DOCSLIB.ORG

Deciphering the Role of Protein Kinase D1 (PKD1) in Cellular Proliferation Ilige Youssef1,2 and Jean-Marc Ricort1,2,3

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Deciphering the Role of Protein Kinase D1 (PKD1) in Cellular Proliferation Ilige Youssef1,2 and Jean-Marc Ricort1,2,3 Published OnlineFirst July 16, 2019; DOI: 10.1158/1541-7786.MCR-19-0125 Review Molecular Cancer Research Deciphering the Role of Protein Kinase D1 (PKD1) in Cellular Proliferation Ilige Youssef1,2 and Jean-Marc Ricort1,2,3 Abstract Protein kinase D1 (PKD1) is a serine/threonine kinase that context-dependent and poorly understood. In this review, belongs to the calcium/calmodulin-dependent kinase family, we present and discuss the current landscape of studies and is involved in multiple mechanisms implicated in tumor investigating the role of PKD1 in the proliferation of both progression such as cell motility, invasion, proliferation, pro- cancerous and normal cells. Indeed, as a potential thera- tein transport, and apoptosis. While it is expressed in most peutic target, deciphering whether PKD1 exerts a pro- or tissues in the normal state, PKD1 expression may increase or antiproliferative effect, and under what conditions, is of decrease during tumorigenesis, and its role in proliferation is paramount importance. Introduction several biological processes such as cell proliferation, migra- tion, invasion, apoptosis, angiogenesis, cardiac contraction, PKD1, also called PKCm, is a serine/threonine kinase that and immune regulation (5). In this context, its dysregulation belongs to the PKD family, a subgroup of the calcium/calmodu- (over- or underexpression) was shown to be associated to lin-dependent kinase (CAMK) family (1). PKD1 is a 912 amino diverse pathologies such as inflammation, cardiac hypertrophy, acid residue protein with an apparent molecular weight of and cancer (6). However, it remains largely unknown what 115 kDa that contains a carboxy-terminus catalytic domain regulates PKD1 gene (prkd1)expressionintumors.PKD1gene and a regulatory domain at the amino-terminus. The latter promoter was shown to be either activated by the oncogenic regulates the catalytic activity of PKD1 by maintaining the KRas–NFkB pathway increasing the expression of PKD1 in proteininaninactivestatethroughanautoinhibitorymech- pancreatic cancer cells (7) or inhibited by b-catenin in prostate anism exerted toward the catalytic domain (2). PKD1 can be cancer (8). It was also shown to bethetargetofepigenetic activated by a wide variety of extracellular stimuli including methylation decreasing PKD1 expression in some breast tumor growth factors, vasoactive peptides, chemokines, neuropep- cells (9–11). These different molecular mechanisms lead to tides, phorbol esters, and others. To date, the best characterized tumor tissue–specific PKD1 mRNA expression profiles. Accord- signaling pathway responsible for the activation of PKD1 ing to TCGA data, PKD1 mRNAs are mostly expressed in involves the activation of phospholipases Cb or g (PLC or b prostate cancer and melanoma (Fig. 1). Also, the data relative PLCg;ref.3).Theseproteinssynthesize inositol-triphosphate to 11 studies [Breast Invasive Carcinoma, Colorectal Adeno- (IP ) and diaglycerol (DAG), which allows the activation of 3 carcinoma, Head and Neck Squamous Cell Carcinoma, Kidney several protein kinase C (PKC) isoforms and their recruitment Renal Clear Cell Carcinoma, Kidney Renal Papillary Cell Car- close to PKD1. Once nearby, PKCs phosphorylate PKD1 onto cinoma, Lung Adenocarcinoma, Lung Squamous Cell Carcino- two serine residues (738 and 742, or 744 and 748, human or ma, Pancreatic Adenocarcinoma, Prostate Adenocarcinoma, murine numbering, respectively) localized in its activation Skin Cutaneous Melanoma, Stomach Adenocarcinoma (TCGA, loop leading to the stimulation of the catalytic domain and PanCancer Atlas)], has shown PKD1 mRNA levels to be upre- its autophosphorylation onto its serine 