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      Targeting autophagy-related protein kinases for potential therapeutic purpose

      review-article
      Author(s): a , † , a , † , a , † , b , ∗ , a , ∗ , a , c , ∗
      Publication date (Electronic):
      Journal: Acta Pharmaceutica Sinica. B
      Publisher: Elsevier
      Keywords: Autophagy, Protein kinases, Autophagy-related kinase, Phosphorylation, Small-molecule kinase inhibitors/activators, Human disease therapy, 4E-BP1, eukaryotic translation initiation factor 4E-binding protein, AKT1, AKT serine/threonine kinase 1, AMBRA1, autophagy/beclin-1 regulator 1, AMPK, AMP-activated protein kinase, ARF, auxin response factor gene, ATG, autophagy-related protein, CaMKK2, calcium/calmodulin-dependent protein kinase kinase 2, DAPK, death associated protein kinase, FIP200, FAK family kinase-interacting protein of 200 kDa, GAP, GTPase-activating protein, GO, gene ontology, GSK3α, glycogen synthase kinase 3 alpha, HMGB1, high mobility group protein B1, JNK1, C-Jun N-terminal kinase, LC3, microtubule-associated protein 1 light chain 3, LKB1, serine/threonine-protein kinase stk11, LPS, lipopolysaccharide, LRRK2, leucine rich repeat kinase 2, mTOR, mammalian target of rapamycin, mTORC1, mammalian target of rapamycin complex 1, PD, Parkinson's disease, PI, phosphatidylinositol, PI3 kinase, phosphoinositide 3-kinase, PI3P, phosphatidylinositol triphosphate, PIM2, proviral insertion in murine lymphomas 2, PINK1, PTEN-induced putative kinase 1, PIP2, phosphatidylinositol-4,5-bisphosphate, PKACα, a protein kinase cAMP-activated catalytic subunit alpha, PKCα, protein kinase C alpha type, PKD1, polycystin-1, PPIs, protein–protein interactions, PROTAC, proteolysis targeting chimeras, PTMs, post-translational modifications, Rheb, the RAS homolog enriched in brain, TAK1, transforming growth factor activated kinase-1, TFEB, transcription factor EB, TNBC, triple-negative breast cancer, TSC1/2, tuberous sclerosis complex proteins 1/2, ULK complex, ULK1–mATG13–FIP200–ATG101 complex, ULK1, unc-51-like kinase 1, UVRAG, ultraviolet resistance-associated gene

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          Abstract

          Autophagy, defined as a scavenging process of protein aggregates and damaged organelles mediated by lysosomes, plays a significant role in the quality control of macromolecules and organelles. Since protein kinases are integral to the autophagy process, it is critically important to understand the role of kinases in autophagic regulation. At present, intervention of autophagic processes by small-molecule modulators targeting specific kinases has becoming a reasonable and prevalent strategy for treating several varieties of human disease, especially cancer. In this review, we describe the role of some autophagy-related kinase targets and kinase-mediated phosphorylation mechanisms in autophagy regulation. We also summarize the small-molecule kinase inhibitors/activators of these targets, highlighting the opportunities of these new therapeutic agents.

          Graphical abstract

          This review elaborates in detail the role of some autophagy-related kinase targets and phosphorylation in autophagy regulation, and further summarizes the application of small-molecule kinase inhibitors/activators for autophagy inhibition and induction. Understanding how these autophagy-related kinases regulate autophagy machinery is critical for the potential therapeutic application of autophagy.

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          Most cited references106

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          The protein kinase complement of the human genome.

          G. Manning (2002)
          We have catalogued the protein kinase complement of the human genome (the "kinome") using public and proprietary genomic, complementary DNA, and expressed sequence tag (EST) sequences. This provides a starting point for comprehensive analysis of protein phosphorylation in normal and disease states, as well as a detailed view of the current state of human genome analysis through a focus on one large gene family. We identify 518 putative protein kinase genes, of which 71 have not previously been reported or described as kinases, and we extend or correct the protein sequences of 56 more kinases. New genes include members of well-studied families as well as previously unidentified families, some of which are conserved in model organisms. Classification and comparison with model organism kinomes identified orthologous groups and highlighted expansions specific to human and other lineages. We also identified 106 protein kinase pseudogenes. Chromosomal mapping revealed several small clusters of kinase genes and revealed that 244 kinases map to disease loci or cancer amplicons.
          Article 0 comments Cited 1902 times – based on 0 reviews     Review now
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            Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase.

