Enzyme Dysfunction in Disease (30 pts)
Protein kinases are key regulators of cellular physiology and, consequently, their dysfunction is associated with many diseases. Conversely, mutations and other defects sometimes help to illuminate gene function. Continuing with the exploration of the PI3K/AKT pathway, this exercise will seek to illuminate the role of certain residues and motifs in molecular functioning of AKT.
(1) Diseases associated with AKT1 mutations were identified in the first exercise. Following the same procedure and PUBMED searches, identify diseases associated mutations of AKT2 and AKT3 (some relevant papers are provided below).
(2) Through literature search or the references below, generate a table of disease-associated mutations of the above genes.
(4) Generate a hypothesis on the role of the PI3K/Akt in cancer or any other disease.
(5) Make predictions based on experiments that can be conducted in cell lines.
(4) Conduct sequence alignments of these proteins by selecting homologues from divergent species and identify the most highly conserved residues and motifs.
(5) Download the structure of AKT with and without ligands from the PDB and propose the consequences of the above mutations in protein function.
(6) Propose some experiments to test the predictions.
(7) Highlight three of the most highly conserved motifs on the protein structure and comment on their possible role in AKT function.
1. Revival of the abandoned therapeutic wortmannin by nanoparticle drug delivery.
Karve S, Werner ME, Sukumar R, Cummings ND, Copp JA, Wang EC, Li C, Sethi M, Chen RC, Pacold ME, Wang AZ. Proc Natl Acad Sci U S A. 2012 May 22;109(21):8230-5. doi: 10.1073/pnas.1120508109. Epub 2012 Apr 30. PMID: 22547809 Free PMC Article
2. Phase I clinical, pharmacokinetic, and pharmacodynamic study of the Akt-inhibitor triciribine phosphate monohydrate in patients with advanced hematologic malignancies.
Sampath D, Malik A, Plunkett W, Nowak B, Williams B, Burton M, Verstovsek S, Faderl S, Garcia-Manero G, List AF, Sebti S, Kantarjian HM, Ravandi F, Lancet JE. Leuk Res. 2013 Nov;37(11):1461-7. doi: 10.1016/j.leukres.2013.07.034. Epub 2013 Aug 6.PMID: 23993427
The Mechanism of ATP-Dependent Allosteric Protection of Akt Kinase Phosphorylation.
Lu S, Deng R, Jiang H, Song H, Li S, Shen Q, Huang W, Nussinov R, Yu J, Zhang J.
Structure. 2015 Sep 1;23(9):1725-34. doi: 10.1016/j.str.2015.06.027. Epub 2015 Aug 6.
PMID:26256536
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Select item 262867482.
Alternative activation mechanisms of Protein Kinase B trigger distinct downstream signaling responses.
Balzano D, Fawal MA, Velazquez JV, Santiveri CM, Yang J, Pastor J, Campos-Olivas R, Djouder N, Lietha D.
J Biol Chem. 2015 Aug 18. pii: jbc.M115.651570. [Epub ahead of print]
PMID:26286748
Free Article
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Select item 260530933.
Mutant AKT1-E17K is oncogenic in lung epithelial cells.
De Marco C, Malanga D, Rinaldo N, De Vita F, Scrima M, Lovisa S, Fabris L, Carriero MV, Franco R, Rizzuto A, Baldassarre G, Viglietto G.
Oncotarget. 2015 May 25. [Epub ahead of print]
PMID:
26053093
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Activating AKT2 mutation: hypoinsulinemichypoketotic hypoglycemia.
Arya VB, Flanagan SE, Schober E, Rami-Merhar B, Ellard S, Hussain K.
J ClinEndocrinolMetab. 2014 Feb;99(2):391-4. doi: 10.1210/jc.2013-3228. Epub 2013 Nov 27.
PMID:
24285683
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AGC protein kinases: from structural mechanism of regulation to allosteric drug development for the treatment of human diseases.
Arencibia JM, Pastor-Flores D, Bauer AF, Schulze JO, Biondi RM.
BiochimBiophysActa. 2013 Jul;1834(7):1302-21. doi: 10.1016/j.bbapap.2013.03.010. Epub 2013 Mar 21. Review.
PMID:
23524293
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Resistance of Akt kinases to dephosphorylation through ATP-dependent conformational plasticity.
Chan TO, Zhang J, Rodeck U, Pascal JM, Armen RS, Spring M, Dumitru CD, Myers V, Li X, Cheung JY, Feldman AM.
Proc Natl AcadSci U S A. 2011 Nov 15;108(46):E1120-7. doi: 10.1073/pnas.1109879108. Epub 2011 Oct 26. PMID: 22031698
The nuts and bolts of AGC protein kinases. Pearce LR, Komander D, Alessi DR. Nat Rev Mol Cell Biol. 2010 Jan;11(1):9-22. doi: 10.1038/nrm2822. Review.
PMID: 20027184
Somatic mutations affect key pathways in lung adenocarcinoma.
Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB, Fulton L, Fulton RS, Zhang Q, Wendl MC, Lawrence MS, Larson DE, Chen K, Dooling DJ, Sabo A, Hawes AC, Shen H, Jhangiani SN, Lewis LR, Hall O, Zhu Y, Mathew T, Ren Y, Yao J, Scherer SE, Clerc K, Metcalf GA, Ng B, Milosavljevic A, Gonzalez-Garay ML, Osborne JR, Meyer R, Shi X, Tang Y, Koboldt DC, Lin L, Abbott R, Miner TL, Pohl C, Fewell G, Haipek C, Schmidt H, Dunford-Shore BH, Kraja A, Crosby SD, Sawyer CS, Vickery T, Sander S, Robinson J, Winckler W, Baldwin J, Chirieac LR, Dutt A, Fennell T, Hanna M, Johnson BE, Onofrio RC, Thomas RK, Tonon G, Weir BA, Zhao X, Ziaugra L, Zody MC, Giordano T, Orringer MB, Roth JA, Spitz MR, Wistuba II, Ozenberger B, Good PJ, Chang AC, Beer DG, Watson MA, Ladanyi M, Broderick S, Yoshizawa A, Travis WD, Pao W, Province MA, Weinstock GM, Varmus HE, Gabriel SB, Lander ES, Gibbs RA, Meyerson M, Wilson RK.
Nature. 2008 Oct 23;455(7216):1069-75. doi: 10.1038/nature07423. PMID: 18948947
Mechanism for activation of the growth factor-activated AGC kinases by turn motif phosphorylation. Hauge C, Antal TL, Hirschberg D, Doehn U, Thorup K, Idrissova L, Hansen K, Jensen ON, JĆĀørgensen TJ, Biondi RM, FrĆĀ¶din M. EMBO J. 2007 May 2;26(9):2251-61. Epub 2007 Apr 19. PMID: 17446865
Structure, regulation and function of PKB/AKT--a major therapeutic target.
Hanada M, Feng J, Hemmings BA.
BiochimBiophysActa. 2004 Mar 11;1697(1-2):3-16. Review.
PMID: 15023346
AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation.
Chan TO, Rittenhouse SE, Tsichlis PN Annu Rev Biochem. 1999; 68():965-1014.