910 (or 916 for murine gulatedby1.8%(pancreas)to18%(lungadenocarcinoma) PKD1) residue (4). Activated PKD1 thus translocates into with a mean value of 7.8% (additional files 1 to 8: Supple- different cellular compartments modulating its targets. The mentary Figs. S1–S8). Moreover, analysis of the prkd1 gene wide diversity of its substrates makes PKD1 a main actor in reveals that only 4% of the tumors analyzed (206 patients over 5,615) carry a mutation or a copy number alteration in the 11 1 fi Centre National de la Recherche Scienti que, CNRS UMR_8113, Laboratoire de abovementioned TCGA studies (Fig. 2). Taken together, these Biologie et Pharmacologie Appliquee, Cachan, France. 2Ecole Normale Superieure Paris-Saclay, Universite Paris-Saclay, Cachan, France. 3Centre de results suggest, at least for tumors with the lowest upregulated Recherche des Cordeliers, INSERM, Sorbonne Universite, USPC, Universite Paris values, that a dysregulated PKD1 activity may certainly play a Descartes, Universite Paris Diderot, Paris, France. more significant role in tumor progression than its gene over- fi Note: Supplementary data for this article are available at Molecular Cancer expression or ampli cation. Research Online (http://mcr.aacrjournals.org/). Although PKD1 seems to play an essential role in oncogenesis and is activated by a large variety of stimuli, especially by many Corresponding Author: Jean-Marc Ricort, Ecole Normale Superieure Paris- growth factors, it has a complex relationship with cell prolifera- Saclay, 61 avenue du President Wilson, Cachan 94230, France. Phone: 331- fi 4427-5582; E-mail: [email protected] tion both in normal and cancer cells. In fact, the speci city of the role of PKD1 with regards to cell proliferation depends not only Mol Cancer Res 2019;17:1961–74 on the tissue type but also on the phenotype (normal vs. tumor) doi: 10.1158/1541-7786.MCR-19-0125 because PKD1 has been described to be either proproliferative or Ó2019 American Association for Cancer Research. antiproliferative (Table 1). Moreover, this complexity drastically www.aacrjournals.org 1961 Downloaded from mcr.aacrjournals.org on September 26, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst July 16, 2019; DOI: 10.1158/1541-7786.MCR-19-0125 Youssef and Ricort 25 20 15 Figure 1. 10 Prkd1 RNA expression overview. RNA- seq data in 9 cancer types are 5 reported as median FPKM (number Fragments Per Kilobase of exon per 0 Million reads), generated by the The Kilobase of exon per Million reads) Median FPKM Fragments Per (number Cancer Genome Atlas (TCGA). RNA cancer tissue category is calculated on the basis of mRNA expression levels across all 9 cancer tissues and include: cancer tissue enriched, cancer group enriched, cancer tissue enhanced, expressed in all, mixed and not Head and Breast Lung Stomach Colorectal Renal Prostate Pancreac detected. Table presents the different Melanoma neck invasive cancer cancer cancer cancer cancer cancer representative values obtained for cancer carcinoma Max 4.9 2.6 2.3 12.4 2 3.1 9.9 22.6 5.7 each tumor. 3rd quarle 2.5 1.3 1.1 6.8 0.9 1.6 5.5 13 3.2 Median 1.5 0.7 0.6 4.9 0.4 1.1 3.9 9.5 2.3 1st quarle 0.8 0.4 0.3 2.7 0.2 0.6 2.6 6.5 1.5 Min 0.1 0 0 0.1 0 0 0.2 1.2 0.1 increases when, for a given cell type, some controversial data exist. pharmacologic target in oncology. In this context, it becomes However, increasing data described PKD1 activity as affecting obviously and urgently crucial to have a clear knowledge of its role tumor behavior both in vitro and in vivo through its ability to in cell proliferation. Therefore, this review aims to list the major regulate cell proliferation making PKD1 a putative pertinent data existing to date concerning the pro- or antiproliferative 10 9 Mulple alteraons 8 Deep deleon 7 Amplificaon 6 Fusion 5 Mutaon 4 Alteraon frequency (%) 3 2 1 0 Figure 2. Prkd1 gene mutation and copy number alterations. Prkd1 genomic alteration types obtained by querying 5,609 patients in 11 TCGA PanCan studies. For each study, results are expressed as the frequency of alteration of the prkd1 gene compared with the total number of cancers analyzed in the study. 