7nh4: Difference between revisions

From Proteopedia
Jump to navigation Jump to search
← Older editNewer edit →
No edit summary
No edit summary
Line 1: Line 1:


==Co-Crystal Structure of Akt1 in Complex with Covalent-Allosteric Akt Inhibitor 3==
==Co-Crystal Structure of Akt1 in Complex with Covalent-Allosteric Akt Inhibitor 3==
<StructureSection load='7nh4' size='340' side='right'caption='[[7nh4]]' scene=''>
<StructureSection load='7nh4' size='340' side='right'caption='[[7nh4]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NH4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NH4 FirstGlance]. <br>
<table><tr><td colspan='2'>[[7nh4]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NH4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NH4 FirstGlance]. <br>
</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=7nh4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nh4 OCA], [https://pdbe.org/7nh4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nh4 RCSB], [https://www.ebi.ac.uk/pdbsum/7nh4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nh4 ProSAT]</span></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=UCE:~{N}-[3-[1-[[4-[5-(hydroxymethyl)-3-phenyl-pyridin-2-yl]phenyl]methyl]piperidin-4-yl]-2-oxidanylidene-1~{H}-benzimidazol-5-yl]propanamide'>UCE</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AKT1, PKB, RAC ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=7nh4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nh4 OCA], [https://pdbe.org/7nh4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nh4 RCSB], [https://www.ebi.ac.uk/pdbsum/7nh4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nh4 ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[[https://www.uniprot.org/uniprot/AKT1_HUMAN AKT1_HUMAN]] Defects in AKT1 are a cause of susceptibility to breast cancer (BC) [MIM:[https://omim.org/entry/114480 114480]]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case.  Defects in AKT1 are associated with colorectal cancer (CRC) [MIM:[https://omim.org/entry/114500 114500]].  Note=Genetic variations in AKT1 may play a role in susceptibility to ovarian cancer.  Defects in AKT1 are a cause of Proteus syndrome (PROTEUSS) [MIM:[https://omim.org/entry/176920 176920]]. A highly variable, severe disorder of asymmetric and disproportionate overgrowth of body parts, connective tissue nevi, epidermal nevi, dysregulated adipose tissue, and vascular malformations. Many features of Proteus syndrome overlap with other overgrowth syndromes.<ref>PMID:18954143</ref> <ref>PMID:21793738</ref> 
== Function ==
[[https://www.uniprot.org/uniprot/AKT1_HUMAN AKT1_HUMAN]] AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity. The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I). AKT mediates the antiapoptotic effects of IGF-I. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development. Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3. Phosphorylates STK3/MST2 at 'Thr-117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation. Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation. Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity. Phosphorylation of BAD stimulates its pro-apoptotic activity.<ref>PMID:1718748</ref> <ref>PMID:9829964</ref> <ref>PMID:9512493</ref> <ref>PMID:10358075</ref> <ref>PMID:10576742</ref> <ref>PMID:10926925</ref> <ref>PMID:11154276</ref> <ref>PMID:11994271</ref> <ref>PMID:12042314</ref> <ref>PMID:12150915</ref> <ref>PMID:12244301</ref> <ref>PMID:12878163</ref> <ref>PMID:16139227</ref> <ref>PMID:16417524</ref> <ref>PMID:16982699</ref> <ref>PMID:17726016</ref> <ref>PMID:18507042</ref> <ref>PMID:19592491</ref> <ref>PMID:19934221</ref> <ref>PMID:20086174</ref> <ref>PMID:19940129</ref> <ref>PMID:20682768</ref> <ref>PMID:20471940</ref> <ref>PMID:20231902</ref> <ref>PMID:20333297</ref>  AKT1-specific substrates have been recently identified, including palladin (PALLD), which phosphorylation modulates cytoskeletal organization and cell motility; prohibitin (PHB), playing an important role in cell metabolism and proliferation; and CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization. These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation. Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation.<ref>PMID:1718748</ref> <ref>PMID:9829964</ref> <ref>PMID:9512493</ref> <ref>PMID:10358075</ref> <ref>PMID:10576742</ref> <ref>PMID:10926925</ref> <ref>PMID:11154276</ref> <ref>PMID:11994271</ref> <ref>PMID:12042314</ref> <ref>PMID:12150915</ref> <ref>PMID:12244301</ref> <ref>PMID:12878163</ref> <ref>PMID:16139227</ref> <ref>PMID:16417524</ref> <ref>PMID:16982699</ref> <ref>PMID:17726016</ref> <ref>PMID:18507042</ref> <ref>PMID:19592491</ref> <ref>PMID:19934221</ref> <ref>PMID:20086174</ref> <ref>PMID:19940129</ref> <ref>PMID:20682768</ref> <ref>PMID:20471940</ref> <ref>PMID:20231902</ref> <ref>PMID:20333297</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The protein kinase Akt plays a pivotal role in cellular processes. However, its isoforms' distinct functions have not been resolved to date, mainly due to the lack of suitable biochemical and cellular tools. Against this background, we present the development of an isoform-dependent Ba/F3 model system to translate biochemical results on isoform specificity to the cellular level. Our cellular model system complemented by protein X-ray crystallography and structure-based ligand design results in covalent-allosteric Akt inhibitors with unique selectivity profiles. In a first proof-of-concept, the developed molecules allow studies on isoform-selective effects of Akt inhibition in cancer cells. Thus, this study will pave the way to resolve isoform-selective roles in health and disease and foster the development of next-generation therapeutics with superior on-target properties.
Cellular model system to dissect the isoform-selectivity of Akt inhibitors.,Quambusch L, Depta L, Landel I, Lubeck M, Kirschner T, Nabert J, Uhlenbrock N, Weisner J, Kostka M, Levy LM, Schultz-Fademrecht C, Glanemann F, Althoff K, Muller MP, Siveke JT, Rauh D Nat Commun. 2021 Sep 6;12(1):5297. doi: 10.1038/s41467-021-25512-8. PMID:34489430<ref>PMID:34489430</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7nh4" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Landel I]]
[[Category: Non-specific serine/threonine protein kinase]]
[[Category: Mueller MP]]
[[Category: Landel, I]]
[[Category: Rauh D]]
[[Category: Mueller, M P]]
[[Category: Rauh, D]]
[[Category: Akt1]]
[[Category: Akt2]]
[[Category: Akt3]]
[[Category: Covalent-allosteric]]
[[Category: Transferase]]