            Simon A. Hawley, David Pan, Kirsty Mustard … (2005)
            The AMP-activated protein kinase (AMPK) is a critical regulator of energy balance at both the cellular and whole-body levels. Two upstream kinases have been reported to activate AMPK in cell-free assays, i.e., the tumor suppressor LKB1 and calmodulin-dependent protein kinase kinase. However, evidence that this is physiologically relevant currently only exists for LKB1. We now report that there is a significant basal activity and phosphorylation of AMPK in LKB1-deficient cells that can be stimulated by Ca2+ ionophores, and studies using the CaMKK inhibitor STO-609 and isoform-specific siRNAs show that CaMKKbeta is required for this effect. CaMKKbeta also activates AMPK much more rapidly than CaMKKalpha in cell-free assays. K(+)-induced depolarization in rat cerebrocortical slices, which increases intracellular Ca2+ without disturbing cellular adenine nucleotide levels, activates AMPK, and this is blocked by STO-609. Our results suggest a potential Ca(2+)-dependent neuroprotective pathway involving phosphorylation and activation of AMPK by CaMKKbeta.
            Article 0 comments Cited 431 times – based on 0 reviews     Review now
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              Dual role of 3-methyladenine in modulation of autophagy via different temporal patterns of inhibition on class I and III phosphoinositide 3-kinase.

              You-Tong Wu, Hui-Ling Tan, Guanghou Shui … (2010)
              A group of phosphoinositide 3-kinase (PI3K) inhibitors, such as 3-methyladenine (3-MA) and wortmannin, have been widely used as autophagy inhibitors based on their inhibitory effect on class III PI3K activity, which is known to be essential for induction of autophagy. In this study, we systematically examined and compared the effects of these two inhibitors on autophagy under both nutrient-rich and deprivation conditions. To our surprise, 3-MA is found to promote autophagy flux when treated under nutrient-rich conditions with a prolonged period of treatment, whereas it is still capable of suppressing starvation-induced autophagy. We first observed that there are marked increases of the autophagic markers in cells treated with 3-MA in full medium for a prolonged period of time (up to 9 h). Second, we provide convincing evidence that the increase of autophagic markers is the result of enhanced autophagic flux, not due to suppression of maturation of autophagosomes or lysosomal function. More importantly, we found that the autophagy promotion activity of 3-MA is due to its differential temporal effects on class I and class III PI3K; 3-MA blocks class I PI3K persistently, whereas its suppressive effect on class III PI3K is transient. Because 3-MA has been widely used as an autophagy inhibitor in the literature, understanding the dual role of 3-MA in autophagy thus suggests that caution should be exercised in the application of 3-MA in autophagy study.
              Article 0 comments Cited 410 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Lan Zhang
                Bo Liu
                Liang Ouyang
                Journal
                Journal ID (nlm-ta): Acta Pharm Sin B
                Journal ID (iso-abbrev): Acta Pharm Sin B
                Title: Acta Pharmaceutica Sinica. B
                Publisher: Elsevier
                ISSN (Print): 2211-3835
                ISSN (Electronic): 2211-3843
                Publication date PMC-release: 18 October 2019
                Publication date (Print): April 2020
                Publication date (Electronic): 18 October 2019
                Volume: 10
                Issue: 4
                Pages: 569-581
                Affiliations
                [a ]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
                [b ]School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
                [c ]State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, China
                Author notes
                [∗ ]Corresponding authors. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu 610041, China. Tel./fax: +86 28 85164063. zhanglanx_9@ 123456126.com liubo2400@ 123456163.com ouyangliang@ 123456scu.edu.cn
                [†]

                These authors made equal contributions to this work.