1962 Mol Cancer Res; 17(10) October 2019 Molecular Cancer Research Downloaded from mcr.aacrjournals.org on September 26, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst July 16, 2019; DOI: 10.1158/1541-7786.MCR-19-0125 The Role of PKD1 in Cell Proliferation Table 1. Role of PKD1 in normal and cancer cell proliferation Anti (À) or pro (þ) Tissue Cell type—cell line/Species proliferative effect Comments References Breast Breast cancer cell lines (human) À Relative expression and invasion/metastasis (9) MCF-7 (human) þ PKD1-overexpressing cells (91, 92) MDA-MB-415 (human) þ (92) MCF-7-ADR (human) - drug resistant cells þ (93) Endothelium HUVEC (human) þ (16) Cell migration (19) EPCs (human) þ Cell migration and tube formation (17) Aortic ring (mouse) þ Microvessel sprouting (18) Zebrafish (in vivo) þ (22) Fibroblast Swiss 3T3 (mouse) þ (24, 25) NIH 3T3 (mouse) þ PKD1-overexpressing cells (30) Head and neck HNSCC cell lines (human) and tissue sections þ (109) squamous cells Kidney M1 (mouse) þ (65, 66) Lung Idiopathic pulmonary fibrosis (human) þ (69) A549, H520 À (71) Pancreas Acinar cells (rat) þ NFkB-dependent pancreatitis (45, 46) Rat (in vivo) þ (46) Acinar cells (mouse) þ Acinar-to-ductal metaplasia, ADM (47) Human pancreatic adenocarcinoma þ PKD1 expression (7, 52) Panc-1 and Panc-28 cells þ WT and PKD1-overexpressing or -depleted cells (21, 51, 53) Colo357, PancTul, Panc89 þ Survival and telomerase activity (52) Prostate ALVA-41, LNCaP, C4-2, DU-145 À PKD1-overexpressing or -depleted cells (75, 77, 78, 81) LNCaP þ Prosurvival (84) LNCaP, PC3 þ (85–88) PC3 þ PKD1-overexpressing cells (88) Skin Primary keratinocytes (murine) þ (30, 32) þ PKD1-overexpressing or -depleted cells (33, 34, 36) Mouse (in vivo) þ DMBA-induced tumors (31) þ Wound healing (35) Human basal cell carcinoma, psoriasis þ (37) Melanoma (human) þ (40) Stomach SNU gastric cell lines (human) À Cell migration and invasion (11) AGS (human) À PKD1-overexpressing cells (54) Small Intestine IEC-18 (rat) þ (58, 59, 61) PKD1 transgenic mouse (in vivo) þ (58, 59, 61) Colon SW480 (human) À PKD1-overexpressing cells (55) effects of PKD1 and tries to bring elements of discussion to VEGFR2, through a PLCg/PKCa-dependent signaling path- explain, when necessary, potentially contradictory results.
Load more

Recommended publications
  • Gene Symbol Gene Description ACVR1B Activin a Receptor, Type IB
    Table S1. Kinase clones included in human kinase cDNA library for yeast two-hybrid screening Gene Symbol Gene Description ACVR1B activin A receptor, type IB ADCK2 aarF domain containing kinase 2 ADCK4 aarF domain containing kinase 4 AGK multiple substrate lipid kinase;MULK AK1 adenylate kinase 1 AK3 adenylate kinase 3 like 1 AK3L1 adenylate kinase 3 ALDH18A1 aldehyde dehydrogenase 18 family, member A1;ALDH18A1 ALK anaplastic lymphoma kinase (Ki-1) ALPK1 alpha-kinase 1 ALPK2 alpha-kinase 2 AMHR2 anti-Mullerian hormone receptor, type II ARAF v-raf murine sarcoma 3611 viral oncogene homolog 1 ARSG arylsulfatase G;ARSG AURKB aurora kinase B AURKC aurora kinase C BCKDK branched chain alpha-ketoacid dehydrogenase kinase BMPR1A bone morphogenetic protein receptor, type IA BMPR2 bone morphogenetic protein receptor, type II (serine/threonine kinase) BRAF v-raf murine sarcoma viral oncogene homolog B1 BRD3 bromodomain containing 3 BRD4 bromodomain containing 4 BTK Bruton agammaglobulinemia tyrosine kinase BUB1 BUB1 budding uninhibited by benzimidazoles 1 homolog (yeast) BUB1B BUB1 budding uninhibited by benzimidazoles 1 homolog beta (yeast) C9orf98 chromosome 9 open reading frame 98;C9orf98 CABC1 chaperone, ABC1 activity of bc1 complex like (S. pombe) CALM1 calmodulin 1 (phosphorylase kinase, delta) CALM2 calmodulin 2 (phosphorylase kinase, delta) CALM3 calmodulin 3 (phosphorylase kinase, delta) CAMK1 calcium/calmodulin-dependent protein kinase I CAMK2A calcium/calmodulin-dependent protein kinase (CaM kinase) II alpha CAMK2B calcium/calmodulin-dependent
