Login Register Cart 0
Generic placeholder image

Current Diabetes Reviews

Editor-in-Chief

ISSN (Print): 1573-3998
ISSN (Online): 1875-6417

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

3-Phosphoinositide-Dependent Kinase 1 as a Therapeutic Target for Treating Diabetes

In Press, (this is not the final "Version of Record"). Available online 11 March, 2024
Author(s): Xie Xiang, Pan Shuya, Zhang Jiamin, Zhang Zihan, Yang Xumei and Liu Jingjin*
Published on: 11 March, 2024

Article ID: e110324227852

DOI: 10.2174/0115733998278669240226061329

Price: $95

Abstract

The role of 3-phosphoinositide-dependent kinase 1 (PDK1) has been welldocumented in the development of diabetes. This review offers a thorough examination of its composition and associated routes, specifically focusing on insulin signaling and glucose processing. By examining the precise connection between PDK1 and diabetes, various strategies specifically targeting PDK1 were also investigated. Additionally, recent discoveries from mouse models were compiled where PDK1 was knocked out in certain tissues, which demonstrated encouraging outcomes for focused treatments despite the absence of any currently approved clinical PDK1 activators. Moreover, the dual nature of PDK1 activation was discussed, encompassing both anti-diabetic and pro-oncogenic effects. Hence, the development of a PDK1 modifier is of utmost importance, as it can activate anti-diabetic pathways while inhibiting pro-oncogenic pathways, thus aiding in the treatment of diabetes. In general, PDK1 presents a noteworthy opportunity for future therapeutic strategies in the treatment of diabetes.

[1]
Mahgoub MO, Ali II, Adeghate JO, Tekes K, Kalász H, Adeghate EA. An update on the molecular and cellular basis of pharmacotherapy in type 2 diabetes mellitus. Int J Mol Sci 2023; 24(11): 9328.
[http://dx.doi.org/10.3390/ijms24119328] [PMID: 37298274]
[2]
Nakae J, Biggs WH III, Kitamura T, et al. Regulation of insulin action and pancreatic β-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1. Nat Genet 2002; 32(2): 245-53.
[http://dx.doi.org/10.1038/ng890] [PMID: 12219087]
[3]
Jiang Q, Zhang X, Dai X, et al. S6K1-mediated phosphorylation of PDK1 impairs AKT kinase activity and oncogenic functions. Nat Commun 2022; 13(1): 1548.
[http://dx.doi.org/10.1038/s41467-022-28910-8] [PMID: 35318320]
[4]
Bayascas JR. PDK1: The major transducer of PI 3-kinase actions. Curr Top Microbiol Immunol 2010; 346: 9-29.
[http://dx.doi.org/10.1007/82_2010_43] [PMID: 20563709]
[5]
Dong LQ, Zhang R, Langlais P, et al. Primary structure, tissue distribution, and expression of mouse phosphoinositide-dependent protein kinase-1, a protein kinase that phosphorylates and activates protein kinase Czeta. J Biol Chem 1999; 274(12): 8117-22.
[http://dx.doi.org/10.1074/jbc.274.12.8117] [PMID: 10075713]
[6]
Tawaramoto K, Kotani K, Hashiramoto M, et al. Ablation of 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vascular endothelial cells enhances insulin sensitivity by reducing visceral fat and suppressing angiogenesis. Mol Endocrinol 2012; 26(1): 95-109.
[http://dx.doi.org/10.1210/me.2010-0412] [PMID: 22108800]
[7]
Song BR, Alam MB, Lee SH. Terpenoid-rich extract of dillenia indica l. bark displays antidiabetic action in insulin-resistant c2c12 cells and stz-induced diabetic mice by attenuation of oxidative stress. Antioxidants 2022; 11(7): 1227.
[http://dx.doi.org/10.3390/antiox11071227] [PMID: 35883721]
[8]
Maiese K, Daniela Morhan S, Zhong Chong Z. Oxidative stress biology and cell injury during type 1 and type 2 diabetes mellitus. Curr Neurovasc Res 2007; 4(1): 63-71.
