DOCSLIB.ORG

MAPKAPK2: the Master Regulator of RNA-Binding Proteins Modulates

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
MAPKAPK2: the Master Regulator of RNA-Binding Proteins Modulates Soni et al. Journal of Experimental & Clinical Cancer Research (2019) 38:121 https://doi.org/10.1186/s13046-019-1115-1 REVIEW Open Access MAPKAPK2: the master regulator of RNA- binding proteins modulates transcript stability and tumor progression Sourabh Soni1,2, Prince Anand1,2 and Yogendra S. Padwad1,2* Abstract The p38 mitogen-activated protein kinase (p38MAPK) pathway has been implicated in a variety of pathological conditions including inflammation and metastasis. Post-transcriptional regulation of genes harboring adenine/ uridine-rich elements (AREs) in their 3′-untranslated region (3′-UTR) is controlled by MAPK-activated protein kinase 2 (MAPKAPK2 or MK2), a downstream substrate of the p38MAPK. In response to diverse extracellular stimuli, MK2 influences crucial signaling events, regulates inflammatory cytokines, transcript stability and critical cellular processes. Expression of genes involved in these vital cellular cascades is controlled by subtle interactions in underlying molecular networks and post-transcriptional gene regulation that determines transcript fate in association with RNA-binding proteins (RBPs). Several RBPs associate with the 3′-UTRs of the target transcripts and regulate their expression via modulation of transcript stability. Although MK2 regulates important cellular phenomenon, yet its biological significance in tumor progression has not been well elucidated till date. In this review, we have highlighted in detail the importance of MK2 as the master regulator of RBPs and its role in the regulation of transcript stability, tumor progression, as well as the possibility of use of MK2 as a therapeutic target in tumor management. Keywords: Mitogen-activated protein kinase-activated protein kinase 2 (MK2), RNA binding proteins (RBPs), Adenine/ uridine-rich elements (AREs), 3′-untranslated region (3′-UTR), Transcript stability, Inhibitors, Therapeutics − − Background MK2 / mice, indicating regulation at the translational A variety of stimuli evokes specific responses in cells via level which might be imparted via a MK2 substrate. p38 mitogen-activated protein kinase (p38MAPK) signal In response to stress stimuli, p38MAPK phosphorylates pathway activation. The stress-activated p38MAPK signal- and activates MK2 which further regulates a cascade of ing pathway regulates a plethora of cellular processes in biological events and participates in a multitude of pro- particular apoptosis, cell division, cell invasion, and inflam- cesses like cell apoptosis [2], cell cycle [3], movement [4] matory response [1]. p38MAPK pathway’sdownstream and response to oxidative stress [5]. MK2 was discovered substrate, mitogen-activated protein kinase-activated pro- as an extracellular signal-regulated kinase (ERK1/2)-acti- tein kinase 2 (MAPKAPK2 or MK2) is involved in the vated protein kinase that phosphorylates and inactivates post-translational regulation of cytokines as evident in heat shock protein (Hsp27) [6]. MK2 has been shown to − − MK2 knockout (MK2 / ) mice showing attenuated pro- govern the activation and deactivation of RNA-binding duction of tumor necrosis factor (TNFα) protein when proteins (RBPs) [7]. These RBPs modulate the gene ex- compared to wild-type mice. The mRNA levels, however, pression of mRNAs encoding several proto-oncogenes, cy- in wild-type mice were quite similar as compared to tokines, chemokines and pro-inflammatory factors that control cell-cycle progression, proliferation, angiogenesis, metastasis, and cell death [8, 9]. Experimental evidence in- dicates that MK2, the prime target of p38MAPK, regulates * Correspondence: [email protected] 1Pharmacology and Toxicology Laboratory, Food and Nutraceuticals Division, the stability of essential genes involved in tumor patho- CSIR-Institute of Himalayan Bioresource Technology (CSIR-IHBT), Palampur, genesis that harbour adenine/uridine-rich elements Himachal Pradesh, India (AREs) in their 3′-untranslated region (3′-UTRs) [8]. 