Single Kinase Substrate Peptides
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Novel Motor Phenotypes in Patients with VRK1 Mutations Without Pontocerebellar Hypoplasia
Published Ahead of Print on June 8, 2016 as 10.1212/WNL.0000000000002813 Novel motor phenotypes in patients with VRK1 mutations without pontocerebellar hypoplasia Marion Stoll, PhD* ABSTRACT * Hooiling Teoh, MBBS Objective: To describe the phenotypes in 2 families with vaccinia-related kinase 1 (VRK1)muta- * James Lee, MBBS tions including one novel VRK1 mutation. Stephen Reddel, FRACP Methods: VRK1 mutations were found by whole exome sequencing in patients presenting with Ying Zhu, PhD motor neuron disorders. Michael Buckley, VRK1 MBChB, FRCPA, PhD Results: We identified pathogenic mutations in the gene in the affected members of 2 VRK1 . Hugo Sampaio, MBBCh, families. In family 1, compound heterozygous mutations were identified in ,c.356A G; . * MPhil, FRACP p.H119R, and c.1072C T; p.R358 , in 2 siblings with adult onset distal spinal muscular atrophy VRK1 . Tony Roscioli, MBBS, (SMA). In family 2, a novel mutation, c.403G A; p.G135R and c.583T G; p.L195V, were FRACP, PhD‡ identified in a child with motor neuron disease. Michelle Farrar, MBBS, Conclusions: VRK1 mutations can produce adult-onset SMA and motor neuron disease in children FRACP, PhD‡ without pontocerebellar hypoplasia. Neurology® 2016;87:1–6 Garth Nicholson, MBBS, PhD‡ GLOSSARY ALS 5 amyotrophic lateral sclerosis; dHMN 1 PS 5 distal hereditary motor neuronopathy and pyramidal tract signs; SMA 5 spinal muscular atrophies; WES 5 whole exome sequencing. Correspondence to Dr. Garth Nicholson: The spinal muscular atrophies (SMA) are an inherited group of conditions characterized by [email protected] motor neuron loss in the spinal cord and brainstem, causing proximal and distal muscle weak- ness and atrophy. -
Defective Lymphocyte Chemotaxis in Я-Arrestin2- and GRK6-Deficient Mice
Defective lymphocyte chemotaxis in -arrestin2- and GRK6-deficient mice Alan M. Fong*, Richard T. Premont*, Ricardo M. Richardson*, Yen-Rei A. Yu†, Robert J. Lefkowitz*‡§, and Dhavalkumar D. Patel*†¶ Departments of *Medicine, ‡Biochemistry, and †Immunology, and §Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710 Contributed by Robert J. Lefkowitz, April 4, 2002 Lymphocyte chemotaxis is a complex process by which cells move kinase, extracellular receptor kinase, and c-jun terminal kinase within tissues and across barriers such as vascular endothelium and activation (9–12), they might also act as positive regulators of is usually stimulated by chemokines such as stromal cell-derived chemotaxis. To evaluate the role of the GRK-arrestin pathway factor-1 (CXCL12) acting via G protein-coupled receptors. Because in chemotaxis, we studied the chemotactic responses of lym- members of this receptor family are regulated (‘‘desensitized’’) by phocytes from -arrestin- and GRK-deficient mice toward G protein-coupled receptor kinase (GRK)-mediated receptor phos- gradients of stromal cell-derived factor 1 (CXCL12), a well  phorylation and -arrestin binding, we examined signaling and characterized chemokine whose receptor is CXCR4, a core- chemotactic responses in splenocytes derived from knockout mice ceptor for HIV. deficient in various -arrestins and GRKs, with the expectation that these responses might be enhanced. Knockouts of -arrestin2, Materials and Methods GRK5, and GRK6 were examined because all three proteins are :expressed at high levels in purified mouse CD3؉ T and B220؉ B Mice. The following mouse strains were used in this study splenocytes. CXCL12 stimulation of membrane GTPase activity was -arrestin2-deficient (back-crossed for six generations onto the unaffected in splenocytes derived from GRK5-deficient mice but C57͞BL6 background; ref. -
