Abstract
All cells and intracellular components are remodeled and recycled in order to replace the old and damaged cells. Autophagy is a process by which damaged, and unwanted cells are degraded in the lysosomes. There are three different types of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy. Autophagy has an effect on adaptive and innate immunity, suppression of any tumour, and the elimination of various microbial pathogens. The process of autophagy has both positive and negative effects, and this pertains to any specific disease or its stage of progression. Autophagy involves various processes which are controlled by various signaling pathways, such as Jun N-terminal kinase, GSK3, ERK1, Leucine-rich repeat kinase 2, and PTEN-induced putative kinase 1 and parkin RBR E3. Protein kinases are also important for the regulation of autophagy as they regulate the process of autophagy either by activation or inhibition. The present review discusses the kinase catalyzed phosphorylated reactions, the kinase inhibitors, types of protein kinase inhibitors and their binding properties to protein kinase domains, the structures of active and inactive kinases, and the hydrophobic spine structures in active and inactive protein kinase domains. The intervention of autophagy by targeting specific kinases may form the mainstay of treatment of many diseases and lead the road to future drug discovery.
Keywords: Autophagy, signaling pathways, kinase inhibitors, drug delivery, cellular degradation, molecular concepts.
[http://dx.doi.org/10.1128/EC.01.1.11-21.2002] [PMID: 12455967]
[http://dx.doi.org/10.1016/S1534-5807(04)00099-1] [PMID: 15068787]
[http://dx.doi.org/10.4161/auto.7.7.14733] [PMID: 21646866]
[http://dx.doi.org/10.1016/j.biocel.2004.04.010] [PMID: 15325582]
[http://dx.doi.org/10.1038/sj.cdd.4401765]
[http://dx.doi.org/10.1089/ars.2013.5371] [PMID: 23725295]
[http://dx.doi.org/10.1016/j.ceb.2009.11.014] [PMID: 20034776]
[http://dx.doi.org/10.1101/gad.1599207] [PMID: 18006683]
[http://dx.doi.org/10.1111/brv.12464] [PMID: 30239126]
[http://dx.doi.org/10.4161/cc.6.15.4511] [PMID: 17671424]
[http://dx.doi.org/10.1038/cr.2011.152] [PMID: 21912435]
[http://dx.doi.org/10.1038/nature06639] [PMID: 18305538]
[http://dx.doi.org/10.1126/science.1099993] [PMID: 15528435]
[http://dx.doi.org/10.1038/nri2161] [PMID: 17767194]
[http://dx.doi.org/10.1172/JCI26390] [PMID: 16200202]
[http://dx.doi.org/10.1007/978-3-642-00302-8_1] [PMID: 19802558]
[http://dx.doi.org/10.1242/jcs.064576] [PMID: 21187343]
[http://dx.doi.org/10.4161/auto.6.6.12709] [PMID: 20639694]
[http://dx.doi.org/10.1038/ncb1991] [PMID: 19898463]
[http://dx.doi.org/10.4161/auto.5.8.10274] [PMID: 19855179]
[http://dx.doi.org/10.1146/annurev-genet-102808-114910] [PMID: 19653858]
[http://dx.doi.org/10.1016/j.cell.2010.04.009] [PMID: 20478256]
[http://dx.doi.org/10.4161/auto.7.1.14015] [PMID: 21068542]
[http://dx.doi.org/10.1038/ncb2078] [PMID: 20639872]
[http://dx.doi.org/10.4161/auto.6.8.13428] [PMID: 20861674]
[http://dx.doi.org/10.3390/ijms13033618] [PMID: 22489171]
