Please wait a minute...

Frontiers in Biology

Front. Biol.    2016, Vol. 11 Issue (2) : 132-140     DOI: 10.1007/s11515-016-1394-2
Targeting secret handshakes of biological processes for novel drug development
Rini Jacob,Anbalagan Moorthy()
School of Bio-Sciences and Technology, VIT University, Vellore-632014, India
Download: PDF(470 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks

In multicellular organisms, several biological processes control the rise and fall of life. Different cell types communicate and co-operate in response to different stimulus through cell to cell signaling and regulate biologic processes in the cell/organism. Signaling in multicellular organism has to be made very secretly so that only the target cell responds to the signal. Of all the biomolecules, nature chose mainly proteins for secret delivery of information both inside and outside the cell. During cell signaling, proteins physically interact and shake hands for transfer of secret information by a phenomenon called as protein – protein interactions (PPIs). In both, extra and intracellular signaling processes PPIs play a crucial role. PPIs involved in cellular signaling are the primary cause for cell proliferation, differentiation, movement, metabolism, death and various other biological processes not mentioned here. These secret handshakes are very specific for specific functions. Any alterations/malfunctions in particular PPIs results in diseased condition. An overview of signaling pathways and importance of PPIs in cellular function and possibilities of targeting PPIs for novel drug development are discussed in this review.

Keywords cell signaling      protein-protein interactions      peptide inhibitors     
Corresponding Authors: Anbalagan Moorthy   
Just Accepted Date: 06 April 2016   Online First Date: 26 April 2016    Issue Date: 17 May 2016
 Cite this article:   
Rini Jacob,Anbalagan Moorthy. Targeting secret handshakes of biological processes for novel drug development[J]. Front. Biol., 2016, 11(2): 132-140.
E-mail this article
E-mail Alert
Articles by authors
Rini Jacob
Anbalagan Moorthy
Fig.1  Different sites where protein-protein interactions can be targeted.
Inhibitor Interacting proteins Effect of the inhibitor Reference
Ligand-receptor mediated inhibition using small molecules Lovastatin, BIRT377 LFA-1/ICAM interaction Inflammatory diseases and graft rejection after transplantation Kallen et al., 1999
SB 247464 Granulocyte-colony stimulating factor stimulant Neutropenia Tian et al., 1998
Ro26-4550 Interaction of IL-2 to IL-2Rα Immuno modulation Tilley et al., 1997
SP4206 Interaction of IL-2 to IL-2Rα Immuno modulation Thanos et al., 2003
U0126 MEK1/2 interaction with ERK Antagonize AP1 transactivation Favata et al., 1998
Small molecules inhibitors of PPI involved in signaling cascade CEP-1347 Kinase activity of MLKs Inhibits JNK signalling Saporito et al., 2001
Gleevec ATP binding site of β amyloid peptide Amyloid plaque formation in Alzheimer’s Netzer et al., 2003
SM164-Smac mimetic XIAP-Caspase interaction Induction of apoptosis in cancer cells Lu et al., 2008
CCG-17444 Shroom3-rho kinase interaction Axon outgrowth- neural repair Dickson et al., 2015
M2I-I( MAD 2 Inhibitor 1) MAD 2/CDC20 interaction Mitotic spindle assembly Kastl et al., 2015
Small molecule inhibitor E3 ligase VHL and HIF1α interaction Chronic anemia Buckley et al., 2012
PPA250 Inhibit iNOS dimerization Tissue damage during inflammation Ohtsuka et al., 2002
HA 14-1 BAK BH3/BCL2 interaction Tumor cells apoptosis Wang et al., 2000
Ppi inhibitors preventing nuclear translocation SC236 Rel/p65 translocation Inflammation inducing gastric cancer Wong et al., 2003
PPI inhibitors in the nucleus BILD 1263 HSV-Ribonucleotide inhibitor Prevents replication of HSV-1 and HSV-2 preventing herpes virus infections Liuzzi et al., 1994
Bazidoxifene Selective estrogen receptor modulator Treatment of post menopausal problems Li et al., 2014
Tab.1  List of different inhibitors inhibiting various PPIs and its applications
Fig.2  Different methods to target protein-protein interactions.
