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A Comprehensive Proteomics and Genomics Analysis Reveals Novel Supplemental Material can be found at: http://www.mcponline.org/cgi/content/full/D600007-MCP200/ DC1 Dataset A Comprehensive Proteomics and Genomics Analysis Reveals Novel Transmembrane Proteins in Human Platelets and Mouse Megakaryocytes Including G6b-B, a Novel Immunoreceptor Tyrosine-based Inhibitory Motif Protein*□S Yotis A. Senis‡§, Michael G. Tomlinson‡¶, A´ ngel Garcíaʈ**, Stephanie Dumon‡, Victoria L. Heath‡, John Herbert‡, Stephen P. Cobbold‡‡, Jennifer C. Spalton‡, Sinem Ayman§§, Robin Antrobusʈ, Nicole Zitzmannʈ, Roy Bicknell‡, Jon Frampton‡, Downloaded from Kalwant S. Authi§§, Ashley Martin¶¶, Michael J. O. Wakelam¶¶, and Stephen P. Watson‡ʈʈ The platelet surface is poorly characterized due to the low tance of mutant mouse models in establishing protein abundance of many membrane proteins and the lack of function in platelets. This approach identified all of the www.mcponline.org specialist tools for their investigation. In this study we major classes of platelet transmembrane receptors, in- identified novel human platelet and mouse megakaryocyte cluding multitransmembrane proteins. Strikingly 17 of the membrane proteins using specialist proteomics and 25 most megakaryocyte-specific genes (relative to 30 genomics approaches. Three separate methods were used other serial analysis of gene expression libraries) were to enrich platelet surface proteins prior to identification by transmembrane proteins, illustrating the unique nature of liquid chromatography and tandem mass spectrometry: the megakaryocyte/platelet surface. The list of novel by Yotis Senis on April 2, 2007 lectin affinity chromatography, biotin/NeutrAvidin affinity plasma membrane proteins identified using proteomics chromatography, and free flow electrophoresis. Many includes the immunoglobulin superfamily member G6b, known, abundant platelet surface transmembrane pro- which undergoes extensive alternate splicing. Specific teins and several novel proteins were identified using antibodies were used to demonstrate expression of the each receptor enrichment strategy. In total, two or more G6b-B isoform, which contains an immunoreceptor ty- unique peptides were identified for 46, 68, and 22 surface rosine-based inhibition motif. G6b-B undergoes tyrosine membrane, intracellular membrane, and membrane pro- phosphorylation and association with the SH2 domain- teins of unknown subcellular localization, respectively. containing phosphatase, SHP-1, in stimulated platelets The majority of these were single transmembrane pro- suggesting that it may play a novel role in limiting platelet teins. To complement the proteomics studies, we ana- activation. Molecular & Cellular Proteomics 6:548–564, lyzed the transcriptome of a highly purified preparation of 2007. mature primary mouse megakaryocytes using serial anal- ysis of gene expression in view of the increasing impor- Platelets are small anucleate cells that circulate in the blood From the ‡Centre for Cardiovascular Sciences, Institute of Biomed- in a quiescent state. Their primary physiological function is to ical Research, University of Birmingham, Wolfson Drive, Edgbaston, stop bleeding from sites of vascular injury by adhering to and Birmingham B15 2TT, United Kingdom, ʈOxford Glycobiology Insti- forming aggregates on exposed extracellular matrix proteins tute, Department of Biochemistry, University of Oxford, South Parks following blood vessel damage (1, 2). The platelet aggregate or Road, Oxford OX1 3QU, United Kingdom, ‡‡Therapeutic Immunology “primary hemostatic plug” is consolidated by fibrin polymers Group, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, United Kingdom, §§Cardiovas- produced by thrombin generated on the platelet surface (3). cular Division, New Hunts House, King’s College London, London Platelets express a diverse repertoire of surface receptors SE1 1UL, United Kingdom, and ¶¶Division of Cancer Studies, Uni- that allow them to respond to different stimuli and adhere to a versity of Birmingham, Vincent Drive, Edgbaston, Birmingham variety of surfaces. The expression levels of platelet surface B15 2TT, United Kingdom receptors vary widely with the most abundant being the inte- Received, January 12, 2006, and in revised form, December 12, ␣ ␤ 2006 grin IIb 3, which is essential for platelet aggregation. Quies- Published, MCP Papers in Press, December 23, 2006, DOI cent human platelets express 40,000–80,000 copies of 10.1074/mcp.D600007-MCP200 ␣IIb␤3 on their surface, which increases by 30–50% upon 548 Molecular & Cellular Proteomics 6.3 © 2007 by The American Society for Biochemistry and Molecular Biology, Inc. This paper is available on line at http://www.mcponline.org Platelet and Megakaryocyte Transmembrane Proteins platelet