Revision as of 12:03, 29 September 2021

Co-Crystal Structure of Akt1 in Complex with Covalent-Allosteric Akt Inhibitor 3Co-Crystal Structure of Akt1 in Complex with Covalent-Allosteric Akt Inhibitor 3

Structural highlights

7nh4 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
Gene:AKT1, PKB, RAC (HUMAN)
Activity:Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[AKT1_HUMAN] Defects in AKT1 are a cause of susceptibility to breast cancer (BC) [MIM:114480]. A common malignancy originating from breast epithelial tissue. Breast neoplasms can be distinguished by their histologic pattern. Invasive ductal carcinoma is by far the most common type. Breast cancer is etiologically and genetically heterogeneous. Important genetic factors have been indicated by familial occurrence and bilateral involvement. Mutations at more than one locus can be involved in different families or even in the same case. Defects in AKT1 are associated with colorectal cancer (CRC) [MIM:114500]. Note=Genetic variations in AKT1 may play a role in susceptibility to ovarian cancer. Defects in AKT1 are a cause of Proteus syndrome (PROTEUSS) [MIM:176920]. A highly variable, severe disorder of asymmetric and disproportionate overgrowth of body parts, connective tissue nevi, epidermal nevi, dysregulated adipose tissue, and vascular malformations. Many features of Proteus syndrome overlap with other overgrowth syndromes.[1] [2]

Function

[AKT1_HUMAN] AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity. The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I). AKT mediates the antiapoptotic effects of IGF-I. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development. Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3. Phosphorylates STK3/MST2 at 'Thr-117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation. Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation. Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity. Phosphorylation of BAD stimulates its pro-apoptotic activity.[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] AKT1-specific substrates have been recently identified, including palladin (PALLD), which phosphorylation modulates cytoskeletal organization and cell motility; prohibitin (PHB), playing an important role in cell metabolism and proliferation; and CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization. These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation. Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation.[28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52]