Class Peptide Peptide Sequence Inhibition
Peptides inhibiting Receptor-protein interactions Pep2-8 TVFTSWEEYLDWV PCSK9 protein binding to LDL Receptor (Zhang et al., 2014)
Akt in (AKT inhibitor) AVTDHPDRLWAWEKF TCL1-Akt interaction AKT kinase activity (Hiromura et al.,2004)
Peptides inhibiting protein interactions involved during signalling cascade I-JIP (Inhibitor of JNK based on JIP-1) GPGTGSGDTYRPKRPTTLNLF JNK activity towards c-Jun, Elk and ATF-2 (Barr et al., 2002)
NBD pepteide (NEMO-binding domain peptide) FTALDWSWLQTE IKKβ- NEMO interaction , inhibiting NF-κB activity (May et al., 2000)
MEK1 peptide inhibitor GYGRKKRRQRRRGMPKKKPTPIQLNP ERK activation by MEK (Kelemen et al., 2001)
TLR2-BBP RQIKIWFQNRRMKWKKLHKRDFVPGKWIID LPS induced ERK activation-TLR signalling(Toshchakov et al., 2007)
MK2i(MK2 inhibitor) WLRRIKAWLRRIKALNRQLGVAA TGF-β1-induced HSP27 phosphorylation (Lopes et al., 2009)
TAT-MKK3b peptide YGRKKRRQRRRGKGKSKRKKDLRI Prevents p38 activation by LPS induced TNFα secretion (Fu et al., 2008)
Peptides inhibiting nuclear translocation of proteins TLR4-BBP RQIKIWFQNRRMKWKKLHYRDFIPGVAIAA LPS induced NFκB translocation and IL-1β mRNA expression (Toshchakov et al., 2007)
PT5 peptide QGQVVSNGKSTDEQS TAB/p38 α interaction decreasing myocardial I/R injury ( Wang et al., 2013)
Peptides inhibiting protein interactions in the nucleus DPMI-α TNWYANLEKLLR p53-MDM2 interaction (Liu et al., 2010)
Tab.2  Peptide inhibitors targeting PPIs at various levels and its applications
1 Asteria C (2002). T-box and isolated ACTH deficiency. Eur J Endocrinol, 146(4): 463–465
doi: 10.1530/eje.0.1460463 pmid: 11916612
2 Barr R K, Kendrick T S, Bogoyevitch M A (2002). Identification of the critical features of a small peptide inhibitor of JNK activity. J Biol Chem, 277(13): 10987–10997
doi: 10.1074/jbc.M107565200 pmid: 11790767
3 Berggård T, Linse S, James P (2007). Methods for the detection and analysis of protein-protein interactions. Proteomics, 7(16): 2833–2842
doi: 10.1002/pmic.200700131 pmid: 17640003
4 Black A, Black J (2013). Protein kinase C signaling and cell cycle regulation. Front Immun, 3: 423
5 Blikstad C, Ivarsson Y (2015). High-throughput methods for identification of protein-protein interactions involving short linear motifs. Cell Commun Signal, 13(1): 38
doi: 10.1186/s12964-015-0116-8 pmid: 26297553
6 Bononi A, Agnoletto C, De Marchi E, Marchi S, Patergnani S, Bonora M, Giorgi C, Missiroli S, Poletti F, Rimessi A, Pinton P (2011). Protein kinases and phosphatases in the control of cell fate. Enzyme Res, 2011: 329098
doi: 10.4061/2011/329098 pmid: 21904669
7 Buckley D L, Gustafson J L, Van Molle I, Roth A G, Tae H S, Gareiss P C, Jorgensen W L, Ciulli A, Crews C M (2012). Small-molecule inhibitors of the interaction between the E3 ligase VHL and HIF1α. Angew Chem Int Ed Engl, 51(46): 11463–11467
doi: 10.1002/anie.201206231 pmid: 23065727
8 Coffin J M, Hughes S H, Varmus H E, eds. (1997). Immunopathogenic Mechanisms of HIV Infection Retroviruses. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press
9 Copolovici D M, Langel K, Eriste E, Langel Ü (2014). Cell-penetrating peptides: design, synthesis, and applications. ACS Nano, 8(3): 1972–1994
