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| | ==Crystal structure of p110alpha in complex with iSH2 of p85alpha and the inhibitor PIK-108== | | ==Crystal structure of p110alpha in complex with iSH2 of p85alpha and the inhibitor PIK-108== |
| - | <StructureSection load='4a55' size='340' side='right' caption='[[4a55]], [[Resolution|resolution]] 3.50Å' scene=''> | + | <StructureSection load='4a55' size='340' side='right'caption='[[4a55]], [[Resolution|resolution]] 3.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4a55]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4A55 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4A55 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4a55]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4A55 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4A55 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=P08:PIK-108'>P08</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.5Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2iuh|2iuh]], [[2v1y|2v1y]], [[1h9o|1h9o]], [[1a0n|1a0n]], [[1pkt|1pkt]], [[1pbw|1pbw]], [[1pht|1pht]], [[2iui|2iui]], [[2iug|2iug]], [[1pks|1pks]], [[1pic|1pic]], [[1azg|1azg]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=P08:PIK-108'>P08</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4a55 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4a55 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4a55 RCSB], [http://www.ebi.ac.uk/pdbsum/4a55 PDBsum]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4a55 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4a55 OCA], [https://pdbe.org/4a55 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4a55 RCSB], [https://www.ebi.ac.uk/pdbsum/4a55 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4a55 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PK3CA_MOUSE PK3CA_MOUSE]] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4-phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation in breast cancer cells through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. Has also serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS.<ref>PMID:16625210</ref> <ref>PMID:16647110</ref> <ref>PMID:17060635</ref> <ref>PMID:17540175</ref> <ref>PMID:18449193</ref> <ref>PMID:21540297</ref> [[http://www.uniprot.org/uniprot/P85A_HUMAN P85A_HUMAN]] Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Necessary for the insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissues. Plays an important role in signaling in response to FGFR1, FGFR2, FGFR3, FGFR4, KITLG/SCF, KIT, PDGFRA and PDGFRB. Likewise, plays a role in ITGB2 signaling.<ref>PMID:7518429</ref> <ref>PMID:17626883</ref> <ref>PMID:19805105</ref> | + | [https://www.uniprot.org/uniprot/PK3CA_MOUSE PK3CA_MOUSE] Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4-phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation in breast cancer cells through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. Has also serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS.<ref>PMID:16625210</ref> <ref>PMID:16647110</ref> <ref>PMID:17060635</ref> <ref>PMID:17540175</ref> <ref>PMID:18449193</ref> <ref>PMID:21540297</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 4a55" style="background-color:#fffaf0;"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Phosphoinositide 3-Kinases|Phosphoinositide 3-Kinases]] | + | *[[Phosphoinositide 3-kinase 3D structures|Phosphoinositide 3-kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| | + | [[Category: Large Structures]] |
| | [[Category: Mus musculus]] | | [[Category: Mus musculus]] |
| - | [[Category: Berndt, A]] | + | [[Category: Berndt A]] |
| - | [[Category: Hon, W C]] | + | [[Category: Hon W-C]] |
| - | [[Category: Williams, R L]] | + | [[Category: Williams RL]] |
| - | [[Category: Cancer mutation]]
| + | |
| - | [[Category: Enzyme regulation]]
| + | |
| - | [[Category: Growth factor signalling]]
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| - | [[Category: Lipid kinase]]
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| - | [[Category: Membrane binding]]
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| - | [[Category: Non-atp competitive ligand binding site]]
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| - | [[Category: Oncogene]]
| + | |
| - | [[Category: Pi3-kinase inhibitor]]
| + | |
| - | [[Category: Structure-activity relationship]]
| + | |
| - | [[Category: Transferase]]
| + | |
| - | [[Category: Tumour]]
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| Structural highlights
Function
PK3CA_MOUSE Phosphoinositide-3-kinase (PI3K) that phosphorylates PtdIns (Phosphatidylinositol), PtdIns4P (Phosphatidylinositol 4-phosphate) and PtdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation in breast cancer cells through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. Has also serine-protein kinase activity: phosphorylates PIK3R1 (p85alpha regulatory subunit), EIF4EBP1 and HRAS.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