Publication Abstract from PubMed

The protein kinase Akt plays a pivotal role in cellular processes. However, its isoforms' distinct functions have not been resolved to date, mainly due to the lack of suitable biochemical and cellular tools. Against this background, we present the development of an isoform-dependent Ba/F3 model system to translate biochemical results on isoform specificity to the cellular level. Our cellular model system complemented by protein X-ray crystallography and structure-based ligand design results in covalent-allosteric Akt inhibitors with unique selectivity profiles. In a first proof-of-concept, the developed molecules allow studies on isoform-selective effects of Akt inhibition in cancer cells. Thus, this study will pave the way to resolve isoform-selective roles in health and disease and foster the development of next-generation therapeutics with superior on-target properties.

Cellular model system to dissect the isoform-selectivity of Akt inhibitors.,Quambusch L, Depta L, Landel I, Lubeck M, Kirschner T, Nabert J, Uhlenbrock N, Weisner J, Kostka M, Levy LM, Schultz-Fademrecht C, Glanemann F, Althoff K, Muller MP, Siveke JT, Rauh D Nat Commun. 2021 Sep 6;12(1):5297. doi: 10.1038/s41467-021-25512-8. PMID:34489430[53]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Landgraf KE, Pilling C, Falke JJ. Molecular mechanism of an oncogenic mutation that alters membrane targeting: Glu17Lys modifies the PIP lipid specificity of the AKT1 PH domain. Biochemistry. 2008 Nov 25;47(47):12260-9. doi: 10.1021/bi801683k. PMID:18954143 doi:10.1021/bi801683k
  2. ↑ Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, Turner J, Cannons JL, Bick D, Blakemore L, Blumhorst C, Brockmann K, Calder P, Cherman N, Deardorff MA, Everman DB, Golas G, Greenstein RM, Kato BM, Keppler-Noreuil KM, Kuznetsov SA, Miyamoto RT, Newman K, Ng D, O'Brien K, Rothenberg S, Schwartzentruber DJ, Singhal V, Tirabosco R, Upton J, Wientroub S, Zackai EH, Hoag K, Whitewood-Neal T, Robey PG, Schwartzberg PL, Darling TN, Tosi LL, Mullikin JC, Biesecker LG. A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med. 2011 Aug 18;365(7):611-9. doi: 10.1056/NEJMoa1104017. Epub 2011 Jul, 27. PMID:21793738 doi:10.1056/NEJMoa1104017
  3. ↑ Coffer PJ, Woodgett JR. Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families. Eur J Biochem. 1991 Oct 15;201(2):475-81. PMID:1718748
  4. ↑ Du K, Montminy M. CREB is a regulatory target for the protein kinase Akt/PKB. J Biol Chem. 1998 Dec 4;273(49):32377-9. PMID:9829964
  5. ↑ Walker KS, Deak M, Paterson A, Hudson K, Cohen P, Alessi DR. Activation of protein kinase B beta and gamma isoforms by insulin in vivo and by 3-phosphoinositide-dependent protein kinase-1 in vitro: comparison with protein kinase B alpha. Biochem J. 1998 Apr 1;331 ( Pt 1):299-308. PMID:9512493
  6. ↑ Rena G, Guo S, Cichy SC, Unterman TG, Cohen P. Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B. J Biol Chem. 1999 Jun 11;274(24):17179-83. PMID:10358075