Combined Integrin Phosphoproteomic Analyses and Small Interfering RNA–Based Functional Screening Identify Key Regulators for Cancer Cell Adhesion and Migration
Published OnlineFirst April 7, 2009; DOI: 10.1158/0008-5472.CAN-08-2515 Published Online First on April 7, 2009 as 10.1158/0008-5472.CAN-08-2515 Research Article Combined Integrin Phosphoproteomic Analyses and Small Interfering RNA–Based Functional Screening Identify Key Regulators for Cancer Cell Adhesion and Migration Yanling Chen,1 Bingwen Lu,2 Qingkai Yang,1 Colleen Fearns,3 John R. Yates III,2 and Jiing-Dwan Lee1 Departments of 1Immunology, 2Chemical Physiology, and 3Chemistry, The Scripps Research Institute, La Jolla, California Abstract cytoskeletal components (2, 7) and regulation of cell survival, Integrins interact with extracellular matrix (ECM) and deliver proliferation, differentiation, cell cycle, and migration (8, 9). Understanding the mechanism by which integrins modulate these intracellular signaling for cell proliferation, survival, and motility. During tumor metastasis, integrin-mediated cell cellular activities is of significant biological importance. adhesion to and migration on the ECM proteins are required The most common cancers in human include breast cancer, for cancer cell survival and adaptation to the new microen- prostate cancer, lung cancer, colon cancer, and ovarian cancer (10, 11), and their metastasis is the leading cause of mortality in vironment. Using stable isotope labeling by amino acids in cell cancer patients, causing 90% of deaths from solid tumors (11, 12). culture–mass spectrometry, we profiled the phosphoproteo- During the process of metastasis, tumor cells leave the primary mic changes induced by the interactions of cell integrins with site, travel via blood and/or lymphatic circulatory systems, attach type I collagen, the most common ECM substratum. Integrin- to the substratum of ECM at a distant site, and establish a ECM interactions modulate phosphorylation of 517 serine, secondary tumor, accompanied by angiogenesis of the newly threonine, or tyrosine residues in 513 peptides, corresponding formed neoplasm (12). -
Supplementary Figure S1. Intracellular Ca2+ Levels Following Decursin Treatment in F11 Cells in the Presence of Menthol
Supplementary Figure S1. Intracellular Ca2+ levels following decursin treatment in F11 cells in the presence of menthol (A) Intracellular Ca2+ levels after treatment with decursin every 3 s. The red arrow indicates the duration of treatment with 200 μM of menthol and decursin. NC: The negative control treated with DMSO only; PC: The positive control treated with 200 μM menthol without decursin. (B) Average intracellular Ca2+ levels after treatment with decursin. The average was quantified from the normalized Δ340/380 ratio for 10 cycles after treatment with the decursin solution at the 10th cycle, as shown in Fig. 1A. The normalized Δ340/380 ratio was calculated using the following for- mula: [ratio of fluorescence intensity at 510 nm (emission) to that at 340 nm (excitation)]/[ratio of fluorescence intensity at 510 nm (emission) to that at a wavelength of 380 nm (excitation)]. Cells 2021, 10, 547. https://doi.org/10.3390/cells10030547 www.mdpi.com/journal/cells Cells 2021, 10, 547 2 of 5 Table S1. List of protein targets of decursin detected by the SwissTargetPrediction web tool Common Target Uniprot ID ChEMBL ID Target Class Probability name Poly [ADP-ribose] polymerase-1 PARP1 P09874 CHEMBL3105 Enzyme 0.104671941 N-acylsphingosine-amidohydro- NAAA Q02083 CHEMBL4349 Enzyme 0.104671941 lase Acid ceramidase ASAH1 Q13510 CHEMBL5463 Enzyme 0.104671941 Family A G protein- Neuropeptide Y receptor type 5 NPY5R Q15761 CHEMBL4561 0.104671941 coupled receptor Family A G protein- Melatonin receptor 1A MTNR1A P48039 CHEMBL1945 0.104671941 coupled -