[http://dx.doi.org/10.2174/156720207779940653] [PMID: 17311546]
[9]
Katase N, Nishimatsu SI, Yamauchi A, Yamamura M, Fujita S. DKK3 knockdown confers negative effects on the malignant potency of head and neck squamous cell carcinoma cells via the PI3K/Akt and MAPK signaling pathways. Int J Oncol 2019; 54(3): 1021-32.
[PMID: 30569110]
[10]
Sato S, Fujita N, Tsuruo T. Involvement of 3-phosphoinositide-dependent protein kinase-1 in the MEK/MAPK signal transduction pathway. J Biol Chem 2004; 279(32): 33759-67.
[http://dx.doi.org/10.1074/jbc.M402055200] [PMID: 15175348]
[11]
Liu C, Pei J, Mu X, Yu B, Gong T, Liang W. Ponatinib inhibits the proliferation of SNU-449 human hepatocellular cancer cells and blocks MAPK and PDK1/AKT/mTOR signaling pathways. Xibao Yu Fenzi Mianyixue Zazhi 2022; 38(5): 425-31.
[PMID: 35603651]
[12]
Hosooka T, Hosokawa Y, Matsugi K, et al. The PDK1-FoxO1 signaling in adipocytes controls systemic insulin sensitivity through the 5-lipoxygenase–leukotriene B 4 axis. Proc Natl Acad Sci 2020; 117(21): 11674-84.
[http://dx.doi.org/10.1073/pnas.1921015117] [PMID: 32393635]
[13]
Alessi DR, James SR, Downes CP, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Bα. Curr Biol 1997; 7(4): 261-9.
[http://dx.doi.org/10.1016/S0960-9822(06)00122-9] [PMID: 9094314]
[14]
Alessi DR, Deak M, Casamayor A, et al. 3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase. Curr Biol 1997; 7(10): 776-89.
[http://dx.doi.org/10.1016/S0960-9822(06)00336-8] [PMID: 9368760]
[15]
Pearce LR, Komander D, Alessi DR. The nuts and bolts of AGC protein kinases. Nat Rev Mol Cell Biol 2010; 11(1): 9-22.
[http://dx.doi.org/10.1038/nrm2822] [PMID: 20027184]
[16]
Biondi RM, Komander D, Thomas CC, et al. High resolution crystal structure of the human PDK1 catalytic domain defines the regulatory phosphopeptide docking site. EMBO J 2002; 21(16): 4219-28.
[http://dx.doi.org/10.1093/emboj/cdf437] [PMID: 12169624]
[17]
Komander D, Kular G, Deak M, Alessi DR, van Aalten DMF. Role of T-loop phosphorylation in PDK1 activation, stability, and substrate binding. J Biol Chem 2005; 280(19): 18797-802.
[http://dx.doi.org/10.1074/jbc.M500977200] [PMID: 15741170]
[18]
Collins BJ, Deak M, Murray-Tait V, Storey KG, Alessi DR. In vivo role of the phosphate groove of PDK1 defined by knockin mutation. J Cell Sci 2005; 118(21): 5023-34.
[http://dx.doi.org/10.1242/jcs.02617] [PMID: 16219676]
[19]
Xu X, Chen Y, Fu Q, et al. The chemical diversity and structure-based discovery of allosteric modulators for the PIF-pocket of protein kinase PDK1. J Enzyme Inhib Med Chem 2019; 34(1): 361-74.
[http://dx.doi.org/10.1080/14756366.2018.1553167] [PMID: 30734603]
[20]
Boucher J, Kleinridders A, Kahn CR. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol 2014; 6(1): a009191.
[http://dx.doi.org/10.1101/cshperspect.a009191] [PMID: 24384568]
[21]
Park H, Lee S, Shrestha P, et al. AMIGO2, a novel membrane anchor of PDK1, controls cell survival and angiogenesis via Akt activation. J Cell Biol 2015; 211(3): 619-37.