  7. ↑ Zimmermann S, Moelling K. Phosphorylation and regulation of Raf by Akt (protein kinase B). Science. 1999 Nov 26;286(5445):1741-4. PMID:10576742
  8. ↑ Koh H, Lee KH, Kim D, Kim S, Kim JW, Chung J. Inhibition of Akt and its anti-apoptotic activities by tumor necrosis factor-induced protein kinase C-related kinase 2 (PRK2) cleavage. J Biol Chem. 2000 Nov 3;275(44):34451-8. PMID:10926925 doi:10.1074/jbc.M001753200
  9. ↑ Kim AH, Khursigara G, Sun X, Franke TF, Chao MV. Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol Cell Biol. 2001 Feb;21(3):893-901. PMID:11154276 doi:10.1128/MCB.21.3.893-901.2001
  10. ↑ Kane S, Sano H, Liu SC, Asara JM, Lane WS, Garner CC, Lienhard GE. A method to identify serine kinase substrates. Akt phosphorylates a novel adipocyte protein with a Rab GTPase-activating protein (GAP) domain. J Biol Chem. 2002 Jun 21;277(25):22115-8. Epub 2002 May 6. PMID:11994271 doi:10.1074/jbc.C200198200
  11. ↑ Fujita N, Sato S, Katayama K, Tsuruo T. Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization. J Biol Chem. 2002 Aug 9;277(32):28706-13. Epub 2002 May 31. PMID:12042314 doi:10.1074/jbc.M203668200
  12. ↑ Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell. 2002 Jul;10(1):151-62. PMID:12150915
  13. ↑ Shin I, Yakes FM, Rojo F, Shin NY, Bakin AV, Baselga J, Arteaga CL. PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Nat Med. 2002 Oct;8(10):1145-52. Epub 2002 Sep 16. PMID:12244301 doi:10.1038/nm759
  14. ↑ Lennartsson J, Wernstedt C, Engstrom U, Hellman U, Ronnstrand L. Identification of Tyr900 in the kinase domain of c-Kit as a Src-dependent phosphorylation site mediating interaction with c-Crk. Exp Cell Res. 2003 Aug 1;288(1):110-8. PMID:12878163
  15. ↑ Enomoto A, Murakami H, Asai N, Morone N, Watanabe T, Kawai K, Murakumo Y, Usukura J, Kaibuchi K, Takahashi M. Akt/PKB regulates actin organization and cell motility via Girdin/APE. Dev Cell. 2005 Sep;9(3):389-402. PMID:16139227 doi:S1534-5807(05)00295-9
  16. ↑ Srinivas H, Xia D, Moore NL, Uray IP, Kim H, Ma L, Weigel NL, Brown PH, Kurie JM. Akt phosphorylates and suppresses the transactivation of retinoic acid receptor alpha. Biochem J. 2006 May 1;395(3):653-62. PMID:16417524 doi:10.1042/BJ20051794
  17. ↑ Heron-Milhavet L, Franckhauser C, Rana V, Berthenet C, Fisher D, Hemmings BA, Fernandez A, Lamb NJ. Only Akt1 is required for proliferation, while Akt2 promotes cell cycle exit through p21 binding. Mol Cell Biol. 2006 Nov;26(22):8267-80. Epub 2006 Sep 18. PMID:16982699 doi:10.1128/MCB.00201-06
  18. ↑ Jang SW, Yang SJ, Srinivasan S, Ye K. Akt phosphorylates MstI and prevents its proteolytic activation, blocking FOXO3 phosphorylation and nuclear translocation. J Biol Chem. 2007 Oct 19;282(42):30836-44. Epub 2007 Aug 28. PMID:17726016 doi:10.1074/jbc.M704542200
  19. ↑ Han EK, Mcgonigal T, Butler C, Giranda VL, Luo Y. Characterization of Akt overexpression in MiaPaCa-2 cells: prohibitin is an Akt substrate both in vitro and in cells. Anticancer Res. 2008 Mar-Apr;28(2A):957-63. PMID:18507042