doi: 10.1021/nn4057269 pmid: 24559246
10 De Luca A, Maiello M R, D’Alessio A, Pergameno M, Normanno N (2012). The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches. Expert OpinTher Targets, 16(Suppl 2): S17–S27
doi: 10.1517/14728222.2011.639361 pmid: 22443084
11 Dickson H M, Wilbur A, Reinke A A, Young M A, Vojtek A B (2015). Targeted inhibition of the Shroom3-Rho kinase protein-protein interaction circumvents Nogo66 to promote axon outgrowth. BMC Neurosci, 16(1): 34
doi: 10.1186/s12868-015-0171-5 pmid: 26077244
12 Dikic I, Giordano S (2003).Negative receptor signalling. CurrOpin Cell Biol, 15(2): 128–135
doi: 10.1016/S0955-0674(03)00004-8 pmid: 12648667
13 El Ghouzzi V, Legeai-Mallet L, Aresta S, Benoist C, Munnich A, de Gunzburg J, Bonaventure J (2000). Saethre-Chotzen mutations cause TWIST protein degradation or impaired nuclear location. Hum Mol Genet, 9(5): 813–819
doi: 10.1093/hmg/9.5.813 pmid: 10749989
14 Enslen H, Davis R J (2001). Regulation of MAP kinases by docking domains. Biol Cell, 93(1-2): 5–14
doi: 10.1016/S0248-4900(01)01156-X pmid: 11730322
15 Favata M F, Horiuchi K Y, Manos E J, Daulerio A J, Stradley D A, Feeser W S, Van Dyk D E, Pitts W J, Earl R A, Hobbs F, Copeland R A, Magolda R L, Scherle P A, Trzaskos J M (1998). Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem, 273(29): 18623–18632
doi: 10.1074/jbc.273.29.18623 pmid: 9660836
16 Filicori M, Flamigni C (1988). GnRH agonists and antagonists.Current clinical status. Drugs, 35(1): 63–82
doi: 10.2165/00003495-198835010-00004 pmid: 3278879
17 Fosgerau K, Hoffmann T (2015). Peptide therapeutics: current status and future directions. Drug Discov Today, 20(1): 122–128
doi: 10.1016/j.drudis.2014.10.003 pmid: 25450771
18 Fu J, Meng X, He J, Gu J (2008). Inhibition of inflammation by a p38 MAP kinase targeted cell permeable peptide. Med Chem, 4(6): 597–604
doi: 10.2174/157340608786242106 pmid: 18991745
19 Gu H, Saito K, Klaman L D, Shen J, Fleming T, Wang Y, Pratt J C, Lin G, Lim B, Kinet J P, Neel B G (2001). Essential role for Gab2 in the allergic response. Nature, 412(6843): 186–190
doi: 10.1038/35084076 pmid: 11449275
20 Hasegawa K, Martin F, Huang G, Tumas D, Diehl L, Chan A C (2004). PEST domain-enriched tyrosine phosphatase (PEP) regulation of effector/memory T cells. Science, 303(5658): 685–689
doi: 10.1126/science.1092138 pmid: 14752163
21 Hiromura M, Okada F, Obata T, Auguin D, Shibata T, Roumestand C, Noguchi M (2004). Inhibition of Akt kinase activity by a peptide spanning the betaA strand of the proto-oncogene TCL1. J Biol Chem, 279(51): 53407–53418
doi: 10.1074/jbc.M403775200 pmid: 15459205
22 Hoelder S, Clarke P A, Workman P (2012). Discovery of small molecule cancer drugs: successes, challenges and opportunities. MolOncol, 6(2): 155–176
doi: 10.1016/j.molonc.2012.02.004 pmid: 22440008
23 Hornák V, Dvorský R, Sturdík E (1999). Receptor-ligand interaction and molecular modelling. Gen Physiol Biophys, 18(3): 231–248
pmid: 10703740
24 Jameson D M, Vetromile C M, James N G (2013).Investigations of protein-protein interactions using time-resolved fluorescence and phasors. Methods, 59(3): 278–286
doi: 10.1016/j.ymeth.2013.01.004 pmid: 23348372
