha/p110 alpha complex. In the presence of the p85 alpha/p110 alpha complex, v-Ras suppressed cell growth, but an effector-domain mutant of v-Ras did not. The growth-suppressive effect of v-Ras was not seen for any other combination of expressed proteins. The phenotype induced by v-Ras was consistent with activation of the p85 alpha/p110 alpha complex: it was sensitive to the phosphatidylinositol 3-kinase inhibitor, wortmannin, and the cells accumulated 3-phosphorylated polyphosphoinositides. Activation of purified p85 alpha/p110 alpha by purified recombinant Ras in vitro was also demonstrated. CONCLUSIONS: The phosphatidylinositol 3-kinase complex, p85 alpha/p110 alpha, shows a suppressed catalytic function in vivo when compared with free p110 alpha. This complex can, however, be activated by Ras. We suggest that the phosphatidylinositol 3-kinase p85 alpha/p110 alpha complex is a downstream effector of Ras.
- Rodriguez-Viciana P et al.
- Phosphatidylinositol-3-OH kinase as a direct target of Ras.
- Nature. 1994; 370: 527-32
- Display abstract
Ras (p21ras) interacts directly with the catalytic subunit of phosphatidylinositol-3-OH kinase in a GTP-dependent manner through the Ras effector site. In vivo, dominant negative Ras mutant N17 inhibits growth factor induced production of 3' phosphorylated phosphoinositides in PC12 cells, and transfection of Ras, but not Raf, into COS cells results in a large elevation in the level of these lipids. Therefore Ras can probably regulate phosphatidylinositol-3-OH kinase, providing a point of divergence in signalling pathways downstream of Ras.
- Metabolism (metabolic pathways involving proteins which contain this domain)
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Click the image to view the interactive version of the map in iPath | 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 PI3K_rbd domain which could be assigned to a KEGG orthologous group, and not all proteins containing PI3K_rbd 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 PI3K_rbd 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 |  | |
| 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 |  | |
| 3ene |  | |
| 3hhm |  | |
| 3hiz |  | |
| 3ibe |  | |
- Links (links to other resources describing this domain)
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to expand nodes. To display all proteins with a PI3K_rbd domain in a specific node, click on it.