ARTICLES Fibroblast Growth Factors 1, 2, 17, and 19 Are The
0031-3998/07/6103-0267 PEDIATRIC RESEARCH Vol. 61, No. 3, 2007 Copyright © 2007 International Pediatric Research Foundation, Inc. Printed in U.S.A. ARTICLES Fibroblast Growth Factors 1, 2, 17, and 19 Are the Predominant FGF Ligands Expressed in Human Fetal Growth Plate Cartilage PAVEL KREJCI, DEBORAH KRAKOW, PERTCHOUI B. MEKIKIAN, AND WILLIAM R. WILCOX Medical Genetics Institute [P.K., D.K., P.B.M., W.R.W.], Cedars-Sinai Medical Center, Los Angeles, California 90048; Department of Obstetrics and Gynecology [D.K.] and Department of Pediatrics [W.R.W.], UCLA School of Medicine, Los Angeles, California 90095 ABSTRACT: Fibroblast growth factors (FGF) regulate bone growth, (G380R) or TD (K650E) mutations (4–6). When expressed at but their expression in human cartilage is unclear. Here, we deter- physiologic levels, FGFR3-G380R required, like its wild-type mined the expression of entire FGF family in human fetal growth counterpart, ligand for activation (7). Similarly, in vitro cul- plate cartilage. Using reverse transcriptase PCR, the transcripts for tivated human TD chondrocytes as well as chondrocytes FGF1, 2, 5, 8–14, 16–19, and 21 were found. However, only FGF1, isolated from Fgfr3-K644M mice had an identical time course 2, 17, and 19 were detectable at the protein level. By immunohisto- of Fgfr3 activation compared with wild-type chondrocytes and chemistry, FGF17 and 19 were uniformly expressed within the showed no receptor activation in the absence of ligand (8,9). growth plate. In contrast, FGF1 was found only in proliferating and hypertrophic chondrocytes whereas FGF2 localized predominantly to Despite the importance of the FGF ligand for activation of the resting and proliferating cartilage. -
Table 2. Significant
Table 2. Significant (Q < 0.05 and |d | > 0.5) transcripts from the meta-analysis Gene Chr Mb Gene Name Affy ProbeSet cDNA_IDs d HAP/LAP d HAP/LAP d d IS Average d Ztest P values Q-value Symbol ID (study #5) 1 2 STS B2m 2 122 beta-2 microglobulin 1452428_a_at AI848245 1.75334941 4 3.2 4 3.2316485 1.07398E-09 5.69E-08 Man2b1 8 84.4 mannosidase 2, alpha B1 1416340_a_at H4049B01 3.75722111 3.87309653 2.1 1.6 2.84852656 5.32443E-07 1.58E-05 1110032A03Rik 9 50.9 RIKEN cDNA 1110032A03 gene 1417211_a_at H4035E05 4 1.66015788 4 1.7 2.82772795 2.94266E-05 0.000527 NA 9 48.5 --- 1456111_at 3.43701477 1.85785922 4 2 2.8237185 9.97969E-08 3.48E-06 Scn4b 9 45.3 Sodium channel, type IV, beta 1434008_at AI844796 3.79536664 1.63774235 3.3 2.3 2.75319499 1.48057E-08 6.21E-07 polypeptide Gadd45gip1 8 84.1 RIKEN cDNA 2310040G17 gene 1417619_at 4 3.38875643 1.4 2 2.69163229 8.84279E-06 0.0001904 BC056474 15 12.1 Mus musculus cDNA clone 1424117_at H3030A06 3.95752801 2.42838452 1.9 2.2 2.62132809 1.3344E-08 5.66E-07 MGC:67360 IMAGE:6823629, complete cds NA 4 153 guanine nucleotide binding protein, 1454696_at -3.46081884 -4 -1.3 -1.6 -2.6026947 8.58458E-05 0.0012617 beta 1 Gnb1 4 153 guanine nucleotide binding protein, 1417432_a_at H3094D02 -3.13334396 -4 -1.6 -1.7 -2.5946297 1.04542E-05 0.0002202 beta 1 Gadd45gip1 8 84.1 RAD23a homolog (S. -
Induction of Erythropoietin Increases the Cell Proliferation Rate in a Hypoxia‑Inducible Factor‑1‑Dependent and ‑Independent Manner in Renal Cell Carcinoma Cell Lines