    [Show full text]
  • Protein Kinase D1 Regulates Hypoxic Metabolism Through HIF-1Α and Glycolytic Enzymes Incancer Cells
    ONCOLOGY REPORTS 40: 1073-1082, 2018 Protein kinase D1 regulates hypoxic metabolism through HIF-1α and glycolytic enzymes incancer cells JIAO CHEN*, BOMIAO CUI*, YAPING FAN*, XIAOYING LI, QIAN LI, YUE DU, YUN FENG and PING ZHANG State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China Received October 7, 2017; Accepted April 3, 2018 DOI: 10.3892/or.2018.6479 Abstract. Protein kinase D1 (PKD1), one of the protein Introduction kinase D (PKD) family members, plays a prominent role in multiple bio-behaviors of cancer cells. Low pH and hypoxia Oral cancer is a major public health issue and a social chal- are unique characteristics of the tumor microenvironment. lenge. Tongue squamous cell carcinoma (TSCC) is the most The aim of this study was to investigate the role and mecha- aggressive type of oral cancer. Environmental factors, genetics nism of PKD1 in regulating metabolism in the human tongue and immune status have been confirmed to be related to the squamous cell carcinoma (TSCC) cell line SCC25 under a tumorigenesis of tongue cancer (1). The tumor microenviron- hypoxic condition, as well as growth and apoptosis. Here, we ment, which is composed of complex components including found that hypoxia not only induced the expression of HIF-1α, stem cells, fibroblasts, immune cells and their secreted factors, but also induced the expression and activation of PKD1. is critical to the initiation, development and maintenance of Moreover, we inhibited the expression of PKD1 by shRNA tumorigenesis (1). As the ‘residence niche’ of cancer cells, the interference, and the growth of SCC25 cells under hypoxia was composition and structure of the tumor microenvironment significantly decreased, as well as the expression of HIF-1α, not only affects the bio-behavior, but also determines the while the percentage of apoptotic SCC25 cells was increased.
    [Show full text]
  • A Novel Kinase Inhibitor Establishes a Predominant Role for Protein Kinase D As a Cardiac Class Iia Histone Deacetylase Kinase
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector FEBS Letters 584 (2010) 631–637 journal homepage: www.FEBSLetters.org A novel kinase inhibitor establishes a predominant role for protein kinase D as a cardiac class IIa histone deacetylase kinase Lauren Monovich a,*, Richard B. Vega a, Erik Meredith a, Karl Miranda a, Chang Rao a, Michael Capparelli a, Douglas D. Lemon b, Dillon Phan b, Keith A. Koch b, Joseph A. Chapo b, David B. Hood b, Timothy A. McKinsey b,* a Novartis Institutes for Biomedical Research, 3333 Walnut Street, Boulder, CO 80301, United States b Gilead Colorado, Inc., 3333 Walnut Street, Boulder, CO 80301, United States article info abstract Article history: Class IIa histone deacetylases (HDACs) repress genes involved in pathological cardiac hypertrophy. Received 13 November 2009 The anti-hypertrophic action of class IIa HDACs is overcome by signals that promote their phosphor- Revised 8 December 2009 ylation-dependent nuclear export. Several kinases have been shown to phosphorylate class IIa Accepted 11 December 2009 HDACs, including calcium/calmodulin-dependent protein kinase (CaMK), protein kinase D (PKD) Available online 14 December 2009 and G protein-coupled receptor kinase (GRK). However, the identity of the kinase(s) responsible Edited by Ivan Sadowski for phosphorylating class IIa HDACs during cardiac hypertrophy has remained controversial. We describe a novel and selective small molecule inhibitor of PKD, bipyridyl PKD inhibitor (BPKDi). BPKDi blocks signal-dependent phosphorylation and nuclear export of class IIa HDACs in cardio- Keywords: Kinase myocytes and concomitantly suppresses hypertrophy of these cells.