[http://dx.doi.org/10.1083/jcb.78.1.152] [PMID: 670291]
[http://dx.doi.org/10.1016/S0021-9258(19)69010-1] [PMID: 7019210]
[http://dx.doi.org/10.1074/jbc.273.34.21883] [PMID: 9705327]
[http://dx.doi.org/10.1083/jcb.111.2.329] [PMID: 2166050]
[http://dx.doi.org/10.1074/jbc.M900573200] [PMID: 19258318]
[http://dx.doi.org/10.1083/jcb.200712064] [PMID: 18443221]
[http://dx.doi.org/10.4161/auto.5.7.9296] [PMID: 19597335]
[http://dx.doi.org/10.1091/mbc.e08-12-1249] [PMID: 19225151]
[http://dx.doi.org/10.4161/auto.5.5.8249] [PMID: 19287211]
[http://dx.doi.org/10.1074/jbc.273.51.33889] [PMID: 9852036]
[http://dx.doi.org/10.1093/emboj/19.21.5720] [PMID: 11060023]
[http://dx.doi.org/10.1038/ncb2979] [PMID: 24875736]
[PMID: 24345374]
[http://dx.doi.org/10.1074/jbc.M702824200] [PMID: 17580304]
[http://dx.doi.org/10.1242/jcs.03172] [PMID: 16940348]
[http://dx.doi.org/10.1016/j.semcdb.2016.07.009] [PMID: 27422330]
[http://dx.doi.org/10.1146/annurev-biochem-060815-014556] [PMID: 26865532]
[http://dx.doi.org/10.1016/j.cell.2012.11.001] [PMID: 23217709]
[http://dx.doi.org/10.1038/nature05185] [PMID: 17035995]
[http://dx.doi.org/10.4161/auto.22162] [PMID: 22992453]
[http://dx.doi.org/10.3390/cancers13061211] [PMID: 33802014]
[http://dx.doi.org/10.1126/science.1196371] [PMID: 21205641]
[http://dx.doi.org/10.1038/s41598-018-30977-7] [PMID: 30140075]
[http://dx.doi.org/10.1038/sj.cr.7290105] [PMID: 11942415]
[http://dx.doi.org/10.18632/genesandcancer.155] [PMID: 29234486]
[http://dx.doi.org/10.1111/j.1745-7254.2007.00579.x] [PMID: 17439715]
[http://dx.doi.org/10.1016/j.ceb.2007.02.001] [PMID: 17303404]
[http://dx.doi.org/10.1186/1756-9966-33-8] [PMID: 24438216]
[http://dx.doi.org/10.1002/med.21574] [PMID: 30912203]
[http://dx.doi.org/10.1038/onc.2009.487] [PMID: 20101227]
[http://dx.doi.org/10.3892/etm.2017.4529] [PMID: 28672972]
[http://dx.doi.org/10.1128/MMBR.00025-06] [PMID: 17158707]
[http://dx.doi.org/10.1016/j.cell.2005.07.002] [PMID: 16179260]
[http://dx.doi.org/10.1016/j.molcel.2008.06.001] [PMID: 18570871]
[http://dx.doi.org/10.1101/gad.1984311] [PMID: 21325132]
[http://dx.doi.org/10.1155/2017/4629495] [PMID: 29379583]
[http://dx.doi.org/10.1016/j.molcel.2013.03.022] [PMID: 23623684]
[http://dx.doi.org/10.1038/onc.2014.390] [PMID: 25500539]
[http://dx.doi.org/10.3390/cells10020262] [PMID: 33572709]
[http://dx.doi.org/10.1074/jbc.M114.616714] [PMID: 25561726]
[http://dx.doi.org/10.1038/s12276-021-00570-6] [PMID: 33654220]
[http://dx.doi.org/10.1038/sj.onc.1210412] [PMID: 17496916]
[http://dx.doi.org/10.1152/physrev.00028.2011] [PMID: 22535895]
[http://dx.doi.org/10.1074/jbc.M210998200] [PMID: 12609989]
[http://dx.doi.org/10.1074/jbc.M006198200] [PMID: 10993892]
[http://dx.doi.org/10.1158/0008-5472.CAN-05-3557] [PMID: 16818664]
[http://dx.doi.org/10.1074/jbc.M109.026013] [PMID: 19520853]
[http://dx.doi.org/10.1016/j.tem.2014.03.006] [PMID: 24751357]
[http://dx.doi.org/10.1155/2012/151039] [PMID: 22970411]
[http://dx.doi.org/10.1111/febs.13305] [PMID: 25899482]