2Academy of Scientific and Innovative Research, Chennai, Tamil Nadu, India © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Soni et al. Journal of Experimental & Clinical Cancer Research (2019) 38:121 Page 2 of 18 Systemic side effects like hepatic and cardiac toxicity interact in a majorly receptor-mediator manner and help as well as central nervous system disorders caused by trigger the phosphorylation of a MAPK kinase kinase the small molecules p38MAPK inhibitors have hindered (MAP3K) specifically which further causes the phosphoryl- their translational use. This might be attributed to the ation of its downstream substrate MAPK kinase (MAP2K). fact that p38MAPK regulates more than sixty substrates After MAP2K phosphorylation, its substrate MAPK is sub- and therefore its direct inhibitors have failed in their sequently phosphorylated (Fig. 1). Activated MAPKs fur- clinical utility due to undesired side effects [10]. This ther leads to the phosphorylation and activation of several has prompted researchers to look for novel therapeutic downstream protein kinases, proto-oncogenes, and tran- targets in downstream regulators of this signaling scription factors [11]. pathway, prominent among them being MK2. Hence, insights into the putative role of MK2 in the post-transcriptional regulation of pathogenesis-linked Major kinases in the p38MAPK signaling pathway transcripts have become pertinent. In this review, we MAPK pathways comprises of an array of three ki- have highlighted the importance of MK2 as the master nases: Firstly, a MAP3K which is responsible to acti- regulator of RBPs and its role in the regulation of tran- vates a MAP2K that in turn phosphorylates and script stability and tumor progression. Furthermore, we activates a MAPK which occurs via a dual phosphor- have discussed the role of MK2 in various cancers and ylation in the activation motif (Thr-X-Tyr where X have also deliberated its significance in various cancer could be any amino acid). Mammalian cells are processes. The possibility of employing MK2 as a thera- known to express fourteen MAPKs which can be fur- peutic inhibitor has also been reviewed. ther segregated into groups based on sequence hom- ology. The classical MAPKs are ERK1 and ERK2 with p38MAPK signaling pathway MAP2Ks, MKK1 or MKK2 activating them. Four iso- p38MAPKs are key MAPKs involved in the production of forms of the p38MAPK family are known (p38α, important inflammatory mediators, including TNFα and p38β,p38γ,andp38δ), and these are activated by the cyclooxygenase-2 (COX-2). Cellular stresses/mitogens MAP2Ks, MKK3, and MKK6 [12]. Fig. 1 p38MAPK signalling cascade. A multitude of extracellular stimuli and mitogens lead to the activation of p38MAPK signalling pathway consisting of a kinase network as diagrammatically represented in the figure. When activated by p38, MK2 gets exported to the cytoplasm (NLS gets masked and NES is functional) where it controls the transcript stability of tumor pathogenesis related mRNAs harbouring AREs in their 3′-UTRs via regulation of RNA-binding proteins Soni et al. Journal of Experimental & Clinical Cancer