[http://dx.doi.org/10.1083/jcb.201503113] [PMID: 26553931]
[22]
Williams MR, Arthur JSC, Balendran A, et al. The role of 3-phosphoinositide-dependent protein kinase 1 in activating AGC kinases defined in embryonic stem cells. Curr Biol 2000; 10(8): 439-48.
[http://dx.doi.org/10.1016/S0960-9822(00)00441-3] [PMID: 10801415]
[23]
Gagliardi PA, Puliafito A, Primo L. PDK1: At the crossroad of cancer signaling pathways. Semin Cancer Biol 2018; 48: 27-35.
[http://dx.doi.org/10.1016/j.semcancer.2017.04.014] [PMID: 28473254]
[24]
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005; 307(5712): 1098-101.
[http://dx.doi.org/10.1126/science.1106148] [PMID: 15718470]
[25]
Alessi DR, Kozlowski MT, Weng QP, Morrice N, Avruch J. 3-Phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates and activates the p70 S6 kinase in vivo and in vitro. Curr Biol 1998; 8(2): 69-81.
[http://dx.doi.org/10.1016/S0960-9822(98)70037-5] [PMID: 9427642]
[26]
Park J, Leong ML, Buse P, Maiyar AC, Firestone GL, Hemmings BA. Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway. EMBO J 1999; 18(11): 3024-33.
[http://dx.doi.org/10.1093/emboj/18.11.3024] [PMID: 10357815]
[27]
Jensen CJ, Buch MB, Krag TO, Hemmings BA, Gammeltoft S, Frödin M. 90-kDa ribosomal S6 kinase is phosphorylated and activated by 3-phosphoinositide-dependent protein kinase-1. J Biol Chem 1999; 274(38): 27168-76.
[http://dx.doi.org/10.1074/jbc.274.38.27168] [PMID: 10480933]
[28]
Casamayor A, Morrice NA, Alessi DR. Alessi, Phosphorylation of Ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1: identification of five sites of phosphorylation in vivo. Biochem J 1999; 342: 287-92.
[29]
Levina A, Fleming KD, Burke JE, Leonard TA. Activation of the essential kinase PDK1 by phosphoinositide-driven trans-autophosphorylation. Nat Commun 2022; 13(1): 1874.
[http://dx.doi.org/10.1038/s41467-022-29368-4] [PMID: 35387990]
[30]
Masters TA, Calleja V, Armoogum DA, et al. Regulation of 3-phosphoinositide-dependent protein kinase 1 activity by homodimerization in live cells. Sci Signal 2010; 3(145): ra78.
[http://dx.doi.org/10.1126/scisignal.2000738] [PMID: 20978239]
[31]
Sacerdoti M, Gross LZF, Riley AM, et al. Modulation of the substrate specificity of the kinase PDK1 by distinct conformations of the full-length protein. Sci Signal 2023; 16(789): eadd3184.
[http://dx.doi.org/10.1126/scisignal.add3184] [PMID: 37311034]
[32]
King CC, Gardiner EMM, Zenke FT, et al. p21-activated kinase (PAK1) is phosphorylated and activated by 3-phosphoinositide-dependent kinase-1 (PDK1). J Biol Chem 2000; 275(52): 41201-9.
[http://dx.doi.org/10.1074/jbc.M006553200] [PMID: 10995762]
[33]
Tan J, Li Z, Lee PL, et al. PDK1 signaling toward PLK1-MYC activation confers oncogenic transformation, tumor-initiating cell activation, and resistance to mTOR-targeted therapy. Cancer Discov 2013; 3(10): 1156-71.
[http://dx.doi.org/10.1158/2159-8290.CD-12-0595] [PMID: 23887393]
[34]
di Blasio L, Gagliardi PA, Puliafito A, et al. PDK1 regulates focal adhesion disassembly by modulating endocytosis of αvβ3 integrin. J Cell Sci 2015; 128(5): 863-77.