[http://dx.doi.org/10.1074/jbc.M708718200] [PMID: 18397888]
[http://dx.doi.org/10.1126/scisignal.123pe27] [PMID: 18544747]
[http://dx.doi.org/10.1111/jnc.14908] [PMID: 31693760]
[http://dx.doi.org/10.1007/978-3-319-49969-7_5] [PMID: 28353280]
[http://dx.doi.org/10.3389/fnins.2020.00498] [PMID: 32523507]
[http://dx.doi.org/10.1002/mds.23767] [PMID: 21626551]
[http://dx.doi.org/10.1093/hmg/ddr481] [PMID: 22012985]
[http://dx.doi.org/10.1042/BST20120138] [PMID: 22988879]
[http://dx.doi.org/10.1080/15548627.2018.1532259] [PMID: 30290714]
[http://dx.doi.org/10.1186/s40478-020-01062-w] [PMID: 33168089]
[http://dx.doi.org/10.1083/jcb.200910140] [PMID: 20404107]
[http://dx.doi.org/10.1083/jcb.201402104] [PMID: 24751536]
[http://dx.doi.org/10.1093/hmg/ddq419] [PMID: 20871098]
[http://dx.doi.org/10.1073/pnas.1405752111] [PMID: 25294927]
[http://dx.doi.org/10.1016/j.phrs.2021.105463] [PMID: 33513356]
[http://dx.doi.org/10.1021/cb300610s] [PMID: 23276252]
[http://dx.doi.org/10.1038/nbt0302-301] [PMID: 11875433]
[http://dx.doi.org/10.1016/S0968-0004(00)01712-6] [PMID: 11116185]
[http://dx.doi.org/10.1126/science.1075762] [PMID: 12471243]
[http://dx.doi.org/10.1038/nchembio.1938] [PMID: 26485069]
[http://dx.doi.org/10.1021/ar0201207] [PMID: 12809533]
[http://dx.doi.org/10.1038/nchembio.297] [PMID: 20154661]
[http://dx.doi.org/10.1021/ml500071m] [PMID: 24900819]
[PMID: 33513356]
[http://dx.doi.org/10.1186/s12943-018-0804-2] [PMID: 29455673]
[http://dx.doi.org/10.1038/nrd3252] [PMID: 21283106]
[http://dx.doi.org/10.1002/jat.2813] [PMID: 22961481]
[http://dx.doi.org/10.1016/j.taap.2009.12.032] [PMID: 20045709]
[http://dx.doi.org/10.1146/annurev-biochem-090308-173656] [PMID: 21548788]
[http://dx.doi.org/10.1021/jm901443h] [PMID: 20000735]
[http://dx.doi.org/10.1126/science.3755548] [PMID: 3755548]
[http://dx.doi.org/10.1111/bph.13096] [PMID: 25630872]
[http://dx.doi.org/10.5772/intechopen.98552]
[http://dx.doi.org/10.1128/MCB.24.8.3112-3124.2004] [PMID: 15060135]
[http://dx.doi.org/10.1007/s00401-001-0481-9] [PMID: 11904760]
[http://dx.doi.org/10.1038/sj.onc.1204085] [PMID: 11426645]
[http://dx.doi.org/10.1038/9035] [PMID: 10559866]
[http://dx.doi.org/10.1016/S0092-8674(00)00122-7] [PMID: 11057903]
[http://dx.doi.org/10.1046/j.1471-4159.2001.t01-1-00251.x] [PMID: 11279265]
[http://dx.doi.org/10.1186/s13058-015-0661-5] [PMID: 26857361]
[http://dx.doi.org/10.1080/14656566.2020.1738385] [PMID: 32164461]
[http://dx.doi.org/10.21037/atm.2019.11.105] [PMID: 31930082]
[http://dx.doi.org/10.1073/pnas.1522938113] [PMID: 26747602]
[http://dx.doi.org/10.3390/cancers13050947] [PMID: 33668248]
[http://dx.doi.org/10.1126/science.3291115] [PMID: 3291115]
[http://dx.doi.org/10.1096/fasebj.9.8.7768349] [PMID: 7768349]
[http://dx.doi.org/10.1016/j.phrs.2015.07.010] [PMID: 26207888]
[http://dx.doi.org/10.1007/s11010-016-2878-8] [PMID: 27868170]
[http://dx.doi.org/10.1073/pnas.1816012116] [PMID: 31076554]
[http://dx.doi.org/10.1186/s12943-018-0801-5] [PMID: 29455664]
[PMID: 8217408]
[http://dx.doi.org/10.1517/13543784.14.9.1157] [PMID: 16144499]