25 Kallen J, Welzenbach K, Ramage P, Geyl D, Kriwacki R, Legge G, Cottens S, Weitz-Schmidt G, Hommel U (1999). Structural basis for LFA-1 inhibition upon lovastatin binding to the CD11a I-domain. J Mol Biol, 292(1): 1–9
doi: 10.1006/jmbi.1999.3047 pmid: 10493852
26 Kastl J, Braun J, Prestel A, Möller H M, Huhn T, Mayer T U (2015). Mad2 inhibitor-1 (M2I-1): A small molecule protein-protein interaction inhibitor targeting the mitotic spindle assembly checkpoint. ACS Chem Biol, 10(7): 1661–1666
doi: 10.1021/acschembio.5b00121 pmid: 25978000
27 Kelemen B R, Hsiao K, Goueli S A (2002). Selective in vivo inhibition of mitogen-activated protein kinase activation using cell-permeable peptides. J Biol Chem, 277(10): 8741–8748
doi: 10.1074/jbc.M108459200 pmid: 11756441
28 Kuan C Y, Burke R E (2005). Targeting the JNK signaling pathway for stroke and Parkinson’s diseases therapy. Curr Drug Targets CNS Neurol Disord, 4(1): 63–67
doi: 10.2174/1568007053005145 pmid: 15723614
29 Li H, Xiao H, Lin L, Jou D, Kumari V, Lin J, Li C (2014). Drug design targeting protein-protein interactions (PPIs) using multiple ligand simultaneous docking (MLSD) and drug repositioning: discovery of raloxifene and bazedoxifene as novel inhibitors of IL-6/GP130 interface. J Med Chem, 57(3): 632–641
doi: 10.1021/jm401144z pmid: 24456369
30 Li S H, Li X J (2004). Huntingtin-protein interactions and the pathogenesis of Huntington’s disease. Trends Genet, 20(3): 146–154
doi: 10.1016/j.tig.2004.01.008 pmid: 15036808
31 Lim J, Hao T, Shaw C, Patel A J, Szabó G, Rual J F, Fisk C J, Li N, Smolyar A, Hill D E, Barabási A L, Vidal M, Zoghbi H Y (2006). A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell, 125(4): 801–814
doi: 10.1016/j.cell.2006.03.032 pmid: 16713569
32 Liu M, Li C, Pazgier M, Li C, Mao Y, Lv Y, Gu B, Wei G, Yuan W, Zhan C, Lu W Y, Lu W (2010). D-peptide inhibitors of the p53-MDM2 interaction for targeted molecular therapy of malignant neoplasms. ProcNatlAcadSci USA, 107(32): 14321–14326
doi: 10.1073/pnas.1008930107 pmid: 20660730
33 Liuzzi M, Déziel R, Moss N, Beaulieu P, Bonneau A M, Bousquet C, Chafouleas J G, Garneau M, Jaramillo J, Krogsrud R L, Lagacé L, McCollum R S, Nawoot S, Guindon Y (1994). A potent peptidomimetic inhibitor of HSV ribonucleotide reductase with antiviral activity in vivo. Nature, 372(6507): 695–698
doi: 10.1038/372695a0 pmid: 7990963
34 Lodish H, Berk A, Zipursky S L, Matsudaira P, Baltimore D, Darnell J (2000). Molecular Cell Biology. 4th ed. New York: W. H. Freeman and Company
35 Lopes L B, Flynn C, Komalavilas P, Panitch A, Brophy C M, Seal B L (2009).Inhibition of HSP27 phosphorylation by a cell-permeant MAPKAP Kinase 2 inhibitor. BiochemBiophys Res Commun, 382(3): 535–539
doi: 10.1016/j.bbrc.2009.03.056 pmid: 19289101
36 Lu J, Bai L, Sun H, Nikolovska-Coleska Z, McEachern D, Qiu S, Miller R S, Yi H, Shangary S, Sun Y, Meagher J L, Stuckey J A, Wang S (2008). SM-164: a novel, bivalent Smac mimetic that induces apoptosis and tumor regression by concurrent removal of the blockade of cIAP-1/2 and XIAP. Cancer Res, 68(22): 9384–9393
doi: 10.1158/0008-5472.CAN-08-2655 pmid: 19010913
37 Maruyama I N (2015).Activation of transmembrane cell-surface receptors via a common mechanism?The “rotation model”. BioEssays, 37(9): 959–967