ONCOLOGY LETTERS 5: 1765-1770, 2013 Induction of erythropoietin increases the cell proliferation rate in a hypoxia‑inducible factor‑1‑dependent and ‑independent manner in renal cell carcinoma cell lines YUTAKA FUJISUE1, TAKATOSHI NAKAGAWA2, KIYOSHI TAKAHARA1, TERUO INAMOTO1, SATOSHI KIYAMA1, HARUHITO AZUMA1 and MICHIO ASAHI2 Departments of 1Urology and 2Pharmacology, Faculty of Medicine, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan Received November 28, 2012; Accepted February 25, 2013 DOI: 10.3892/ol.2013.1283 Abstract. Erythropoietin (Epo) is a potent inducer of erythro- Introduction poiesis that is mainly produced in the kidney. Epo is expressed not only in the normal kidney, but also in renal cell carcinomas Erythropoietin (Epo) is a 30-kDa glycoprotein that functions (RCCs). The aim of the present study was to gain insights as an important cytokine in erythrocytes. Epo is usually into the roles of Epo and its receptor (EpoR) in RCC cells. produced by stromal cells of the adult kidney cortex or fetal The study used two RCC cell lines, Caki-1 and SKRC44, in liver and then released into the blood, with its production which Epo and EpoR are known to be highly expressed. The initially induced by hypoxia or hypotension (1-5). In the bone proliferation rate and expression level of hypoxia-inducible marrow, Epo binds to the erythropoietin receptor (EpoR) factor-1α (HIF-1α) were measured prior to and following expressed in erythroid progenitor cells or undifferentiated Epo treatment and under normoxic and hypoxic conditions. erythroblasts, which induces signal transduction mechanisms To examine whether HIF-1α or Epo were involved in cellular that protect the undifferentiated erythrocytes from apoptosis proliferation during hypoxia, these proteins were knocked and promote their proliferation and differentiation. -
Protein Identities in Evs Isolated from U87-MG GBM Cells As Determined by NG LC-MS/MS
Protein identities in EVs isolated from U87-MG GBM cells as determined by NG LC-MS/MS. No. Accession Description Σ Coverage Σ# Proteins Σ# Unique Peptides Σ# Peptides Σ# PSMs # AAs MW [kDa] calc. pI 1 A8MS94 Putative golgin subfamily A member 2-like protein 5 OS=Homo sapiens PE=5 SV=2 - [GG2L5_HUMAN] 100 1 1 7 88 110 12,03704523 5,681152344 2 P60660 Myosin light polypeptide 6 OS=Homo sapiens GN=MYL6 PE=1 SV=2 - [MYL6_HUMAN] 100 3 5 17 173 151 16,91913397 4,652832031 3 Q6ZYL4 General transcription factor IIH subunit 5 OS=Homo sapiens GN=GTF2H5 PE=1 SV=1 - [TF2H5_HUMAN] 98,59 1 1 4 13 71 8,048185945 4,652832031 4 P60709 Actin, cytoplasmic 1 OS=Homo sapiens GN=ACTB PE=1 SV=1 - [ACTB_HUMAN] 97,6 5 5 35 917 375 41,70973209 5,478027344 5 P13489 Ribonuclease inhibitor OS=Homo sapiens GN=RNH1 PE=1 SV=2 - [RINI_HUMAN] 96,75 1 12 37 173 461 49,94108966 4,817871094 6 P09382 Galectin-1 OS=Homo sapiens GN=LGALS1 PE=1 SV=2 - [LEG1_HUMAN] 96,3 1 7 14 283 135 14,70620005 5,503417969 7 P60174 Triosephosphate isomerase OS=Homo sapiens GN=TPI1 PE=1 SV=3 - [TPIS_HUMAN] 95,1 3 16 25 375 286 30,77169764 5,922363281 8 P04406 Glyceraldehyde-3-phosphate dehydrogenase OS=Homo sapiens GN=GAPDH PE=1 SV=3 - [G3P_HUMAN] 94,63 2 13 31 509 335 36,03039959 8,455566406 9 Q15185 Prostaglandin E synthase 3 OS=Homo sapiens GN=PTGES3 PE=1 SV=1 - [TEBP_HUMAN] 93,13 1 5 12 74 160 18,68541938 4,538574219 10 P09417 Dihydropteridine reductase OS=Homo sapiens GN=QDPR PE=1 SV=2 - [DHPR_HUMAN] 93,03 1 1 17 69 244 25,77302971 7,371582031 11 P01911 HLA class II histocompatibility antigen, -
Circrna LRIG3 Knockdown Inhibits Hepatocellular Carcinoma Progression by Regulating Mir-223-3P and MAPK/ERK Pathway