[http://dx.doi.org/10.1152/ajpcell.2000.278.1.C57] [PMID: 10644512]
[http://dx.doi.org/10.1126/science.1715094] [PMID: 1715094]
[http://dx.doi.org/10.1038/372739a0] [PMID: 7997261]
[http://dx.doi.org/10.1016/0014-5793(95)00357-F] [PMID: 7750577]
[http://dx.doi.org/10.1016/S0014-5793(99)00552-9] [PMID: 10371163]
[http://dx.doi.org/10.3233/JAD-150277] [PMID: 26401942]
[http://dx.doi.org/10.3233/JPD-130192] [PMID: 23938341]
[http://dx.doi.org/10.1126/science.aar5683] [PMID: 29622645]
[http://dx.doi.org/10.1186/s40478-018-0600-7] [PMID: 30249303]
[http://dx.doi.org/10.3390/genes10120986] [PMID: 31795491]
[http://dx.doi.org/10.1038/nrm2203] [PMID: 17585314]
[http://dx.doi.org/10.1016/j.cbpa.2008.01.018] [PMID: 18282484]
[http://dx.doi.org/10.1038/nmeth708] [PMID: 15782149]
[PMID: 9523263]
[http://dx.doi.org/10.1126/scisignal.2000482] [PMID: 20159853]
[http://dx.doi.org/10.1186/1471-2105-7-47] [PMID: 16445868]
[http://dx.doi.org/10.1371/journal.pone.0021169] [PMID: 21829434]
[http://dx.doi.org/10.1042/BJ20051545] [PMID: 16336195]
[http://dx.doi.org/10.1126/science.1172867] [PMID: 19779198]
[http://dx.doi.org/10.1126/scisignal.2100re9] [PMID: 19996458]
[http://dx.doi.org/10.1016/j.tibs.2010.03.002] [PMID: 20399103]
[http://dx.doi.org/10.1021/ja071275i] [PMID: 17417856]
[http://dx.doi.org/10.1074/jbc.M307617200] [PMID: 14578355]
[http://dx.doi.org/10.1073/pnas.94.5.1680] [PMID: 9050838]
[http://dx.doi.org/10.2174/138161212800672813] [PMID: 22571662]
[http://dx.doi.org/10.1021/jm400378w] [PMID: 23941661]
[http://dx.doi.org/10.1021/jm0608107] [PMID: 17266192]
[http://dx.doi.org/10.1016/bs.armc.2017.08.001]
[http://dx.doi.org/10.2174/1568026617666170224121313] [PMID: 28240180]
[http://dx.doi.org/10.1016/j.tips.2015.04.005] [PMID: 25975227]
[http://dx.doi.org/10.1016/j.tips.2019.09.002] [PMID: 31677919]
[http://dx.doi.org/10.1126/science.1862342] [PMID: 1862342]
[http://dx.doi.org/10.1126/science.1862343] [PMID: 1862343]
[http://dx.doi.org/10.1098/rstb.2012.0054] [PMID: 22889904]
[http://dx.doi.org/10.1016/j.molcel.2004.08.024] [PMID: 15350212]
[http://dx.doi.org/10.1016/0006-291X(92)90812-Y] [PMID: 1323290]
[http://dx.doi.org/10.1073/pnas.96.4.1415] [PMID: 9990038]
[http://dx.doi.org/10.1016/S0092-8674(02)00741-9] [PMID: 12015977]
[http://dx.doi.org/10.1371/journal.pbio.1001680] [PMID: 24143133]
[http://dx.doi.org/10.1073/pnas.0607656103] [PMID: 17095602]
[http://dx.doi.org/10.1073/pnas.0807988105] [PMID: 18787129]
[http://dx.doi.org/10.1016/0076-6879(91)00126-H] [PMID: 1956325]
[http://dx.doi.org/10.1038/nrc2559] [PMID: 19104514]
[http://dx.doi.org/10.4161/auto.6398] [PMID: 18567941]
[http://dx.doi.org/10.3389/fonc.2017.00128] [PMID: 28674677]
[http://dx.doi.org/10.1038/nrc.2017.53] [PMID: 28751651]
[http://dx.doi.org/10.1016/j.apsb.2019.10.003] [PMID: 32322463]
[http://dx.doi.org/10.1016/j.tips.2019.10.004] [PMID: 31706618]
[http://dx.doi.org/10.1186/s12943-018-0777-1] [PMID: 29455650]
[http://dx.doi.org/10.1007/978-3-319-91442-8_18] [PMID: 30069773]
[http://dx.doi.org/10.1056/NEJMoa1713137] [PMID: 29151359]