Research (2019) 38:121 Page 3 of 18 Downstream substrates of the p38MAPK signaling pathway Table 1 MK2 regulates transcript stability via RBPs There are numbers of substrates downstream of RNA Binding Protein Target mRNA Influence on mRNA References p38MAPK signaling pathways. MK2 and MK3 were the AUF1 GM-CSF Destabilized [63] first p38MAPK substrates identified [13]. Phosphorylated IL-6 Destabilized [107–109] MK2 or MK3 can activate a variety of substrates, such as TNF-α Destabilized [47, 106] small Hsp27 [14], cyclic AMP-responsive element-binding protein (CREB) [15], and tristetraprolin (TTP), a RBP, VEGF Destabilized [77] known to causes mRNA destabilization thus referring at HuR COX-2 Stabilized [90] p38MAPK’s role in mRNA stability [16]. It has been Cyclins Stabilized [117] shown that p38MAPK modulates MK2 expression both GM-CSF Stabilized [68] transcriptionally and post-transcriptionally in murine cell α − − HIF-1 Stabilized [112, 113] lines and embryos while it is lost in p38 / mice [17]. IL-6 Stabilized [120] Mitogen-activated protein kinase-activated IL-8 Stabilized [120] protein kinase 2 MMP-9 Stabilized [58] p38MAPK’s downstream substrate responsible for a pleth- p21 Stabilized [122] ora of signaling cascades in response to numerous extra- p27 Represses Translation [122] cellular stimuli ranging from apoptosis, cell division and TGF-β Stabilized [120] differentiation, cell motility to inflammation is a Ser/Tyr TNF-α Stabilized [120] protein kinase, MK2 [6]. MK2 acts as an important driver in the signaling pathways triggered in reply to DNA dam- VEGF Stabilized [113, 120] age. A recent report has identified MK2 as protumorigenic TTP COX-2 Destabilized [110] with its role been shown in tumor progression [18]. Past GM-CSF Destabilized [68] reports have elucidated the expression of MK2 in a variety IL-1 Destabilized [107] of cell types such as endothelial cells [19], smooth muscle IL-6 Destabilized
Load more

Recommended publications
  • Autophagy Processes Are Dependent on EGF Receptor Signaling
    www.oncotarget.com Oncotarget, 2018, Vol. 9, (No. 54), pp: 30289-30303 Research Paper Autophagy processes are dependent on EGF receptor signaling Vincenzo De Iuliis1, Antonio Marino1, Marika Caruso1, Sabrina Capodifoglio1, Vincenzo Flati2, Anna Marynuk3, Valeria Marricareda3, Sebastiano Ursi1, Paola Lanuti4, Claudio Talora5, Pio Conti6, Stefano Martinotti1,7 and Elena Toniato7 1Unit of Predictive Medicine, SS Annunziata University Hospital of Chieti, Chieti, Italy 2Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy 3Odessa National Medical University, Odesa, Odessa Oblsat, Ucraina 4Department of Medicine and Aging Sciences, University G. d’Annunzio of Chieti, Chieti, Italy 5Department of Molecular Medicine, University of Rome “La Sapienza”, Rome, Italy 6Postgraduate Medical School, University of Chieti, Chieti, Italy 7Department of Medical, Oral and Biotechnological Sciences, University G. d’Annunzio of Chieti, Chieti, Italy Correspondence to: Elena Toniato, email: [email protected] Keywords: apoptosis; autophagy; Beclin 1; EGF receptor; MAPK pathway Received: May 03, 2018 Accepted: June 13, 2018 Published: July 13, 2018 Copyright: De Iuliis et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Autophagy is a not well-understood conserved mechanism activated during nutritional deprivation in order to maintain cellular homeostasis. In the present study, we investigated the correlations between autophagy, apoptosis and the MAPK pathways in melanoma cell lines. We demonstrated that during starvation the EGF receptor mediated signaling activates many proteins involved in the MAPK pathway.