  20. ↑ Jang SW, Liu X, Fu H, Rees H, Yepes M, Levey A, Ye K. Interaction of Akt-phosphorylated SRPK2 with 14-3-3 mediates cell cycle and cell death in neurons. J Biol Chem. 2009 Sep 4;284(36):24512-25. doi: 10.1074/jbc.M109.026237. Epub 2009, Jul 10. PMID:19592491 doi:10.1074/jbc.M109.026237
  21. ↑ Bristow JM, Sellers MH, Majumdar D, Anderson B, Hu L, Webb DJ. The Rho-family GEF Asef2 activates Rac to modulate adhesion and actin dynamics and thereby regulate cell migration. J Cell Sci. 2009 Dec 15;122(Pt 24):4535-46. doi: 10.1242/jcs.053728. Epub 2009, Nov 24. PMID:19934221 doi:10.1242/jcs.053728
  22. ↑ Romano D, Matallanas D, Weitsman G, Preisinger C, Ng T, Kolch W. Proapoptotic kinase MST2 coordinates signaling crosstalk between RASSF1A, Raf-1, and Akt. Cancer Res. 2010 Feb 1;70(3):1195-203. doi: 10.1158/0008-5472.CAN-09-3147. Epub, 2010 Jan 19. PMID:20086174 doi:10.1158/0008-5472.CAN-09-3147
  23. ↑ Yuan Z, Kim D, Shu S, Wu J, Guo J, Xiao L, Kaneko S, Coppola D, Cheng JQ. Phosphoinositide 3-kinase/Akt inhibits MST1-mediated pro-apoptotic signaling through phosphorylation of threonine 120. J Biol Chem. 2010 Feb 5;285(6):3815-24. doi: 10.1074/jbc.M109.059675. Epub 2009, Nov 24. PMID:19940129 doi:10.1074/jbc.M109.059675
  24. ↑ Nam SY, Seo HH, Park HS, An S, Kim JY, Yang KH, Kim CS, Jeong M, Jin YW. Phosphorylation of CLK2 at serine 34 and threonine 127 by AKT controls cell survival after ionizing radiation. J Biol Chem. 2010 Oct 8;285(41):31157-63. doi: 10.1074/jbc.M110.122044. Epub 2010, Aug 3. PMID:20682768 doi:10.1074/jbc.M110.122044
  25. ↑ Chin YR, Toker A. The actin-bundling protein palladin is an Akt1-specific substrate that regulates breast cancer cell migration. Mol Cell. 2010 May 14;38(3):333-44. doi: 10.1016/j.molcel.2010.02.031. PMID:20471940 doi:10.1016/j.molcel.2010.02.031
  26. ↑ Kim D, Shu S, Coppola MD, Kaneko S, Yuan ZQ, Cheng JQ. Regulation of proapoptotic mammalian ste20-like kinase MST2 by the IGF1-Akt pathway. PLoS One. 2010 Mar 9;5(3):e9616. doi: 10.1371/journal.pone.0009616. PMID:20231902 doi:10.1371/journal.pone.0009616
  27. ↑ Mahajan K, Coppola D, Challa S, Fang B, Chen YA, Zhu W, Lopez AS, Koomen J, Engelman RW, Rivera C, Muraoka-Cook RS, Cheng JQ, Schonbrunn E, Sebti SM, Earp HS, Mahajan NP. Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation. PLoS One. 2010 Mar 19;5(3):e9646. doi: 10.1371/journal.pone.0009646. PMID:20333297 doi:10.1371/journal.pone.0009646
  28. ↑ Coffer PJ, Woodgett JR. Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families. Eur J Biochem. 1991 Oct 15;201(2):475-81. PMID:1718748
  29. ↑ Du K, Montminy M. CREB is a regulatory target for the protein kinase Akt/PKB. J Biol Chem. 1998 Dec 4;273(49):32377-9. PMID:9829964
  30. ↑ Walker KS, Deak M, Paterson A, Hudson K, Cohen P, Alessi DR. Activation of protein kinase B beta and gamma isoforms by insulin in vivo and by 3-phosphoinositide-dependent protein kinase-1 in vitro: comparison with protein kinase B alpha. Biochem J. 1998 Apr 1;331 ( Pt 1):299-308. PMID:9512493
  31. ↑ Rena G, Guo S, Cichy SC, Unterman TG, Cohen P. Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B. J Biol Chem. 1999 Jun 11;274(24):17179-83. PMID:10358075