[PMID: 25588838]
[35]
Pinner S, Sahai E. PDK1 regulates cancer cell motility by antagonising inhibition of ROCK1 by RhoE. Nat Cell Biol 2008; 10(2): 127-37.
[http://dx.doi.org/10.1038/ncb1675] [PMID: 18204440]
[36]
Gagliardi PA, di Blasio L, Puliafito A, et al. PDK1-mediated activation of MRCKα regulates directional cell migration and lamellipodia retraction. J Cell Biol 2014; 206(3): 415-34.
[http://dx.doi.org/10.1083/jcb.201312090] [PMID: 25092657]
[37]
Biondi R. Phosphoinositide-dependent protein kinase 1, a sensor of protein conformation. Trends Biochem Sci 2004; 29(3): 136-42.
[http://dx.doi.org/10.1016/j.tibs.2004.01.005] [PMID: 15003271]
[38]
Gaßel M, Breitenlechner CB, Rüger P, et al. Mutants of protein kinase A that mimic the ATP-binding site of protein kinase B (AKT). J Mol Biol 2003; 329(5): 1021-34.
[http://dx.doi.org/10.1016/S0022-2836(03)00518-7] [PMID: 12798691]
[39]
Bogoyevitch M, Fairlie D. A new paradigm for protein kinase inhibition: Blocking phosphorylation without directly targeting ATP binding. Drug Discov Today 2007; 12(15-16): 622-33.
[http://dx.doi.org/10.1016/j.drudis.2007.06.008] [PMID: 17706543]
[40]
Stroba A, Schaeffer F, Hindie V, et al. 3,5-Diphenylpent-2-enoic acids as allosteric activators of the protein kinase PDK1: structure-activity relationships and thermodynamic characterization of binding as paradigms for PIF-binding pocket-targeting compounds. J Med Chem 2009; 52(15): 4683-93.
[http://dx.doi.org/10.1021/jm9001499] [PMID: 19606904]
[41]
Sadowsky JD, Burlingame MA, Wolan DW, McClendon CL, Jacobson MP, Wells JA. Turning a protein kinase on or off from a single allosteric site via disulfide trapping. Proc Natl Acad Sci USA 2011; 108(15): 6056-61.
[http://dx.doi.org/10.1073/pnas.1102376108] [PMID: 21430264]
[42]
Nussinov R, Tsai CJ. Allostery in disease and in drug discovery. Cell 2013; 153(2): 293-305.
[http://dx.doi.org/10.1016/j.cell.2013.03.034] [PMID: 23582321]
[43]
Fang Z, Grütter C, Rauh D. Strategies for the selective regulation of kinases with allosteric modulators: Exploiting exclusive structural features. ACS Chem Biol 2013; 8(1): 58-70.
[http://dx.doi.org/10.1021/cb300663j] [PMID: 23249378]
[44]
Nagashima K, Shumway SD, Sathyanarayanan S, et al. Genetic and pharmacological inhibition of PDK1 in cancer cells: Characterization of a selective allosteric kinase inhibitor. J Biol Chem 2011; 286(8): 6433-48.
[http://dx.doi.org/10.1074/jbc.M110.156463] [PMID: 21118801]
[45]
Schulze JO, Saladino G, Busschots K, et al. Bidirectional allosteric communication between the ATP-binding site and the regulatory PIF Pocket in PDK1 protein kinase. Cell Chem Biol 2016; 23(10): 1193-205.
[http://dx.doi.org/10.1016/j.chembiol.2016.06.017] [PMID: 27693059]
[46]
Liu W, Li P, Mei Y. Discovery of SBF1 as an allosteric inhibitor targeting the PIF-pocket of 3-phosphoinositide-dependent protein kinase-1. J Mol Model 2019; 25(7): 187.