    [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]
  • Table S1. Numbers of Positive and Negative Data of Different Kinases in Four Hierarchical Levels
    Electronic Supplementary Material (ESI) for Molecular BioSystems This journal is © The Royal Society of Chemistry 2014 Figure S1. Illustration of GSK3B mediated phosphorylation. Frat2 can significantly increase GSK3B mediated phosphorylation of Tau by binding to GSK3B. GSK3B: kinases; Tau: substrate; Frat2: kinase binding protein. Table S1. Numbers of positive and negative data of different kinases in four hierarchical levels Kinase name Positive number Negative number Kinase level CDC2 122 1649 PKCa 110 1608 Ck2alpha 91 1619 Erk2(MAPK1) 82 1700 Erk1(MAPK3) 77 1705 ATM 58 1765 CDK2 53 1720 GSK3B 44 1766 p38a(MAPK14) 44 1741 PLK1 39 1784 CaMK2a 27 1777 BARK1 27 1772 PDK1 24 1799 AurA 22 1801 MAPKAPK2 20 1803 SRC 88 377 LCK 43 419 SYK 35 431 EGFR 34 432 ABL1(Abl) 32 434 FYN 25 438 LYN 27 435 INSR 27 439 Subfamily level CDC2 173 1602 ERK1 118 1659 Alpha 116 1597 ATM 58 1758 Electronic Supplementary Material (ESI) for Molecular BioSystems This journal is © The Royal Society of Chemistry 2014 p38 52 1730 PLK1 39 1777 BARK 30 1765 MAPKAPK 21 1795 SrcA 88 378 SrcB 64 402 Family level PKC 248 1575 CDK 243 1580 MAPK 230 1593 CK2 204 1619 PIKK 88 1735 GRK 63 1760 GSK 58 1765 CAMK2 46 1777 PLK 40 1783 Aur 39 1784 PDK1 24 1799 MAPKAPK 22 1801 Src 173 293 Syk 46 420 EGFR 39 427 INSR 37 429 Abl 33 433 Group level CMGC 719 1104 AGC 660 1163 CAMK 164 1659 Other 158 1665 Atypical 95 1728 TK 452 14 Electronic Supplementary Material (ESI) for Molecular BioSystems This journal is © The Royal Society of Chemistry 2014 Table S2.
    [Show full text]
  • The P90 RSK Family Members: Common Functions and Isoform Specificity
    Published OnlineFirst August 22, 2013; DOI: 10.1158/0008-5472.CAN-12-4448 Cancer Review Research The p90 RSK Family Members: Common Functions and Isoform Specificity Romain Lara, Michael J. Seckl, and Olivier E. Pardo Abstract The p90 ribosomal S6 kinases (RSK) are implicated in various cellular processes, including cell proliferation, survival, migration, and invasion. In cancer, RSKs modulate cell transformation, tumorigenesis, and metastasis. Indeed, changes in the expression of RSK isoforms have been reported in several malignancies, including breast, prostate, and lung cancers. Four RSK isoforms have been identified in humans on the basis of their high degree of sequence homology. Although this similarity suggests some functional redundancy between these proteins, an increasing body of evidence supports the existence of isoform-based specificity among RSKs in mediating particular cellular processes. This review briefly presents the similarities between RSK family members before focusing on the specific function of each of the isoforms and their involvement in cancer progression. Cancer Res; 73(17); 1–8. Ó2013 AACR. Introduction subsequently cloned throughout the Metazoan kingdom (2). The extracellular signal–regulated kinase (ERK)1/2 pathway The genomic analysis of several cancer types suggests that fi is involved in key cellular processes, including cell prolifera- these genes are not frequently ampli ed or mutated, with some tion, differentiation, survival, metabolism, and migration. notable exceptions (e.g., in the case of hepatocellular carcino- More than 30% of all human cancers harbor mutations within ma; ref. 6). Table 1 summarizes reported genetic changes in this pathway, mostly resulting in gain of function and conse- RSK genes.
    [Show full text]
  • Integrated Molecular Characterisation of the MAPK Pathways in Human
    ARTICLE https://doi.org/10.1038/s42003-020-01552-6 OPEN Integrated molecular characterisation of the MAPK pathways in human cancers reveals pharmacologically vulnerable mutations and gene dependencies 1234567890():,; ✉ Musalula Sinkala 1 , Panji Nkhoma 2, Nicola Mulder 1 & Darren Patrick Martin1 The mitogen-activated protein kinase (MAPK) pathways are crucial regulators of the cellular processes that fuel the malignant transformation of normal cells. The molecular aberrations which lead to cancer involve mutations in, and transcription variations of, various MAPK pathway genes. Here, we examine the genome sequences of 40,848 patient-derived tumours representing 101 distinct human cancers to identify cancer-associated mutations in MAPK signalling pathway genes. We show that patients with tumours that have mutations within genes of the ERK-1/2 pathway, the p38 pathways, or multiple MAPK pathway modules, tend to have worse disease outcomes than patients with tumours that have no mutations within the MAPK pathways genes. Furthermore, by integrating information extracted from various large-scale molecular datasets, we expose the relationship between the fitness of cancer cells after CRISPR mediated gene knockout of MAPK pathway genes, and their dose-responses to MAPK pathway inhibitors. Besides providing new insights into MAPK pathways, we unearth vulnerabilities in specific pathway genes that are reflected in the re sponses of cancer cells to MAPK targeting drugs: a revelation with great potential for guiding the development of innovative therapies.