    [Show full text]
  • Supplementary Table 1. in Vitro Side Effect Profiling Study for LDN/OSU-0212320. Neurotransmitter Related Steroids
    Supplementary Table 1. In vitro side effect profiling study for LDN/OSU-0212320. Percent Inhibition Receptor 10 µM Neurotransmitter Related Adenosine, Non-selective 7.29% Adrenergic, Alpha 1, Non-selective 24.98% Adrenergic, Alpha 2, Non-selective 27.18% Adrenergic, Beta, Non-selective -20.94% Dopamine Transporter 8.69% Dopamine, D1 (h) 8.48% Dopamine, D2s (h) 4.06% GABA A, Agonist Site -16.15% GABA A, BDZ, alpha 1 site 12.73% GABA-B 13.60% Glutamate, AMPA Site (Ionotropic) 12.06% Glutamate, Kainate Site (Ionotropic) -1.03% Glutamate, NMDA Agonist Site (Ionotropic) 0.12% Glutamate, NMDA, Glycine (Stry-insens Site) 9.84% (Ionotropic) Glycine, Strychnine-sensitive 0.99% Histamine, H1 -5.54% Histamine, H2 16.54% Histamine, H3 4.80% Melatonin, Non-selective -5.54% Muscarinic, M1 (hr) -1.88% Muscarinic, M2 (h) 0.82% Muscarinic, Non-selective, Central 29.04% Muscarinic, Non-selective, Peripheral 0.29% Nicotinic, Neuronal (-BnTx insensitive) 7.85% Norepinephrine Transporter 2.87% Opioid, Non-selective -0.09% Opioid, Orphanin, ORL1 (h) 11.55% Serotonin Transporter -3.02% Serotonin, Non-selective 26.33% Sigma, Non-Selective 10.19% Steroids Estrogen 11.16% 1 Percent Inhibition Receptor 10 µM Testosterone (cytosolic) (h) 12.50% Ion Channels Calcium Channel, Type L (Dihydropyridine Site) 43.18% Calcium Channel, Type N 4.15% Potassium Channel, ATP-Sensitive -4.05% Potassium Channel, Ca2+ Act., VI 17.80% Potassium Channel, I(Kr) (hERG) (h) -6.44% Sodium, Site 2 -0.39% Second Messengers Nitric Oxide, NOS (Neuronal-Binding) -17.09% Prostaglandins Leukotriene,
    [Show full text]
  • GAK and PRKCD Are Positive Regulators of PRKN-Independent
    bioRxiv preprint doi: https://doi.org/10.1101/2020.11.05.369496; this version posted November 5, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 GAK and PRKCD are positive regulators of PRKN-independent 2 mitophagy 3 Michael J. Munson1,2*, Benan J. Mathai1,2, Laura Trachsel1,2, Matthew Yoke Wui Ng1,2, Laura 4 Rodriguez de la Ballina1,2, Sebastian W. Schultz2,3, Yahyah Aman4, Alf H. Lystad1,2, Sakshi 5 Singh1,2, Sachin Singh 2,3, Jørgen Wesche2,3, Evandro F. Fang4, Anne Simonsen1,2* 6 1Division of Biochemistry, Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo 7 2Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, N-0316, Oslo, Norway. 8 3Department of Molecular Cell Biology, The Norwegian Radium Hospital Montebello, N-0379, Oslo, Norway 9 4Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, 1478 Lørenskog, Norway 10 11 Keywords: GAK, Cyclin G Associated Kinase, PRKCD, Protein Kinase C Delta, Mitophagy, DFP, 12 DMOG, PRKN 13 14 *Corresponding Authors: 15 [email protected] 16 [email protected] 17 bioRxiv preprint doi: https://doi.org/10.1101/2020.11.05.369496; this version posted November 5, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
    [Show full text]
  • Article (Published Version)
    Article Kinases and Cancer CICENAS, Jonas, et al. Abstract Protein kinases are a large family of enzymes catalyzing protein phosphorylation. The human genome contains 518 protein kinase genes, 478 of which belong to the classical protein kinase family and 40 are atypical protein kinases [...]. Reference CICENAS, Jonas, et al. Kinases and Cancer. Cancers, 2018, vol. 10, no. 3 DOI : 10.3390/cancers10030063 PMID : 29494549 Available at: http://archive-ouverte.unige.ch/unige:105089 Disclaimer: layout of this document may differ from the published version. 