                Article
                Publisher ID: S2211-3835(19)30276-X
                DOI: 10.1016/j.apsb.2019.10.003
                PMC ID: 7161711
                PubMed ID: 32322463
                SO-VID: df692bbd-c245-4eac-a777-1732be479a23
                Copyright © © 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 7 July 2019
                Date revision received : 6 August 2019
                Date accepted : 9 September 2019
                Categories
                Subject: Review

                Keywords: autophagy,protein kinases,autophagy-related kinase,phosphorylation,small-molecule kinase inhibitors/activators,human disease therapy,4e-bp1, eukaryotic translation initiation factor 4e-binding protein,akt1, akt serine/threonine kinase 1,ambra1, autophagy/beclin-1 regulator 1,ampk, amp-activated protein kinase,arf, auxin response factor gene,atg, autophagy-related protein,camkk2, calcium/calmodulin-dependent protein kinase kinase 2,dapk, death associated protein kinase,fip200, fak family kinase-interacting protein of 200 kda,gap, gtpase-activating protein,go, gene ontology,gsk3α, glycogen synthase kinase 3 alpha,hmgb1, high mobility group protein b1,jnk1, c-jun n-terminal kinase,lc3, microtubule-associated protein 1 light chain 3,lkb1, serine/threonine-protein kinase stk11,lps, lipopolysaccharide,lrrk2, leucine rich repeat kinase 2,mtor, mammalian target of rapamycin,mtorc1, mammalian target of rapamycin complex 1,pd, parkinson's disease,pi, phosphatidylinositol,pi3 kinase, phosphoinositide 3-kinase,pi3p, phosphatidylinositol triphosphate,pim2, proviral insertion in murine lymphomas 2,pink1, pten-induced putative kinase 1,pip2, phosphatidylinositol-4,5-bisphosphate,pkacα, a protein kinase camp-activated catalytic subunit alpha,pkcα, protein kinase c alpha type,pkd1, polycystin-1,ppis, protein–protein interactions,protac, proteolysis targeting chimeras,ptms, post-translational modifications,rheb, the ras homolog enriched in brain,tak1, transforming growth factor activated kinase-1,tfeb, transcription factor eb,tnbc, triple-negative breast cancer,tsc1/2, tuberous sclerosis complex proteins 1/2,ulk complex, ulk1–matg13–fip200–atg101 complex,ulk1, unc-51-like kinase 1,uvrag, ultraviolet resistance-associated gene
                Data availability:
                Keywords: autophagy, protein kinases, autophagy-related kinase, phosphorylation, small-molecule kinase inhibitors/activators, human disease therapy, 4e-bp1, eukaryotic translation initiation factor 4e-binding protein, akt1, akt serine/threonine kinase 1, ambra1, autophagy/beclin-1 regulator 1, ampk, amp-activated protein kinase, arf, auxin response factor gene, atg, autophagy-related protein, camkk2, calcium/calmodulin-dependent protein kinase kinase 2, dapk, death associated protein kinase, fip200, fak family kinase-interacting protein of 200 kda, gap, gtpase-activating protein, go, gene ontology, gsk3α, glycogen synthase kinase 3 alpha, hmgb1, high mobility group protein b1, jnk1, c-jun n-terminal kinase, lc3, microtubule-associated protein 1 light chain 3, lkb1, serine/threonine-protein kinase stk11, lps, lipopolysaccharide, lrrk2, leucine rich repeat kinase 2, mtor, mammalian target of rapamycin, mtorc1, mammalian target of rapamycin complex 1, pd, parkinson's disease, pi, phosphatidylinositol, pi3 kinase, phosphoinositide 3-kinase, pi3p, phosphatidylinositol triphosphate, pim2, proviral insertion in murine lymphomas 2, pink1, pten-induced putative kinase 1, pip2, phosphatidylinositol-4,5-bisphosphate, pkacα, a protein kinase camp-activated catalytic subunit alpha, pkcα, protein kinase c alpha type, pkd1, polycystin-1, ppis, protein–protein interactions, protac, proteolysis targeting chimeras, ptms, post-translational modifications, rheb, the ras homolog enriched in brain, tak1, transforming growth factor activated kinase-1, tfeb, transcription factor eb, tnbc, triple-negative breast cancer, tsc1/2, tuberous sclerosis complex proteins 1/2, ulk complex, ulk1–matg13–fip200–atg101 complex, ulk1, unc-51-like kinase 1, uvrag, ultraviolet resistance-associated gene

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