[http://dx.doi.org/10.1007/s00894-019-4069-5] [PMID: 31197600]
[47]
Wenthur CJ, Gentry PR, Mathews TP, Lindsley CW. Drugs for allosteric sites on receptors. Annu Rev Pharmacol Toxicol 2014; 54(1): 165-84.
[http://dx.doi.org/10.1146/annurev-pharmtox-010611-134525] [PMID: 24111540]
[48]
Ni D, Song K, Zhang J, Lu S. Molecular dynamics simulations and dynamic network analysis reveal the allosteric unbinding of monobody to H-Ras triggered by R135K mutation. Int J Mol Sci 2017; 18(11): 2249.
[http://dx.doi.org/10.3390/ijms18112249] [PMID: 29072601]
[49]
Wylie AA, Schoepfer J, Jahnke W, et al. The allosteric inhibitor ABL001 enables dual targeting of BCR–ABL1. Nature 2017; 543(7647): 733-7.
[http://dx.doi.org/10.1038/nature21702] [PMID: 28329763]
[50]
Hossen MJ, Kim SC, Yang S, et al. PDK1 disruptors and modulators: A patent review. Expert Opin Ther Pat 2015; 25(5): 513-37.
[http://dx.doi.org/10.1517/13543776.2015.1014801] [PMID: 25684022]
[51]
Hindie V, Stroba A, Zhang H, et al. Structure and allosteric effects of low-molecular-weight activators on the protein kinase PDK1. Nat Chem Biol 2009; 5(10): 758-64.
[http://dx.doi.org/10.1038/nchembio.208] [PMID: 19718043]
[52]
Petersen MC, Shulman GI. Mechanisms of Insulin Action and Insulin Resistance. Physiol Rev 2018; 98(4): 2133-223.
[http://dx.doi.org/10.1152/physrev.00063.2017] [PMID: 30067154]
[53]
Knudsen JR, Fritzen AM, James DE, Jensen TE, Kleinert M, Richter EA. Growth factor-dependent and -independent activation of mTORC2. Trends Endocrinol Metab 2020; 31(1): 13-24.
[http://dx.doi.org/10.1016/j.tem.2019.09.005] [PMID: 31699566]
[54]
Lyu HW, Luo M, Li YX, Jiang HP, Yan JZ, Tong SQ. Overview on hypoglycemic active constituents of traditional Chinese medicine based on insulin receptor signaling pathway. Zhongguo Zhongyao Zazhi 2019; 44(19): 4158-64.
[PMID: 31872693]
[55]
Chadt A, Al-Hasani H. Glucose transporters in adipose tissue, liver, and skeletal muscle in metabolic health and disease. Pflugers Arch 2020; 472(9): 1273-98.
[http://dx.doi.org/10.1007/s00424-020-02417-x] [PMID: 32591906]
[56]
Wang C, Deng Y, Yue Y, et al. Glutamine Enhances the Hypoglycemic Effect of Insulin in L6 Cells via Phosphatidylinositol-3-Kinase (PI3K)/Protein Kinase B (AKT)/Glucose Transporter 4 (GLUT4) Signaling Pathway. Med Sci Monit 2018; 24: 1241-50.
[http://dx.doi.org/10.12659/MSM.909011] [PMID: 29491345]
[57]
Bamodu OA, Chang HL, Ong JR, Lee WH, Yeh CT, Tsai JT. Elevated PDK1 expression drives PI3K/AKT/MTOR signaling promotes radiation-resistant and dedifferentiated phenotype of hepatocellular carcinoma. Cells 2020; 9(3): 746.
[http://dx.doi.org/10.3390/cells9030746] [PMID: 32197467]
[58]
Biondi RM, Kieloch A, Currie RA, Deak M, Alessi DR. The PIF-binding pocket in PDK1 is essential for activation of S6K and SGK, but not PKB. EMBO J 2001; 20(16): 4380-90.
[http://dx.doi.org/10.1093/emboj/20.16.4380] [PMID: 11500365]
[59]
Li S, Feng F, Deng Y. Resveratrol regulates glucose and lipid metabolism in diabetic rats by inhibition of PDK1/AKT phosphorylation and HIF-1α expression. Diabetes Metab Syndr Obes 2023; 16: 1063-74.