    [Show full text]
  • A Senescence Secretory Switch Mediated by PI3K/AKT/Mtor Activation Controls Chemoprotective Endothelial Secretory Responses
    Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press A senescence secretory switch mediated by PI3K/AKT/mTOR activation controls chemoprotective endothelial secretory responses Eric H. Bent,1,2 Luke A. Gilbert,1,2 and Michael T. Hemann1,2 1The David H. Koch Institute for Integrative Cancer Research, 2Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA Cancer therapy targets malignant cells that are surrounded by a diverse complement of nonmalignant stromal cells. Therapy-induced damage of normal cells can alter the tumor microenvironment, causing cellular senescence and activating cancer-promoting inflammation. However, how these damage responses are regulated (both induced and resolved) to preserve tissue homeostasis and prevent chronic inflammation is poorly understood. Here, we detail an acute chemotherapy-induced secretory response that is self-limiting in vitro and in vivo despite the induction of cellular senescence. We used tissue-specific knockout mice to demonstrate that endothelial production of the proinflammatory cytokine IL-6 promotes chemoresistance and show that the chemotherapeutic doxorubicin in- duces acute IL-6 release through reactive oxygen species-mediated p38 activation in vitro. Doxorubicin causes en- dothelial senescence but, surprisingly, without a typical senescence secretory response. We found that endothelial cells repress senescence-associated inflammation through the down-regulation of PI3K/AKT/mTOR signaling and that reactivation of this pathway restores senescence-associated inflammation. Thus, we describe a mechanism by which damage-associated paracrine secretory responses are restrained to preserve tissue homeostasis and prevent chronic inflammation. [Keywords: tumor microenvironment; chemoresistance; paracrine; senescence; endothelial cell; SASP] Supplemental material is available for this article.
    [Show full text]
  • Activation of Diverse Signalling Pathways by Oncogenic PIK3CA Mutations
    ARTICLE Received 14 Feb 2014 | Accepted 12 Aug 2014 | Published 23 Sep 2014 DOI: 10.1038/ncomms5961 Activation of diverse signalling pathways by oncogenic PIK3CA mutations Xinyan Wu1, Santosh Renuse2,3, Nandini A. Sahasrabuddhe2,4, Muhammad Saddiq Zahari1, Raghothama Chaerkady1, Min-Sik Kim1, Raja S. Nirujogi2, Morassa Mohseni1, Praveen Kumar2,4, Rajesh Raju2, Jun Zhong1, Jian Yang5, Johnathan Neiswinger6, Jun-Seop Jeong6, Robert Newman6, Maureen A. Powers7, Babu Lal Somani2, Edward Gabrielson8, Saraswati Sukumar9, Vered Stearns9, Jiang Qian10, Heng Zhu6, Bert Vogelstein5, Ben Ho Park9 & Akhilesh Pandey1,8,9 The PIK3CA gene is frequently mutated in human cancers. Here we carry out a SILAC-based quantitative phosphoproteomic analysis using isogenic knockin cell lines containing ‘driver’ oncogenic mutations of PIK3CA to dissect the signalling mechanisms responsible for oncogenic phenotypes induced by mutant PIK3CA. From 8,075 unique phosphopeptides identified, we observe that aberrant activation of PI3K pathway leads to increased phosphorylation of a surprisingly wide variety of kinases and downstream signalling networks. Here, by integrating phosphoproteomic data with human protein microarray-based AKT1 kinase assays, we discover and validate six novel AKT1 substrates, including cortactin. Through mutagenesis studies, we demonstrate that phosphorylation of cortactin by AKT1 is important for mutant PI3K-enhanced cell migration and invasion. Our study describes a quantitative and global approach for identifying mutation-specific signalling events and for discovering novel signalling molecules as readouts of pathway activation or potential therapeutic targets. 1 McKusick-Nathans Institute of Genetic Medicine and Department of Biological Chemistry, Johns Hopkins University School of Medicine, 733 North Broadway, BRB 527, Baltimore, Maryland 21205, USA.