activation (4). In contrast, the ADP receptor P2Y1 is contain very high levels of mRNA that includes transcripts for among the least abundant with quiescent human platelets all platelet proteins as illustrated by Kim et al. (23) who used expressing ϳ150 copies on their surface (5). SAGE to analyze mRNA in megakaryocytes derived from hu- To fully understand how platelets respond to vessel wall man cord blood CD34ϩ cells. damage we require a comprehensive knowledge of the recep- In this study, we used several membrane protein enrich- tors expressed on their surface. Several novel platelet recep- ment techniques, namely lectin and biotin/NeutraAvidin (NA) tors have been identified in recent years, including the lectin affinity chromatography and free flow electrophoresis in com- receptor CLEC-2 (6); CD40L (7); Eph kinases and their coun- bination with LC-MS/MS to identify novel receptors in human ter-receptors, ephrins (8, 9); cadherins (10); Toll receptors 2, platelets. We also performed LongSAGE on a population of 4, and 9 (11, 12); and the single pass transmembrane natri- well characterized, highly purified mature murine megakaryo- uretic peptide receptor type C (13). These findings suggest cytes (24). The 21-base pair long LongSAGE sequence tags that platelets may express additional receptors that have have the advantage over the 14-base pair tags of standard important roles in modulating their function. SAGE in providing more reliable detection of greater than Proteomics-based approaches have been used to explore 99% of all expressed genes (25). Moreover SAGE provides a the platelet proteome in its entirety (14–16) as well as sub- quantitative measure of mRNA expression unlike DNA mi- proteomes, including the phosphoproteome of thrombin-ac- croarrays (26). We chose to use megakaryocytes rather than tivated platelets (17–19) and the platelet releasate (20). One platelets as the source of RNA to minimize contamination Downloaded from class of proteins conspicuously under-represented in the from other cells and to limit the contribution of mitochondrially early platelet proteomics studies were transmembrane pro- derived mRNA (see above). A major advantage of using teins. This reflects the relatively low abundance of these pro- mouse rather than human megakaryocytes is with regard to teins and also technical difficulties associated with solubiliz- the widespread use of mouse models for functional studies, ing and resolving transmembrane proteins in some of the especially as SAGE analysis of mouse megakaryocytes has www.mcponline.org above techniques, most notably two-dimensional gel electro- not been reported. In this study, Ͼ80% of transmembrane phoresis. More recently, Sickmann and co-workers (21) have proteins identified in human platelets using proteomics were characterized the platelet membrane proteome using a com- also present in the mouse megakaryocyte LongSAGE library, bination of density gradient centrifugation and one-dimen- thereby validating this approach. In total, the present study sional gel electrophoresis (1-DE),1 and 16-benzyldimethyl-n- reports the identification of 136 transmembrane proteins in hexadecylammonium chloride (16-BAC)/SDS-PAGE. This human platelets based on the identification of two or more by Yotis Senis on April 2, 2007 group reported the identification of 83 plasma membrane unique peptide hits of which just under 100 have yet to be proteins and 48 proteins localized to other membrane studied in platelets using biochemical or functional means. compartments. Determination of the functional roles of these proteins will The application of molecular techniques to analyze ex- enable the further understanding of platelet regulation and pressed genes in platelets is fraught with difficulties because may identify novel targets for development of new types of of the lack of a nucleus and the very low levels of mRNA that antiplatelet agents. are carried over from the megakaryocyte. Thus contamination with mRNA from other cell types is a major issue of concern. EXPERIMENTAL PROCEDURES Furthermore only 11% of platelet mRNA appears to be de- Materials—N-Acetyl-D-glucosamine and propidium iodide were rived from genomic DNA; the majority is derived from mito- from Sigma. Wheat germ agglutinin (WGA) conjugated to Sepharose chondrial genes as demonstrated by serial analysis of gene 4B and unconjugated Sepharose 4B beads were from Amersham expression (SAGE) (22). These problems can be overcome to Biosciences. Amicon Centriprep YM-10 and Ultrafree 0.5 centrifugal a large extent by use of a highly purified, mature population of filter devices were from Millipore Corp. (Bedford, MA). EZ-link sulfo- succinimidyl-2-(biotinamido)ethyl-1,3-dithiopropionate (sulfo-NHS- the platelet precursor cell, the megakaryocyte.
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