[http://dx.doi.org/10.1056/NEJMoa1913662] [PMID: 31751012]
[http://dx.doi.org/10.1200/JCO.19.00931] [PMID: 31825714]
[http://dx.doi.org/10.1200/JCO.2018.77.9363] [PMID: 30059262]
[http://dx.doi.org/10.1200/JCO.19.00457] [PMID: 31809241]
[http://dx.doi.org/10.1056/NEJMoa2027071] [PMID: 32955177]
[http://dx.doi.org/10.1021/acs.jmedchem.0c00891] [PMID: 32672461]
[http://dx.doi.org/10.1021/acs.jmedchem.7b01310] [PMID: 29136465]
[http://dx.doi.org/10.1158/1535-7163.MCT-12-0620] [PMID: 23371856]
[http://dx.doi.org/10.1038/s41392-019-0038-9] [PMID: 30854234]
[http://dx.doi.org/10.1002/cncr.29493] [PMID: 26096453]
[PMID: 32414908]
[http://dx.doi.org/10.1158/1538-7445.AM2016-2644]
[http://dx.doi.org/10.1200/JCO.2019.37.15_suppl.9009]
[http://dx.doi.org/10.1080/15548627.2017.1378838] [PMID: 28933638]
[http://dx.doi.org/10.1016/j.jmb.2017.01.002] [PMID: 28077293]
[http://dx.doi.org/10.1038/s41467-019-11671-2] [PMID: 31434890]
[PMID: 27252382]
[http://dx.doi.org/10.3389/fcell.2019.00113] [PMID: 31281815]
[http://dx.doi.org/10.1038/ncb1537] [PMID: 17237771]
[http://dx.doi.org/10.1038/nature25023] [PMID: 29236692]
[http://dx.doi.org/10.1080/15548627.2018.1511504] [PMID: 30145926]
[http://dx.doi.org/10.1016/j.febslet.2014.04.015] [PMID: 24747877]
[http://dx.doi.org/10.1186/s12935-018-0557-4] [PMID: 29713246]
[http://dx.doi.org/10.1146/annurev.pathmechdis.2.010506.091842] [PMID: 18039129]
[http://dx.doi.org/10.1111/j.1749-6632.2000.tb05594.x] [PMID: 11193023]
[http://dx.doi.org/10.1634/theoncologist.12-12-1395] [PMID: 18165616]
[http://dx.doi.org/10.1007/978-1-59745-157-4_11] [PMID: 18425450]
[http://dx.doi.org/10.1038/nrm2335] [PMID: 18216772]
[http://dx.doi.org/10.1016/j.bbamem.2006.08.017] [PMID: 17049336]
[http://dx.doi.org/10.1097/CAD.0b013e328011334d] [PMID: 17159597]
[PMID: 14522923]
[http://dx.doi.org/10.1074/jbc.M401259200] [PMID: 14988393]
[http://dx.doi.org/10.3390/ijms18020321] [PMID: 28165387]
[http://dx.doi.org/10.3892/ol.2017.6107] [PMID: 28693171]
[http://dx.doi.org/10.1210/en.2012-1908] [PMID: 23384836]
[http://dx.doi.org/10.3109/07357907.2013.820315] [PMID: 23915069]
[http://dx.doi.org/10.3892/ol.2016.4606] [PMID: 27347100]
[http://dx.doi.org/10.1016/j.bbrc.2015.03.162] [PMID: 25858318]
[http://dx.doi.org/10.1083/jcb.200510065] [PMID: 16505167]
[http://dx.doi.org/10.1098/rsbl.2017.0540] [PMID: 29321247]
[http://dx.doi.org/10.1371/journal.pone.0163029] [PMID: 27631370]
[http://dx.doi.org/10.1016/j.ceb.2010.01.001] [PMID: 20097051]
[http://dx.doi.org/10.1371/journal.pgen.1006962] [PMID: 28806762]
[http://dx.doi.org/10.1038/s41580-020-0241-0] [PMID: 32372019]
[http://dx.doi.org/10.3892/mmr.2015.4517] [PMID: 26548845]
[http://dx.doi.org/10.1074/jbc.M604298200] [PMID: 17234627]
[http://dx.doi.org/10.1016/j.molcel.2017.05.032] [PMID: 28622524]
[http://dx.doi.org/10.1038/nrm.2017.95] [PMID: 28974774]
[http://dx.doi.org/10.1152/ajpendo.00225.2016] [PMID: 27577854]
[http://dx.doi.org/10.1042/BJ20112026] [PMID: 22233421]
[http://dx.doi.org/10.1042/BCJ20160980] [PMID: 28008135]