    [Show full text]
  • MAPKAPK2, Active MAPKAPK2, Active
    Catalogue # Aliquot Size M40-11G-05 5 µg M40-11G-10 10 µg M40-11G-20 20 µg MAPKAPK2, Active Recombinant human protein expressed in Sf 9 cells Catalog # M40-11G Lot # V192 -1 Product Description Specific Activity Recombinant human MAPKAPK2 (46-end) was expressed by baculovirus in Sf9 insect cells using an N-terminal GST 1,200,000 tag. The gene accession number is NM_032960 . 900,000 Gene Aliases 600,000 MK2 300,000 Activity (cpm) Activity 0 Formulation 0 50 100 150 200 Protein (ng) Recombinant protein stored in 50mM Tris-HCl, pH 7.5, 150mM NaCl, 10mM glutathione, 0.1mM EDTA, 0.25mM The specific activity of MAPKAPK2 was determined to be 315 DTT, 0.1mM PMSF, 25% glycerol nmol /min/mg as per activity assay protocol. Storage and Stability Purity Store product at –70 oC. For optimal storage, aliquot target into smaller quantities after centrifugation and store at recommended temperature. For most favorable performance, avoid repeated handling and multiple The purity was determined to be freeze/thaw cycles. >90% by densitometry. Approx. MW 68kDa . Scientific Background MAPKAPK2 (MAPKAP kinase2) is a Ser/Thr protein kinase which is regulated via direct phosphorylation by p38 MAP kinase (1). In conjunction with p38 MAP kinase, MAPKAPK2 is known to be involved in many cellular processes including stress and inflammatory responses, MAPKAPK2, Active nuclear export, gene expression regulation and cell Recombinant protein expressed in Sf 9 cells proliferation. Heat shock protein HSP27 has been shown to be one of the substrates of MAPKAPK2 in vivo . Catalog Number M40-11G Specific Activity 315 nmol/min/mg References Specific Lot Number V192-1 Purity >90% 1.
    [Show full text]
  • Inhibition of ERK 1/2 Kinases Prevents Tendon Matrix Breakdown Ulrich Blache1,2,3, Stefania L
    www.nature.com/scientificreports OPEN Inhibition of ERK 1/2 kinases prevents tendon matrix breakdown Ulrich Blache1,2,3, Stefania L. Wunderli1,2,3, Amro A. Hussien1,2, Tino Stauber1,2, Gabriel Flückiger1,2, Maja Bollhalder1,2, Barbara Niederöst1,2, Sandro F. Fucentese1 & Jess G. Snedeker1,2* Tendon extracellular matrix (ECM) mechanical unloading results in tissue degradation and breakdown, with niche-dependent cellular stress directing proteolytic degradation of tendon. Here, we show that the extracellular-signal regulated kinase (ERK) pathway is central in tendon degradation of load-deprived tissue explants. We show that ERK 1/2 are highly phosphorylated in mechanically unloaded tendon fascicles in a vascular niche-dependent manner. Pharmacological inhibition of ERK 1/2 abolishes the induction of ECM catabolic gene expression (MMPs) and fully prevents loss of mechanical properties. Moreover, ERK 1/2 inhibition in unloaded tendon fascicles suppresses features of pathological tissue remodeling such as collagen type 3 matrix switch and the induction of the pro-fbrotic cytokine interleukin 11. This work demonstrates ERK signaling as a central checkpoint to trigger tendon matrix degradation and remodeling using load-deprived tissue explants. Tendon is a musculoskeletal tissue that transmits muscle force to bone. To accomplish its biomechanical function, tendon tissues adopt a specialized extracellular matrix (ECM) structure1. Te load-bearing tendon compart- ment consists of highly aligned collagen-rich fascicles that are interspersed with tendon stromal cells. Tendon is a mechanosensitive tissue whereby physiological mechanical loading is vital for maintaining tendon archi- tecture and homeostasis2. Mechanical unloading of the tissue, for instance following tendon rupture or more localized micro trauma, leads to proteolytic breakdown of the tissue with severe deterioration of both structural and mechanical properties3–5.