  32. ↑ Zimmermann S, Moelling K. Phosphorylation and regulation of Raf by Akt (protein kinase B). Science. 1999 Nov 26;286(5445):1741-4. PMID:10576742
  33. ↑ Koh H, Lee KH, Kim D, Kim S, Kim JW, Chung J. Inhibition of Akt and its anti-apoptotic activities by tumor necrosis factor-induced protein kinase C-related kinase 2 (PRK2) cleavage. J Biol Chem. 2000 Nov 3;275(44):34451-8. PMID:10926925 doi:10.1074/jbc.M001753200
  34. ↑ Kim AH, Khursigara G, Sun X, Franke TF, Chao MV. Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol Cell Biol. 2001 Feb;21(3):893-901. PMID:11154276 doi:10.1128/MCB.21.3.893-901.2001
  35. ↑ Kane S, Sano H, Liu SC, Asara JM, Lane WS, Garner CC, Lienhard GE. A method to identify serine kinase substrates. Akt phosphorylates a novel adipocyte protein with a Rab GTPase-activating protein (GAP) domain. J Biol Chem. 2002 Jun 21;277(25):22115-8. Epub 2002 May 6. PMID:11994271 doi:10.1074/jbc.C200198200
  36. ↑ Fujita N, Sato S, Katayama K, Tsuruo T. Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization. J Biol Chem. 2002 Aug 9;277(32):28706-13. Epub 2002 May 31. PMID:12042314 doi:10.1074/jbc.M203668200
  37. ↑ Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell. 2002 Jul;10(1):151-62. PMID:12150915
  38. ↑ Shin I, Yakes FM, Rojo F, Shin NY, Bakin AV, Baselga J, Arteaga CL. PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Nat Med. 2002 Oct;8(10):1145-52. Epub 2002 Sep 16. PMID:12244301 doi:10.1038/nm759
  39. ↑ Lennartsson J, Wernstedt C, Engstrom U, Hellman U, Ronnstrand L. Identification of Tyr900 in the kinase domain of c-Kit as a Src-dependent phosphorylation site mediating interaction with c-Crk. Exp Cell Res. 2003 Aug 1;288(1):110-8. PMID:12878163
  40. ↑ Enomoto A, Murakami H, Asai N, Morone N, Watanabe T, Kawai K, Murakumo Y, Usukura J, Kaibuchi K, Takahashi M. Akt/PKB regulates actin organization and cell motility via Girdin/APE. Dev Cell. 2005 Sep;9(3):389-402. PMID:16139227 doi:S1534-5807(05)00295-9
  41. ↑ Srinivas H, Xia D, Moore NL, Uray IP, Kim H, Ma L, Weigel NL, Brown PH, Kurie JM. Akt phosphorylates and suppresses the transactivation of retinoic acid receptor alpha. Biochem J. 2006 May 1;395(3):653-62. PMID:16417524 doi:10.1042/BJ20051794
  42. ↑ Heron-Milhavet L, Franckhauser C, Rana V, Berthenet C, Fisher D, Hemmings BA, Fernandez A, Lamb NJ. Only Akt1 is required for proliferation, while Akt2 promotes cell cycle exit through p21 binding. Mol Cell Biol. 2006 Nov;26(22):8267-80. Epub 2006 Sep 18. PMID:16982699 doi:10.1128/MCB.00201-06
  43. ↑ Jang SW, Yang SJ, Srinivasan S, Ye K. Akt phosphorylates MstI and prevents its proteolytic activation, blocking FOXO3 phosphorylation and nuclear translocation. J Biol Chem. 2007 Oct 19;282(42):30836-44. Epub 2007 Aug 28. PMID:17726016 doi:10.1074/jbc.M704542200
  44. ↑ Han EK, Mcgonigal T, Butler C, Giranda VL, Luo Y. Characterization of Akt overexpression in MiaPaCa-2 cells: prohibitin is an Akt substrate both in vitro and in cells. Anticancer Res. 2008 Mar-Apr;28(2A):957-63. PMID:18507042