CircRNA LRIG3 knockdown inhibits hepatocellular carcinoma progression by regulating miR-223-3p and MAPK/ERK pathway Type Research paper Keywords hepatocellular carcinoma, miR-223-3p, circ_LRIG3, MAP2K6, MAPK/ERK pathway Abstract Introduction Emerging evidence suggests that circular RNAs (circRNAs) play critical roles in tumorigenesis. However, the roles and molecular mechanisms of circRNA leucine-rich repeat immunoglobulin domain-containing protein 3 (circ_LRIG3) in hepatocellular carcinoma (HCC) has not been investigated. Material and methods The expression levels of circ_LRIG3, miR-223-3p, and mitogen-activated protein kinase kinase 6 (MAP2K6) were determined by qRT-PCR. Flow cytometry was applied to determine the cell cycle distribution and apoptosis. Cell proliferation, migration and invasion were assessed by MTT, colony formation, and transwell assays. Western blot assay was employed to measure the protein levels of the snail, E-cadherin, MAP2K6, mitogen-activated protein kinase (MAPK), phospho-MAPK (p- MAPK), extracellular signal-regulated kinases (ERKs), and phospho-ERKs (p- ERKs). The relationship between miR-223-3p and circ_LRIG3 or MAP2K6 was predicted by bioinformatics tools and verified by dual-luciferase reporter assay. A xenograft tumor model was established to confirm the functions of circ_LRIG3 in vivo. Results Preprint Circ_LRIG3 and MAP2K6 expression were enhanced while miR-223-3p abundance was reduced in HCC tissues and cells. Knockdown of circ_LRIG3 inhibited cell proliferation, metastasis, and increasing apoptosis. MiR-223-3p was a target of circ_LRIG3, and its downregulation reversed the inhibitory effect of circ_LRIG3 knockdown on the progression of HCC cells. Moreover, MAP2K6 could bind to miR-223-3p, and MAP2K6 upregulation also abolished the suppressive impact of circ_LRIG3 interference on progression of HCC cells. -
Age, DNA Methylation and the Malignant Potential of the Serrated Neoplasia Pathway Lochlan John Fennell B
Age, DNA Methylation and the Malignant Potential of the Serrated Neoplasia Pathway Lochlan John Fennell B. Biomed Sci A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2020 Faculty of Medicine ORC ID: 0000-0003-3214-3527 1 Abstract Colorectal cancer is the third most common cancer in Australia and is responsible for the death of over four thousand Australians each year. There are two overarching molecular pathways leading to colorectal cancer. The conventional pathway, which is responsible for ~75% of colorectal cancer diagnoses, occurs in a step-wise manner and is the consequence of a series of genetic alterations including mutations of tumour suppressor genes and gross chromosomal abnormalities. This pathway has been extensively studied over the past three decades. The serrated neoplasia pathway is responsible for the remaining colorectal cancers. This pathway is triggered by oncogenic BRAF mutation and these cancers accumulate epigenetic alterations while progressing to invasive cancer. DNA methylation is important in serrated neoplasia, however the extent and role of DNA methylation on the initiation and progression of serrated lesions is not clear. DNA methylation accumulates in tissues with age, and advanced serrated lesions and cancers occur almost exclusively in elderly patients. How this methylation affects serrated lesions is unknown. In this thesis I set out to address three key research questions related to DNA methylation, age and serrated colorectal neoplasia. First, what is the extent of DNA methylation in colorectal cancers?; Second, Does age-related hypermethylation, and namely that occurring at the loci encoding tumour suppressor genes, increase the risk of serrated colorectal neoplasia?; and if true, how can we reconcile this with the existence of early onset serrated colorectal cancer? In the first chapter of this thesis, I examine the DNA methylation and transcriptional architecture of 216 colorectal cancer samples collected consecutively at the Royal Brisbane and Women’s hospital. -
Targeted Erythropoietin Selectively Stimulates Red Blood Cell Expansion in Vivo