doi: 10.1002/bies.201500041 pmid: 26241732
38 Maximov P Y, Lee T M, Jordan V C (2013). The discovery and development of selective estrogen receptor modulators (SERMs) for clinical practice. CurrClinPharmacol, 8(2): 135–155
doi: 10.2174/1574884711308020006 pmid: 23062036
39 May M J, D’Acquisto F, Madge L A, Glöckner J, Pober J S, Ghosh S (2000).Selective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB kinase complex. Science, 289(5484): 1550–1554
doi: 10.1126/science.289.5484.1550 pmid: 10968790
40 Meyn M A3rd, Smithgall T E (2008). Small molecule inhibitors of Lck: the search for specificity within a kinase family. Mini Rev Med Chem, 8(6): 628–637
doi: 10.2174/138955708784534454 pmid: 18537718
41 Nakaoka Y, Komuro I (2013). Gab docking proteins in cardiovascular disease, cancer, and inflammation. Int J Inflamm, 2013: 141068
doi: 10.1155/2013/141068 pmid: 23431498
42 Netzer W J, Dou F, Cai D, Veach D, Jean S, Li Y, Bornmann W G, Clarkson B, Xu H, Greengard P (2003). Gleevec inhibits β-amyloid production but not Notch cleavage. Proc Natl Acad Sci USA, 100(21): 12444–12449
doi: 10.1073/pnas.1534745100 pmid: 14523244
43 Ohtsuka M, Konno F, Honda H, Oikawa T, Ishikawa M, Iwase N, Isomae K, Ishii F, Hemmi H, Sato S (2002). PPA250 [3-(2,4-difluorophenyl)-6-[2-[4-(1H-imidazol-1-ylmethyl) phenoxy]ethoxy]-2-phenylpyridine], a novel orally effective inhibitor of the dimerization of inducible nitric-oxide synthase, exhibits an anti-inflammatory effect in animal models of chronic arthritis. J PharmacolExpTher, 303(1): 52–57
doi: 10.1124/jpet.102.035857 pmid: 12235232
44 Reiman E M, Webster J A, Myers A J, Hardy J, Dunckley T, Zismann V L, Joshipura K D, Pearson J V, Hu-Lince D, Huentelman M J, Craig D W, Coon K D, Liang W S, Herbert R H, Beach T, Rohrer K C, Zhao A S, Leung D, Bryden L, Marlowe L, Kaleem M, Mastroeni D, Grover A, Heward C B, Ravid R, Rogers J, Hutton M L, Melquist S, Petersen R C, Alexander G E, Caselli R J, Kukull W, Papassotiropoulos A, Stephan D A (2007). GAB2 alleles modify Alzheimer’s risk in APOE e4 carriers. Neuron, 54(5): 713–720
doi: 10.1016/j.neuron.2007.05.022 pmid: 17553421
45 Rigaut G, Shevchenko A, Rutz B, Wilm M, Mann M, Séraphin B (1999). A generic protein purification method for protein complex characterization and proteome exploration. Nat Biotechnol, 17(10): 1030–1032
doi: 10.1038/13732 pmid: 10504710
46 Saporito M S, Hudkins R L, Maroney A C (2002). Discovery of CEP-1347/KT-7515, an inhibitor of the JNK/SAPK pathway for the treatment of neurodegenerative diseases. Prog Med Chem, 40: 23–62
doi: 10.1016/S0079-6468(08)70081-X pmid: 12516522
47 Secko D (2013). Cell surface receptors: a biological conduit for information transfer. TSCQ, Issue 8
48 Seto M L, Lee S J, Sze R W, Cunningham M L (2001). Another TWIST on Baller-Gerold syndrome. Am J Med Genet, 104(4): 323–330
doi: 10.1002/ajmg.10065 pmid: 11754069
49 Sever R, Glass C K (2013). Signaling by nuclear receptors. Cold Spring Harb Perspect Biol, 5(3): a016709
doi: 10.1101/cshperspect.a016709 pmid: 23457262
50 Thanos C D, Randal M, Wells J A (2003).Potent small-molecule binding to a dynamic hot spot on IL-2. J Am ChemSoc, 125(50): 15280–15281