[http://dx.doi.org/10.2147/DMSO.S403893] [PMID: 37090841]
[60]
Yamada T, Katagiri H, Asano T, et al. Role of PDK1 in insulin-signaling pathway for glucose metabolism in 3T3-L1 adipocytes. Am J Physiol Endocrinol Metab 2002; 282(6): E1385-94.
[http://dx.doi.org/10.1152/ajpendo.00486.2001] [PMID: 12006370]
[61]
Paul DS, Harmon AW, Devesa V, Thomas DJ, Stýblo M. Molecular mechanisms of the diabetogenic effects of arsenic: inhibition of insulin signaling by arsenite and methylarsonous acid. Environ Health Perspect 2007; 115(5): 734-42.
[http://dx.doi.org/10.1289/ehp.9867] [PMID: 17520061]
[62]
Kim S, Lee E, Jung J, et al. microRNA-155 positively regulates glucose metabolism via PIK3R1-FOXO3a-cMYC axis in breast cancer. Oncogene 2018; 37(22): 2982-91.
[http://dx.doi.org/10.1038/s41388-018-0124-4] [PMID: 29527004]
[63]
Manne BK, Münzer P, Badolia R, et al. PDK1 governs thromboxane generation and thrombosis in platelets by regulating activation of Raf1 in the MAPK pathway. J Thromb Haemost 2018; 16(6): 1211-25.
[http://dx.doi.org/10.1111/jth.14005] [PMID: 29575487]
[64]
Navé BT, et al. Mammalian target of rapamycin is a direct target for protein kinase B: Identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation Biochem J 1999; 344: 427-31.
[http://dx.doi.org/10.1042/bj3440427]
[65]
Obata A, Kimura T, Obata Y, et al. Vascular endothelial PDPK1 plays a pivotal role in the maintenance of pancreatic beta cell mass and function in adult male mice. Diabetologia 2019; 62(7): 1225-36.
[http://dx.doi.org/10.1007/s00125-019-4878-1] [PMID: 31055616]
[66]
Watanabe S, Matsumoto T, Oda M, et al. Insulin augments serotonin-induced contraction via activation of the IR/PI3K/PDK1 pathway in the rat carotid artery. Pflugers Arch 2016; 468(4): 667-77.
[http://dx.doi.org/10.1007/s00424-015-1759-4] [PMID: 26577585]
[67]
Sharma S, Singh M, Sharma PL. Beneficial effect of insulin in hyperhomocysteinemia and diabetes mellitus-induced vascular endothelium dysfunction: role of phosphoinositide dependent kinase and protein kinase B. Mol Cell Biochem 2011; 348(1-2): 21-32.
[http://dx.doi.org/10.1007/s11010-010-0633-0] [PMID: 21069435]
[68]
Accili D, Arden KC. FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell 2004; 117(4): 421-6.
[http://dx.doi.org/10.1016/S0092-8674(04)00452-0] [PMID: 15137936]
[69]
Liu J, Xie X, Yan D, et al. Up‐regulation of FoxO1 contributes to adverse vascular remodelling in type 1 diabetic rats. J Cell Mol Med 2020; 24(23): 13727-38.
[http://dx.doi.org/10.1111/jcmm.15935] [PMID: 33108705]
[70]
Kawano Y, Nakae J, Watanabe N, et al. Loss of Pdk1-Foxo1 signaling in myeloid cells predisposes to adipose tissue inflammation and insulin resistance. Diabetes 2012; 61(8): 1935-48.
[http://dx.doi.org/10.2337/db11-0770] [PMID: 22586579]
[71]
Spiegelman BM, Flier JS. Obesity and the regulation of energy balance. Cell 2001; 104(4): 531-43.