Targeted erythropoietin selectively stimulates red blood cell expansion in vivo Devin R. Burrilla, Andyna Verneta, James J. Collinsa,b,c,d, Pamela A. Silvera,e,1, and Jeffrey C. Waya aWyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115; bSynthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139; cInstitute for Medical Engineering & Science, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; dBroad Institute of MIT and Harvard, Cambridge, MA 02139; and eDepartment of Systems Biology, Harvard Medical School, Boston, MA 02115 Edited by Ronald A. DePinho, University of Texas MD Anderson Cancer Center, Houston, TX, and approved March 30, 2016 (received for review December 23, 2015) The design of cell-targeted protein therapeutics can be informed peptide linker that permits simultaneous binding of both elements by natural protein–protein interactions that use cooperative phys- to the same cell surface. The targeting element anchors the mu- ical contacts to achieve cell type specificity. Here we applied this tated activity element to the desired cell surface (Fig. 1A, Middle), approach in vivo to the anemia drug erythropoietin (EPO), to direct thereby creating a high local concentration and driving receptor its activity to EPO receptors (EPO-Rs) on red blood cell (RBC) pre- binding despite the mutation (Fig. 1A, Bottom). Off-target sig- cursors and prevent interaction with EPO-Rs on nonerythroid cells, naling should be minimal (Fig. 1B) and should decrease in pro- such as platelets. Our engineered EPO molecule was mutated to portion to the mutation strength. weaken its affinity for EPO-R, but its avidity for RBC precursors Here we tested the chimeric activator strategy in vivo using was rescued via tethering to an antibody fragment that specifi- erythropoietin (EPO) as the drug to be targeted. -
Immunohistochemical Expression of Erythropoietin in Invasive Breast Carcinoma with Metastasis to Lymph Nodes
Review and Research on Cancer Treatment Volume 4, Issue 1 (2018) ISSN 2544-2147 Immunohistochemical expression of erythropoietin in invasive breast carcinoma with metastasis to lymph nodes Maksimiuk M.* Students' Scientific Organization at the Medical University of Warsaw, Oczki 1a, 02-007 Warsaw Sobiborowicz A. Students' Scientific Organization at the Medical University of Warsaw, Oczki 1a, 02-007 Warsaw Sobieraj M. Students' Scientific Organization at the Medical University of Warsaw, Oczki 1a, 02-007 Warsaw Liszcz A. Students' Scientific Organization at the Medical University of Warsaw, Oczki 1a, 02-007 Warsaw Sobol M. Department of Biophysics and Human Physiology, Medical University of Warsaw, Chałubińskiego 5, 02-004 Warsaw Patera J. Department of Pathomorphology, Military Institute of Health Services, Warsaw, Poland Badowska-Kozakiewicz A.M. Department of Biophysics and Human Physiology, Medical University of Warsaw, Chałubińskiego 5, 02-004 Warsaw *corresponding author: Marta Maksimiuk, Department of Biophysics and Human Physiology, Medical University of Warsaw, Chałubińskiego 5, 02-004 Warsaw, [email protected], tel: 691 – 230 – 268 Abstract: Introduction: Tumor characteristics, such as size, lymph node status, histological type of the neoplasm and its grade, are well known prognostic factors in breast cancer. The ongoing search for new prognostic factors include Bcl2, Bax, Cox-2 or HIF1- alpha, which plays a key role in phenomenon of tumor hypoxia and might induce transcription of the EPO gene. Erythropoietin may influence lymph node metastasis or stimulate tumor progression, thus it seemed interesting to determine its expression in invasive breast cancers with lymph node metastases presenting different basic immunohistochemical profiles (ER, PR, HER2). Aim: To evaluate the relationship between histological grade, tumor size, lymph node status, expression of ER, PR, HER2 and immunohistochemical expression of erythropoietin in invasive breast cancer with metastasis to lymph nodes.