1 / 1 cancers Editorial Kinases and Cancer Jonas Cicenas 1,2,3,* ID , Egle Zalyte 2, Amos Bairoch 4,5 ID and Pascale Gaudet 4,* 1 Department of Microbiology, Immunology and Genetics, Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria 2 Proteomics Center, Institute of Biochemistry, Vilnius University Life Sciences Center, Sauletekio al. 7, LT-10257 Vilnius, Lithuania; [email protected] 3 MAP Kinase Resource, Bioinformatics, Melchiorstrasse 9, 3027 Bern, Switzerland 4 CALIPHO Group, SIB Swiss Institute of Bioinformatics, 1 rue Michel-Servet, CH-1211 Geneva 4, Switzerland; [email protected] 5 Faculty of Medicine; University of Geneva; 1 rue Michel-Servet, CH-1211 Geneva 4, Switzerland * Correspondence: [email protected] (J.C.); [email protected] (P.G.); Tel.: +43-664-5875822 (J.C.) Received: 27 February 2018; Accepted: 28 February 2018; Published: 1 March 2018 Protein kinases are a large family of enzymes catalyzing protein phosphorylation. The human genome contains 518 protein kinase genes, 478 of which belong to the classical protein kinase family and 40 are atypical protein kinases.
    [Show full text]
  • TLR9 Signaling Protein Kinase D1
    Protein Kinase D1: A New Component in TLR9 Signaling Jeoung-Eun Park, Young-In Kim and Ae-Kyung Yi This information is current as J Immunol 2008; 181:2044-2055; ; of September 27, 2021. doi: 10.4049/jimmunol.181.3.2044 http://www.jimmunol.org/content/181/3/2044 Downloaded from References This article cites 58 articles, 35 of which you can access for free at: http://www.jimmunol.org/content/181/3/2044.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 27, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Protein Kinase D1: A New Component in TLR9 Signaling1 Jeoung-Eun Park,* Young-In Kim,* and Ae-Kyung Yi2*† Protein kinase D1 (PKD1) is expressed ubiquitously and regulates diverse cellular processes such as oxidative stress, gene ex- pression, cell survival, and vesicle trafficking. However, the presence and function of PKD1 in monocytic cells are currently unknown.
    [Show full text]
  • The Role of GSK-3 in the Regulation of Protein Turnover, Myosin
    International Journal of Molecular Sciences Review The Role of GSK-3β in the Regulation of Protein Turnover, Myosin Phenotype, and Oxidative Capacity in Skeletal Muscle under Disuse Conditions Timur M. Mirzoev * , Kristina A. Sharlo and Boris S. Shenkman Myology Laboratory, Institute of Biomedical Problems RAS, 123007 Moscow, Russia; [email protected] (K.A.S.); [email protected] (B.S.S.) * Correspondence: [email protected] Abstract: Skeletal muscles, being one of the most abundant tissues in the body, are involved in many vital processes, such as locomotion, posture maintenance, respiration, glucose homeostasis, etc. Hence, the maintenance of skeletal muscle mass is crucial for overall health, prevention of various diseases, and contributes to an individual’s quality of life. Prolonged muscle inactivity/disuse (due to limb immobilization, mechanical ventilation, bedrest, spaceflight) represents one of the typical causes, leading to the loss of muscle mass and function. This disuse-induced muscle loss primarily results from repressed protein synthesis and increased proteolysis. Further, prolonged disuse results in slow-to-fast fiber-type transition, mitochondrial dysfunction and reduced oxidative capacity. Glycogen synthase kinase 3β (GSK-3β) is a key enzyme standing at the crossroads of various signaling pathways regulating a wide range of cellular processes. This review discusses various important roles of GSK-3β in the regulation of protein turnover, myosin phenotype, and oxidative capacity in skeletal muscles under disuse/unloading conditions and subsequent recovery. According Citation: Mirzoev, T.M.; Sharlo, K.A.; to its vital functions, GSK-3β may represent a perspective therapeutic target in the treatment of Shenkman, B.S. The Role of GSK-3β muscle wasting induced by chronic disuse, aging, and a number of diseases.