    [Show full text]
  • PRODUCTS and SERVICES Target List
    PRODUCTS AND SERVICES Target list Kinase Products P.1-11 Kinase Products Biochemical Assays P.12 "QuickScout Screening Assist™ Kits" Kinase Protein Assay Kits P.13 "QuickScout Custom Profiling & Panel Profiling Series" Targets P.14 "QuickScout Custom Profiling Series" Preincubation Targets Cell-Based Assays P.15 NanoBRET™ TE Intracellular Kinase Cell-Based Assay Service Targets P.16 Tyrosine Kinase Ba/F3 Cell-Based Assay Service Targets P.17 Kinase HEK293 Cell-Based Assay Service ～ClariCELL™ ～ Targets P.18 Detection of Protein-Protein Interactions ～ProbeX™～ Stable Cell Lines Crystallization Services P.19 FastLane™ Structures ～Premium～ P.20-21 FastLane™ Structures ～Standard～ Kinase Products For details of products, please see "PRODUCTS AND SERVICES" on page 1～3. Tyrosine Kinases Note: Please contact us for availability or further information. Information may be changed without notice. Expression Protein Kinase Tag Carna Product Name Catalog No. Construct Sequence Accession Number Tag Location System HIS ABL(ABL1) 08-001 Full-length 2-1130 NP_005148.2 N-terminal His Insect (sf21) ABL(ABL1) BTN BTN-ABL(ABL1) 08-401-20N Full-length 2-1130 NP_005148.2 N-terminal DYKDDDDK Insect (sf21) ABL(ABL1) [E255K] HIS ABL(ABL1)[E255K] 08-094 Full-length 2-1130 NP_005148.2 N-terminal His Insect (sf21) HIS ABL(ABL1)[T315I] 08-093 Full-length 2-1130 NP_005148.2 N-terminal His Insect (sf21) ABL(ABL1) [T315I] BTN BTN-ABL(ABL1)[T315I] 08-493-20N Full-length 2-1130 NP_005148.2 N-terminal DYKDDDDK Insect (sf21) ACK(TNK2) GST ACK(TNK2) 08-196 Catalytic domain
    [Show full text]
  • Table S3. RAE Analysis of Well-Differentiated Liposarcoma
    Table S3. RAE analysis of well-differentiated liposarcoma Model Chromosome Region start Region end Size q value freqX0* # genes Genes Amp 1 145009467 145122002 112536 0.097 21.8 2 PRKAB2,PDIA3P Amp 1 145224467 146188434 963968 0.029 23.6 10 CHD1L,BCL9,ACP6,GJA5,GJA8,GPR89B,GPR89C,PDZK1P1,RP11-94I2.2,NBPF11 Amp 1 147475854 148412469 936616 0.034 23.6 20 PPIAL4A,FCGR1A,HIST2H2BF,HIST2H3D,HIST2H2AA4,HIST2H2AA3,HIST2H3A,HIST2H3C,HIST2H4B,HIST2H4A,HIST2H2BE, HIST2H2AC,HIST2H2AB,BOLA1,SV2A,SF3B4,MTMR11,OTUD7B,VPS45,PLEKHO1 Amp 1 148582896 153398462 4815567 1.5E-05 49.1 152 