  45. ↑ Jang SW, Liu X, Fu H, Rees H, Yepes M, Levey A, Ye K. Interaction of Akt-phosphorylated SRPK2 with 14-3-3 mediates cell cycle and cell death in neurons. J Biol Chem. 2009 Sep 4;284(36):24512-25. doi: 10.1074/jbc.M109.026237. Epub 2009, Jul 10. PMID:19592491 doi:10.1074/jbc.M109.026237
  46. ↑ Bristow JM, Sellers MH, Majumdar D, Anderson B, Hu L, Webb DJ. The Rho-family GEF Asef2 activates Rac to modulate adhesion and actin dynamics and thereby regulate cell migration. J Cell Sci. 2009 Dec 15;122(Pt 24):4535-46. doi: 10.1242/jcs.053728. Epub 2009, Nov 24. PMID:19934221 doi:10.1242/jcs.053728
  47. ↑ Romano D, Matallanas D, Weitsman G, Preisinger C, Ng T, Kolch W. Proapoptotic kinase MST2 coordinates signaling crosstalk between RASSF1A, Raf-1, and Akt. Cancer Res. 2010 Feb 1;70(3):1195-203. doi: 10.1158/0008-5472.CAN-09-3147. Epub, 2010 Jan 19. PMID:20086174 doi:10.1158/0008-5472.CAN-09-3147
  48. ↑ Yuan Z, Kim D, Shu S, Wu J, Guo J, Xiao L, Kaneko S, Coppola D, Cheng JQ. Phosphoinositide 3-kinase/Akt inhibits MST1-mediated pro-apoptotic signaling through phosphorylation of threonine 120. J Biol Chem. 2010 Feb 5;285(6):3815-24. doi: 10.1074/jbc.M109.059675. Epub 2009, Nov 24. PMID:19940129 doi:10.1074/jbc.M109.059675
  49. ↑ Nam SY, Seo HH, Park HS, An S, Kim JY, Yang KH, Kim CS, Jeong M, Jin YW. Phosphorylation of CLK2 at serine 34 and threonine 127 by AKT controls cell survival after ionizing radiation. J Biol Chem. 2010 Oct 8;285(41):31157-63. doi: 10.1074/jbc.M110.122044. Epub 2010, Aug 3. PMID:20682768 doi:10.1074/jbc.M110.122044
  50. ↑ Chin YR, Toker A. The actin-bundling protein palladin is an Akt1-specific substrate that regulates breast cancer cell migration. Mol Cell. 2010 May 14;38(3):333-44. doi: 10.1016/j.molcel.2010.02.031. PMID:20471940 doi:10.1016/j.molcel.2010.02.031
  51. ↑ Kim D, Shu S, Coppola MD, Kaneko S, Yuan ZQ, Cheng JQ. Regulation of proapoptotic mammalian ste20-like kinase MST2 by the IGF1-Akt pathway. PLoS One. 2010 Mar 9;5(3):e9616. doi: 10.1371/journal.pone.0009616. PMID:20231902 doi:10.1371/journal.pone.0009616
  52. ↑ Mahajan K, Coppola D, Challa S, Fang B, Chen YA, Zhu W, Lopez AS, Koomen J, Engelman RW, Rivera C, Muraoka-Cook RS, Cheng JQ, Schonbrunn E, Sebti SM, Earp HS, Mahajan NP. Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation. PLoS One. 2010 Mar 19;5(3):e9646. doi: 10.1371/journal.pone.0009646. PMID:20333297 doi:10.1371/journal.pone.0009646
  53. ↑ Quambusch L, Depta L, Landel I, Lubeck M, Kirschner T, Nabert J, Uhlenbrock N, Weisner J, Kostka M, Levy LM, Schultz-Fademrecht C, Glanemann F, Althoff K, Muller MP, Siveke JT, Rauh D. Cellular model system to dissect the isoform-selectivity of Akt inhibitors. Nat Commun. 2021 Sep 6;12(1):5297. doi: 10.1038/s41467-021-25512-8. PMID:34489430 doi:http://dx.doi.org/10.1038/s41467-021-25512-8

7nh4, resolution 2.30Å

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA
Retrieved from "https://proteopedia.openfox.io/wiki/index.php?title=7nh4&oldid=3453514"