    [Show full text]
  • REGULATION of CANCER METASTASIS by PROTEIN KINASE D1: a GLOBAL REGULATORY CASCADE Aditya Ganju
    University of Tennessee Health Science Center UTHSC Digital Commons Theses and Dissertations (ETD) College of Graduate Health Sciences 12-2016 REGULATION OF CANCER METASTASIS BY PROTEIN KINASE D1: A GLOBAL REGULATORY CASCADE Aditya Ganju Follow this and additional works at: https://dc.uthsc.edu/dissertations Part of the Genetic Processes Commons, Medical Biochemistry Commons, Other Medical Sciences Commons, and the Pharmacy and Pharmaceutical Sciences Commons Recommended Citation Ganju, Aditya (http://orcid.org/0000-0003-1258-0105), "REGULATION OF CANCER METASTASIS BY PROTEIN KINASE D1: A GLOBAL REGULATORY CASCADE" (2016). Theses and Dissertations (ETD). Paper 413. http://dx.doi.org/10.21007/ etd.cghs.2016.0421. This Dissertation is brought to you for free and open access by the College of Graduate Health Sciences at UTHSC Digital Commons. It has been accepted for inclusion in Theses and Dissertations (ETD) by an authorized administrator of UTHSC Digital Commons. For more information, please contact [email protected]. REGULATION OF CANCER METASTASIS BY PROTEIN KINASE D1: A GLOBAL REGULATORY CASCADE Document Type Dissertation Degree Name Doctor of Philosophy (PhD) Program Pharmaceutical Sciences Track Bioanalysis Research Advisor Meena Jaggi, Ph.D. Committee Stephen W. Behrman, Ph.D. Santosh Kumar, Ph.D. Yi Lu, Ph.D. Murali M. Yallapu, Ph.D ORCID http://orcid.org/0000-0003-1258-0105 DOI 10.21007/etd.cghs.2016.0421 Comments One year embargo expires December 2017. This dissertation is available at UTHSC Digital Commons: https://dc.uthsc.edu/dissertations/413 REGULATION OF CANCER METASTASIS BY PROTEIN KINASE D1: A GLOBAL REGULATORY CASCADE A Dissertation Presented for The Graduate Studies Council The University of Tennessee Health Science Center In Partial Fulfillment Of the Requirements for the Degree Doctor of Philosophy From The University of Tennessee By Aditya Ganju December 2016 Chapter 2 © 2014 by Impact Journals, LLC.
    [Show full text]
  • Protein Kinase D1 Maintains the Epithelial Phenotype by Inducing a DNA-Bound, Inactive SNAI1 Transcriptional Repressor Complex
    Protein Kinase D1 Maintains the Epithelial Phenotype by Inducing a DNA-Bound, Inactive SNAI1 Transcriptional Repressor Complex Ligia I. Bastea., Heike Do¨ ppler., Bolanle Balogun, Peter Storz* Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida, United States of America Abstract Background: Protein Kinase D1 is downregulated in its expression in invasive ductal carcinoma of the breast and in invasive breast cancer cells, but its functions in normal breast epithelial cells is largely unknown. The epithelial phenotype is maintained by cell-cell junctions formed by E-cadherin. In cancer cells loss of E-cadherin expression contributes to an invasive phenotype. This can be mediated by SNAI1, a transcriptional repressor for E-cadherin that contributes to epithelial- to-mesenchymal transition (EMT). Methodology/Principal Findings: Here we show that PKD1 in normal murine mammary gland (NMuMG) epithelial cells is constitutively-active in its basal state and prevents a transition to a mesenchymal phenotype. Investigation of the involved mechanism suggested that PKD1 regulates the expression of E-cadherin at the promoter level through direct phosphorylation of the transcriptional repressor SNAI1. PKD1-mediated phosphorylation of SNAI1 occurs in the nucleus and generates a nuclear, inactive DNA/SNAI1 complex that shows decreased interaction with its co-repressor Ajuba. Analysis of human tissue samples with a newly-generated phosphospecific antibody for PKD1-phosphorylated SNAI1 showed that regulation of SNAI1 through PKD1 occurs in vivo in normal breast ductal tissue and is decreased or lost in invasive ductal carcinoma. Conclusions/Significance: Our data describe a mechanism of how PKD1 maintains the breast epithelial phenotype. Moreover, they suggest, that the analysis of breast tissue for PKD-mediated phosphorylation of SNAI1 using our novel phosphoS11-SNAI1-specific antibody may allow predicting the invasive potential of breast cancer cells.