PRPF3,RPRD2,TARS2,ECM1,ADAMTSL4,MCL1,ENSA,GOLPH3L,HORMAD1,CTSS,CTSK,ARNT,SETDB1,LASS2,ANXA9, FAM63A,PRUNE,BNIPL,C1orf56,CDC42SE1,MLLT11,GABPB2,SEMA6C,TNFAIP8L2,LYSMD1,SCNM1,TMOD4,VPS72, PIP5K1A,PSMD4,ZNF687,PI4KB,RFX5,SELENBP1,PSMB4,POGZ,CGN,TUFT1,SNX27,TNRC4,MRPL9,OAZ3,TDRKH,LINGO4, RORC,THEM5,THEM4,S100A10,S100A11,TCHHL1,TCHH,RPTN,HRNR,FLG,FLG2,CRNN,LCE5A,CRCT1,LCE3E,LCE3D,LCE3C,LCE3B, LCE3A,LCE2D,LCE2C,LCE2B,LCE2A,LCE4A,KPRP,LCE1F,LCE1E,LCE1D,LCE1C,LCE1B,LCE1A,SMCP,IVL,SPRR4,SPRR1A,SPRR3, SPRR1B,SPRR2D,SPRR2A,SPRR2B,SPRR2E,SPRR2F,SPRR2C,SPRR2G,LELP1,LOR,PGLYRP3,PGLYRP4,S100A9,S100A12,S100A8, S100A7A,S100A7L2,S100A7,S100A6,S100A5,S100A4,S100A3,S100A2,S100A16,S100A14,S100A13,S100A1,C1orf77,SNAPIN,ILF2, NPR1,INTS3,SLC27A3,GATAD2B,DENND4B,CRTC2,SLC39A1,CREB3L4,JTB,RAB13,RPS27,NUP210L,TPM3,C1orf189,C1orf43,UBAP2L,HAX1, AQP10,ATP8B2,IL6R,SHE,TDRD10,UBE2Q1,CHRNB2,ADAR,KCNN3,PMVK,PBXIP1,PYGO2,SHC1,CKS1B,FLAD1,LENEP,ZBTB7B,DCST2, DCST1,ADAM15,EFNA4,EFNA3,EFNA1,RAG1AP1,DPM3 Amp 1
    [Show full text]
  • Prevention of Melanoma Extravasation As a New Treatment Option Exemplified by P38/MK2 Inhibition
    International Journal of Molecular Sciences Perspective Prevention of Melanoma Extravasation as a New Treatment Option Exemplified by p38/MK2 Inhibition Peter Petzelbauer Skin & Endothelial Research Division, Department of Dermatology, Medical University Vienna, A-1090 Vienna, Austria; [email protected] Received: 19 October 2020; Accepted: 2 November 2020; Published: 6 November 2020 Abstract: Melanoma releases numerous tumor cells into the circulation; however, only a very small fraction of these cells is able to establish distant metastasis. Intravascular survival of circulating tumor cells is limited through hemodynamic forces and by the lack of matrix interactions. The extravasation step is, thus, of unique importance to establish metastasis. Similar to leukocyte extravasation, this process is under the control of adhesion molecule pairs expressed on melanoma and endothelial cells, and as for leukocytes, ligands need to be adequately presented on cell surfaces. Based on melanoma plasticity, there is considerable heterogeneity even within one tumor and one patient resulting in a mixture of invasive or proliferative cells. The molecular control for this switch is still ill-defined. Recently, the balance between two kinase pathways, p38 and JNK, has been shown to determine growth characteristics of melanoma. While an active JNK pathway induces a proliferative phenotype with reduced invasive features, an active p38/MK2 pathway results in an invasive phenotype and supports the extravasation step via the expression of molecules capable of binding to endothelial integrins. Therapeutic targeting of MK2 to prevent extravasation might reduce metastatic spread. Keywords: melanoma; extravasation; p38; MK2; endothelium 1. Melanoma Dissemination Melanoma arises from melanocytes residing in the basal layers of the epidermis or from nevi.
    [Show full text]