Somatic missense mutations in PIK3CA, which encodes the p110alpha catalytic subunit of phosphoinositide 3-kinases, occur frequently in human cancers. Activating mutations spread across multiple domains, some of which are located at inhibitory contact sites formed with the regulatory subunit p85alpha. PIK3R1, which encodes p85alpha, also has activating somatic mutations. We find a strong correlation between lipid kinase and lipid-binding activities for both wild-type (WT) and a representative set of oncogenic mutant complexes of p110alpha/p85alpha. Lipid binding involves both electrostatic and hydrophobic interactions. Activation caused by a phosphorylated receptor tyrosine kinase (RTK) peptide binding to the p85alpha N-terminal SH2 domain (nSH2) induces lipid binding. This depends on the polybasic activation loop as well as a conserved hydrophobic motif in the C-terminal region of the kinase domain. The hotspot E545K mutant largely mimics the activated WT p110alpha. It shows the highest basal activity and lipid binding, and is not significantly activated by an RTK phosphopeptide. Both the hotspot H1047R mutant and rare mutations (C420R, M1043I, H1047L, G1049R and p85alpha-N564D) also show increased basal kinase activities and lipid binding. However, their activities are further enhanced by an RTK phosphopeptide to levels markedly exceeding that of activated WT p110alpha. Phosphopeptide binding to p110beta/p85alpha and p110delta/p85alpha complexes also induces their lipid binding. We present a crystal structure of WT p110alpha complexed with the p85alpha inter-SH2 domain and the inhibitor PIK-108. Additional to the ATP-binding pocket, an unexpected, second PIK-108 binding site is observed in the kinase C-lobe. We show a global conformational change in p110alpha consistent with allosteric regulation of the kinase domain by nSH2. These findings broaden our understanding of the differential biological outputs exhibited by distinct types of mutations regarding growth factor dependence, and suggest a two-tier classification scheme relating p110alpha and p85alpha mutations with signalling potential.Oncogene advance online publication, 28 November 2011; doi:10.1038/onc.2011.532.
Regulation of lipid binding underlies the activation mechanism of class IA PI3-kinases.,Hon WC, Berndt A, Williams RL Oncogene. 2011 Nov 28. doi: 10.1038/onc.2011.532. PMID:22120714[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Foukas LC, Claret M, Pearce W, Okkenhaug K, Meek S, Peskett E, Sancho S, Smith AJ, Withers DJ, Vanhaesebroeck B. Critical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature. 2006 May 18;441(7091):366-70. Epub 2006 Apr 12. PMID:16625210 doi:http://dx.doi.org/10.1038/nature04694
- ↑ Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O, Loewith R, Stokoe D, Balla A, Toth B, Balla T, Weiss WA, Williams RL, Shokat KM. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell. 2006 May 19;125(4):733-47. Epub 2006 Apr 27. PMID:16647110 doi:http://dx.doi.org/10.1016/j.cell.2006.03.035
- ↑ Zhao JJ, Cheng H, Jia S, Wang L, Gjoerup OV, Mikami A, Roberts TM. The p110alpha isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation. Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16296-300. Epub 2006 Oct 23. PMID:17060635 doi:http://dx.doi.org/10.1073/pnas.0607899103
- ↑ Gupta S, Ramjaun AR, Haiko P, Wang Y, Warne PH, Nicke B, Nye E, Stamp G, Alitalo K, Downward J. Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice. Cell. 2007 Jun 1;129(5):957-68. PMID:17540175 doi:http://dx.doi.org/10.1016/j.cell.2007.03.051
- ↑ Graupera M, Guillermet-Guibert J, Foukas LC, Phng LK, Cain RJ, Salpekar A, Pearce W, Meek S, Millan J, Cutillas PR, Smith AJ, Ridley AJ, Ruhrberg C, Gerhardt H, Vanhaesebroeck B. Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration. Nature. 2008 May 29;453(7195):662-6. doi: 10.1038/nature06892. Epub 2008 Apr 30. PMID:18449193 doi:http://dx.doi.org/10.1038/nature06892
- ↑ Bekhite MM, Finkensieper A, Binas S, Muller J, Wetzker R, Figulla HR, Sauer H, Wartenberg M. VEGF-mediated PI3K class IA and PKC signaling in cardiomyogenesis and vasculogenesis of mouse embryonic stem cells. J Cell Sci. 2011 Jun 1;124(Pt 11):1819-30. doi: 10.1242/jcs.077594. Epub 2011 May, 3. PMID:21540297 doi:http://dx.doi.org/10.1242/jcs.077594
- ↑ Hon WC, Berndt A, Williams RL. Regulation of lipid binding underlies the activation mechanism of class IA PI3-kinases. Oncogene. 2011 Nov 28. doi: 10.1038/onc.2011.532. PMID:22120714 doi:10.1038/onc.2011.532
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