[http://dx.doi.org/10.1016/S0092-8674(01)00240-9] [PMID: 11239410]
[72]
Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 2006; 116(7): 1784-92.
[http://dx.doi.org/10.1172/JCI29126] [PMID: 16823476]
[73]
Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006; 444(7121): 860-7.
[http://dx.doi.org/10.1038/nature05485] [PMID: 17167474]
[74]
Mothe-Satney I, Filloux C, Amghar H, et al. Adipocytes secrete leukotrienes: Contribution to obesity-associated inflammation and insulin resistance in mice. Diabetes 2012; 61(9): 2311-9.
[http://dx.doi.org/10.2337/db11-1455] [PMID: 22688342]
[75]
Jo K, Lee SE, Lee SW, Hwang JK. Prunus yedoensis Matsum. stimulates glucose uptake in L6 rat skeletal muscle cells by activating AMP-activated protein kinase and phosphatidylinositol 3-kinase/Akt pathways. Nat Prod Res 2012; 26(17): 1610-5.
[http://dx.doi.org/10.1080/14786419.2011.574133] [PMID: 21809954]
[76]
Aierken A, Li B, Liu P, et al. Melatonin treatment improves human umbilical cord mesenchymal stem cell therapy in a mouse model of type II diabetes mellitus via the PI3K/AKT signaling pathway. Stem Cell Res Ther 2022; 13(1): 164.
[http://dx.doi.org/10.1186/s13287-022-02832-0] [PMID: 35414044]
[77]
Mora A, Davies AM, Bertrand L, et al. Deficiency of PDK1 in cardiac muscle results in heart failure and increased sensitivity to hypoxia. EMBO J 2003; 22(18): 4666-76.
[http://dx.doi.org/10.1093/emboj/cdg469] [PMID: 12970179]
[78]
Mora A, Lipina C, Tronche F, Sutherland C, Alessi DR. Deficiency of PDK1 in liver results in glucose intolerance, impairment of insulin-regulated gene expression and liver failure. Biochem J 2005; 385(3): 639-48.
[http://dx.doi.org/10.1042/BJ20041782] [PMID: 15554902]
[79]
Okamoto Y, Ogawa W, Nishizawa A, et al. Restoration of glucokinase expression in the liver normalizes postprandial glucose disposal in mice with hepatic deficiency of PDK1. Diabetes 2007; 56(4): 1000-9.
[http://dx.doi.org/10.2337/db06-1322] [PMID: 17267763]
[80]
Hashimoto N, Kido Y, Uchida T, et al. Ablation of PDK1 in pancreatic β cells induces diabetes as a result of loss of β cell mass. Nat Genet 2006; 38(5): 589-93.
[http://dx.doi.org/10.1038/ng1774] [PMID: 16642023]
[81]
El Ouaamari A, Baroukh N, Martens GA, Lebrun P, Pipeleers D, van Obberghen E. miR-375 targets 3′-phosphoinositide-dependent protein kinase-1 and regulates glucose-induced biological responses in pancreatic beta-cells. Diabetes 2008; 57(10): 2708-17.
[http://dx.doi.org/10.2337/db07-1614] [PMID: 18591395]
[82]
Hosokawa Y, Hosooka T, Imamori M, Yamaguchi K, Itoh Y, Ogawa W. Adipose tissue insulin resistance exacerbates liver inflammation and fibrosis in a diet-induced NASH model. Hepatol Commun 2023; 7(6): e0161.
[http://dx.doi.org/10.1097/HC9.0000000000000161] [PMID: 37219877]
[83]
Bayascas JR, Wullschleger S, Sakamoto K, et al. Mutation of the PDK1 PH domain inhibits protein kinase B/Akt, leading to small size and insulin resistance. Mol Cell Biol 2008; 28(10): 3258-72.
[http://dx.doi.org/10.1128/MCB.02032-07] [PMID: 18347057]
[84]
Bayascas JR, Sakamoto K, Armit L, Arthur JSC, Alessi DR. Evaluation of approaches to generation of tissue-specific knock-in mice. J Biol Chem 2006; 281(39): 28772-81.