    [Show full text]
  • Kinases and Cancer
    cancers Editorial Kinases and Cancer Jonas Cicenas 1,2,3,* ID , Egle Zalyte 2, Amos Bairoch 4,5 ID and Pascale Gaudet 4,* 1 Department of Microbiology, Immunology and Genetics, Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria 2 Proteomics Center, Institute of Biochemistry, Vilnius University Life Sciences Center, Sauletekio al. 7, LT-10257 Vilnius, Lithuania; [email protected] 3 MAP Kinase Resource, Bioinformatics, Melchiorstrasse 9, 3027 Bern, Switzerland 4 CALIPHO Group, SIB Swiss Institute of Bioinformatics, 1 rue Michel-Servet, CH-1211 Geneva 4, Switzerland; [email protected] 5 Faculty of Medicine; University of Geneva; 1 rue Michel-Servet, CH-1211 Geneva 4, Switzerland * Correspondence: [email protected] (J.C.); [email protected] (P.G.); Tel.: +43-664-5875822 (J.C.) Received: 27 February 2018; Accepted: 28 February 2018; Published: 1 March 2018 Protein kinases are a large family of enzymes catalyzing protein phosphorylation. The human genome contains 518 protein kinase genes, 478 of which belong to the classical protein kinase family and 40 are atypical protein kinases. Phosphorylation is one of the critical mechanisms for regulating different cellular functions, such as proliferation, cell cycle, apoptosis, motility, growth, differentiation, among others. Deregulation of kinase activity can result in dramatic changes in these processes. Moreover, deregulated kinases are frequently found to be oncogenic and can be central for the survival and spread of cancer cells [1]. There are several ways for kinases to become involved in cancers: mis-regulated expression and/or amplification, aberrant phosphorylation, mutation, chromosomal translocation, and epigenetic regulation. The CALIPHO group of the SIB Swiss Institute of Bioinformatics develops neXtProt, a knowledge base focused on human proteins [2].
    [Show full text]
  • Kinome Expression Profiling to Target New Therapeutic Avenues in Multiple Myeloma
    Plasma Cell DIsorders SUPPLEMENTARY APPENDIX Kinome expression profiling to target new therapeutic avenues in multiple myeloma Hugues de Boussac, 1 Angélique Bruyer, 1 Michel Jourdan, 1 Anke Maes, 2 Nicolas Robert, 3 Claire Gourzones, 1 Laure Vincent, 4 Anja Seckinger, 5,6 Guillaume Cartron, 4,7,8 Dirk Hose, 5,6 Elke De Bruyne, 2 Alboukadel Kassambara, 1 Philippe Pasero 1 and Jérôme Moreaux 1,3,8 1IGH, CNRS, Université de Montpellier, Montpellier, France; 2Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium; 3CHU Montpellier, Laboratory for Monitoring Innovative Therapies, Department of Biologi - cal Hematology, Montpellier, France; 4CHU Montpellier, Department of Clinical Hematology, Montpellier, France; 5Medizinische Klinik und Poliklinik V, Universitätsklinikum Heidelberg, Heidelberg, Germany; 6Nationales Centrum für Tumorerkrankungen, Heidelberg , Ger - many; 7Université de Montpellier, UMR CNRS 5235, Montpellier, France and 8 Université de Montpellier, UFR de Médecine, Montpel - lier, France ©2020 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol. 2018.208306 Received: October 5, 2018. Accepted: July 5, 2019. Pre-published: July 9, 2019. Correspondence: JEROME MOREAUX - [email protected] Supplementary experiment procedures Kinome Index A list of 661 genes of kinases or kinases related have been extracted from literature9, and challenged in the HM cohort for OS prognostic values The prognostic value of each of the genes was computed using maximally selected rank test from R package MaxStat. After Benjamini Hochberg multiple testing correction a list of 104 significant prognostic genes has been extracted. This second list has then been challenged for similar prognosis value in the UAMS-TT2 validation cohort.
    [Show full text]