doi: 10.1021/ja0382617 pmid: 14664558
51 Tian S S, Lamb P, King A G, Miller S G, Kessler L, Luengo J I, Averill L, Johnson R K, Gleason J G, Pelus L M, Dillon S B, Rosen J (1998). A small, nonpeptidyl mimic of granulocyte-colony-stimulating factor [see commetns]. Science, 281(5374): 257–259
doi: 10.1126/science.281.5374.257 pmid: 9657720
52 Tilley J W, Chen L, Fry D C, Emerson S D, Powers G D, Biondi D, Varnell T, Trilles R, Guthrie R, Mennona F, Kaplan G, LeMahieu R A, Carson M, Han R J, Liu C M, Palermo R, Ju G (1997). Identification of a small molecule inhibitor of the IL2/IL2rα receptor interaction which binds to IL-2. J Am ChemSoc, 119(32): 7589–7590
doi: 10.1021/ja970702x
53 Toshchakov V Y, Fenton M J, Vogel S N (2007). Cutting Edge: Differential inhibition of TLR signaling pathways by cell-permeable peptides representing BB loops of TLRs. J Immunol, 178(5): 2655–2660
doi: 10.4049/jimmunol.178.5.2655 pmid: 17312106
54 Wada T, Nakashima T, Oliveira-dos-Santos A J, Gasser J, Hara H, Schett G, Penninger J M (2005). The molecular scaffold Gab2 is a crucial component of RANK signaling and osteoclastogenesis. Nat Med, 11(4): 394–399
doi: 10.1038/nm1203 pmid: 15750601
55 Wang J L, Liu D, Zhang Z J, Shan S, Han X, Srinivasula S M, Croce C M, Alnemri E S, Huang Z (2000). Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells. Proc Natl Acad Sci USA, 97(13): 7124–7129
doi: 10.1073/pnas.97.13.7124 pmid: 10860979
56 Wang Q, Feng J, Wang J, Zhang X, Zhang D, Zhu T, Wang W, Wang X, Jin J, Cao J, Li X, Peng H, Li Y, Shen B, Zhang J (2013). Disruption of TAB1/p38α interaction using a cell-permeable peptide limits myocardial ischemia/reperfusion injury. Mol Ther, 21(9): 1668–1677
doi: 10.1038/mt.2013.90 pmid: 23877036
57 Wong B C U, Jiang X, Fan X M, Lin M C M, Jiang S H, Lam S K, Kung H F (2003). Suppression of RelA/p65 nuclear translocation independent of IkappaB-α degradation by cyclooxygenase-2 inhibitor in gastric cancer. Oncogene, 22(8): 1189–1197
doi: 10.1038/sj.onc.1206234 pmid: 12606945
58 Young K H (1998). Yeast two-hybrid: so many interactions, (in) so little time...Biol Reprod, 58(2): 302–311
doi: 10.1095/biolreprod58.2.302 pmid: 9475380
59 Zhang W, Liu H T (2002). MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res, 12(1): 9–18
doi: 10.1038/ pmid: 11942415
60 Zhang Y, Diaz-Flores E, Li G, Wang Z, Kang Z, Haviernikova E, Rowe S, Qu C K, Tse W, Shannon K M, Bunting K D (2007). Abnormal hematopoiesis in Gab2 mutant mice. Blood, 110(1): 116–124
doi: 10.1182/blood-2006-11-060707 pmid: 17374739
61 Zhang Y, Eigenbrot C, Zhou L, Shia S, Li W, Quan C, Tom J, Moran P, Di Lello P, Skelton N J, Kong-Beltran M, Peterson A, Kirchhofer D (2014). Identification of a small peptide that inhibits PCSK9 protein binding to the low density lipoprotein receptor. J Biol Chem, 289(2): 942–955
doi: 10.1074/jbc.M113.514067 pmid: 24225950
Related articles from Frontiers Journals
[1] B. Preethi,V. Shanthi,K. Ramanathan. Reckoning the SIX1 mutation’s effects in branchio-oto-renal syndrome — A bioinformatics approach[J]. Front. Biol., 2015, 10(5): 448-457.
[2] Mary Catherine RENEER, Francesc MARTI. The balancing act of AKT in T cells[J]. Front Biol, 2013, 8(2): 160-174.
Full text