[http://dx.doi.org/10.1074/jbc.M606789200] [PMID: 16887794]
[85]
Engel M, Hindie V, Lopez-Garcia LA, et al. Allosteric activation of the protein kinase PDK1 with low molecular weight compounds. EMBO J 2006; 25(23): 5469-80.
[http://dx.doi.org/10.1038/sj.emboj.7601416] [PMID: 17110931]
[86]
Um SH, Frigerio F, Watanabe M, et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 2004; 431(7005): 200-5.
[http://dx.doi.org/10.1038/nature02866] [PMID: 15306821]
[87]
Querfurth H, Marshall J, Parang K, et al. A PDK-1 allosteric agonist neutralizes insulin signaling derangements and beta-amyloid toxicity in neuronal cells and in vitro. PLoS One 2022; 17(1): e0261696.
[http://dx.doi.org/10.1371/journal.pone.0261696] [PMID: 35061720]
[88]
Wang N, Fu J, Li Z, Jiang N, Chen Y, Peng J. The landscape of PDK1 in breast cancer. Cancers 2022; 14(3): 811.
[http://dx.doi.org/10.3390/cancers14030811] [PMID: 35159078]
[89]
Vasudevan KM, Barbie DA, Davies MA, et al. AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 2009; 16(1): 21-32.
[http://dx.doi.org/10.1016/j.ccr.2009.04.012] [PMID: 19573809]
[90]
Scortegagna M, Lau E, Zhang T, et al. PDK1 and SGK3 contribute to the growth of braf-mutant melanomas and are potential therapeutic targets. Cancer Res 2015; 75(7): 1399-412.
[http://dx.doi.org/10.1158/0008-5472.CAN-14-2785] [PMID: 25712345]
[91]
Arsenic R. Immunohistochemical analysis of PDK1 expression in breast cancer. Diagn Pathol 2014; 9(1): 82.
[http://dx.doi.org/10.1186/1746-1596-9-82] [PMID: 24739482]
[92]
Armando Gagliardi P, di Blasio L, Orso F, et al. 3-phosphoinositide-dependent kinase 1 controls breast tumor growth in a kinase-dependent but Akt-independent manner. Neoplasia 2012; 14(8): 719-IN19.
[http://dx.doi.org/10.1593/neo.12856] [PMID: 22952425]
[93]
Eser S, Reiff N, Messer M, et al. Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer. Cancer Cell 2013; 23(3): 406-20.
[http://dx.doi.org/10.1016/j.ccr.2013.01.023] [PMID: 23453624]
[94]
Yu J, Chen KS, Li YN, Yang J, Zhao L. Silencing of PDK1 gene expression by RNA interference suppresses growth of esophageal cancer. Asian Pac J Cancer Prev 2012; 13(8): 4147-51.
[http://dx.doi.org/10.7314/APJCP.2012.13.8.4147] [PMID: 23098536]
[95]
Finlay DK, Sinclair LV, Feijoo C, et al. Phosphoinositide-dependent kinase 1 controls migration and malignant transformation but not cell growth and proliferation in PTEN-null lymphocytes. J Exp Med 2009; 206(11): 2441-54.
[http://dx.doi.org/10.1084/jem.20090219] [PMID: 19808258]
[96]
Scortegagna M, Ruller C, Feng Y, et al. Genetic inactivation or pharmacological inhibition of Pdk1 delays development and inhibits metastasis of BrafV600E:Pten–/– melanoma. Oncogene 2014; 33(34): 4330-9.
[http://dx.doi.org/10.1038/onc.2013.383] [PMID: 24037523]
[97]
Medina JR. Selective 3-phosphoinositide-dependent kinase 1 (PDK1) inhibitors: Dissecting the function and pharmacology of PDK1. J Med Chem 2013; 56(7): 2726-37.
[http://dx.doi.org/10.1021/jm4000227] [PMID: 23448267]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy