Transmembrane adaptor proteins are membrane-anchored proteins consisting of a short extracellular part, a transmembrane domain, and a cytoplasmic part with various protein-protein interaction motifs but lacking any enzymatic activity. They participate in the regulation of various signaling pathways by recruiting other proteins to the proximity of cellular membranes where the signaling is often initiated and propagated. In this work, we show that LST1/A, an incompletely characterized protein encoded by MHCIII locus, is a palmitoylated transmembrane adaptor protein. It is expressed specifically in leukocytes of the myeloid lineage, where it localizes to the tetraspanin-enriched microdomains. In addition, it binds SHP-1 and SHP-2 phosphatases in a phosphotyrosine-dependent manner, facilitating their recruitment to the plasma membrane. These data suggest a role for LST1/A in negative regulation of signal propagation.

Institute of Molecular Genetics Academy of Sciences of the Czech Republic 142 20 Prague Czech Republic

J Biol Chem. 2013 Sep 27;288(39):28309 PubMed

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Holzinger I., de Baey A., Messer G., Kick G., Zwierzina H., Weiss E. H. (1995) Cloning and genomic characterization of LST1: A new gene in the human TNF region. Immunogenetics 42, 315–322 PubMed

Spies T., Blanck G., Bresnahan M., Sands J., Strominger J. L. (1989) A new cluster of genes within the human major histocompatibility complex. Science 243, 214–217 PubMed

Tsuge I., Shen F. W., Steinmetz M., Boyse E. A. (1987) A gene in the H-2S:H-2D interval of the major histocompatibility complex which is transcribed in B cells and macrophages. Immunogenetics 26, 378–380 PubMed

Gruen J. R., Weissman S. M. (2001) Human MHC class III and IV genes and disease associations. Front. Biosci. 6, D960–972 PubMed

de Baey A., Fellerhoff B., Maier S., Martinozzi S., Weidle U., Weiss E. H. (1997) Complex expression pattern of the TNF region gene LST1 through differential regulation, initiation, and alternative splicing. Genomics 45, 591–600 PubMed

Rollinger-Holzinger I., Eibl B., Pauly M., Griesser U., Hentges F., Auer B., Pall G., Schratzberger P., Niederwieser D., Weiss E. H., Zwierzina H. (2000) LST1: A gene with extensive alternative splicing and immunomodulatory function. J. Immunol. 164, 3169–3176 PubMed

Raghunathan A., Sivakamasundari R., Wolenski J., Poddar R., Weissman S. M. (2001) Functional analysis of B144/LST1: A gene in the tumor necrosis factor cluster that induces formation of long filopodia in eukaryotic cells. Exp. Cell Res. 268, 230–244 PubMed

Schiller C., Nitschké M. J., Seidl A., Kremmer E., Weiss E. H. (2009) Rat monoclonal antibodies specific for LST1 proteins. Hybridoma 28, 281–286 PubMed

Mulcahy H., O'Rourke K. P., Adams C., Molloy M. G., O'Gara F. (2006) LST1 and NCR3 expression in autoimmune inflammation and in response to IFN-γ, LPS, and microbial infection. Immunogenetics 57, 893–903 PubMed

Hrdinka M., Dráber P., Stepánek O., Ormsby T., Otáhal P., Angelisová P., Brdicka T., Paces J., Horejsí V., Drbal K. (2011) PRR7 is a transmembrane adaptor protein expressed in activated T cells involved in regulation of T cell receptor signaling and apoptosis. J. Biol. Chem. 286, 19617–19629 PubMed PMC

Larkin M. A., Blackshields G., Brown N. P., Chenna R., McGettigan P. A., McWilliam H., Valentin F., Wallace I. M., Wilm A., Lopez R., Thompson J. D., Gibson T. J., Higgins D. G. (2007) Clustal W and Clustal X version 2.0. Bioinformatics 23, 2947–2948 PubMed

Brdicka T., Imrich M., Angelisová P., Brdicková N., Horváth O., Spicka J., Hilgert I., Lusková P., Dráber P., Novák P., Engels N., Wienands J., Simeoni L., Osterreicher J., Aguado E., Malissen M., Schraven B., Horejsí V. (2002) Non-T cell activation linker (NTAL): A transmembrane adaptor protein involved in immunoreceptor signaling. J. Exp. Med. 196, 1617–1626 PubMed PMC

Wan J., Roth A. F., Bailey A. O., Davis N. G. (2007) Palmitoylated proteins: Purification and identification. Nat. Protoc. 2, 1573–1584 PubMed

Horejsí V., Zhang W., Schraven B. (2004) Transmembrane adaptor proteins: Organizers of immunoreceptor signaling. Nat. Rev. Immunol. 4, 603–616 PubMed

Daëron M., Jaeger S., Du Pasquier L., Vivier E. (2008) Immunoreceptor tyrosine-based inhibition motifs: A quest in the past and future. Immunol. Rev. 224, 11–43 PubMed

Crocker P. R., Paulson J. C., Varki A. (2007) Siglecs and their roles in the immune system. Nat. Rev. Immunol. 7, 255–266 PubMed

von Gunten S., Bochner B. S. (2008) Basic and clinical immunology of Siglecs. Ann. N.Y. Acad. Sci. 1143, 61–82 PubMed PMC

Charrin S., le Naour F., Silvie O., Milhiet P. E., Boucheix C., Rubinstein E. (2009) Lateral organization of membrane proteins: Tetraspanins spin their web. Biochem. J. 420, 133–154 PubMed

Resh M. D. (2006) Palmitoylation of ligands, receptors, and intracellular signaling molecules. Sci. STKE 2006, re14. PubMed

Yáñez-Mó M., Barreiro O., Gordon-Alonso M., Sala-Valdés M., Sánchez-Madrid F. (2009) Tetraspanin-enriched microdomains: A functional unit in cell plasma membranes. Trends Cell Biol. 19, 434–446 PubMed

Brown D. A. (2006) Lipid rafts, detergent-resistant membranes, and raft targeting signals. Physiology 21, 430–439 PubMed

Draber P., Vonkova I., Stepanek O., Hrdinka M., Kucova M., Skopcova T., Otahal P., Angelisova P., Horejsi V., Yeung M., Weiss A., Brdicka T. (2011) SCIMP, a transmembrane adaptor protein involved in major histocompatibility complex class II signaling. Mol. Cell. Biol. 31, 4550–4562 PubMed PMC

Walter R. B., Häusermann P., Raden B. W., Teckchandani A. M., Kamikura D. M., Bernstein I. D., Cooper J. A. (2008) Phosphorylated ITIMs enable ubiquitylation of an inhibitory cell surface receptor. Traffic 9, 267–279 PubMed

Unkeless J. C., Jin J. (1997) Inhibitory receptors, ITIM sequences, and phosphatases. Curr. Opin. Immunol. 9, 338–343 PubMed

Staub E., Rosenthal A., Hinzmann B. (2004) Systematic identification of immunoreceptor tyrosine-based inhibitory motifs in the human proteome. Cell Signal. 16, 435–456 PubMed

Wu C., Orozco C., Boyer J., Leglise M., Goodale J., Batalov S., Hodge C. L., Haase J., Janes J., Huss J. W., 3rd, Su A. I. (2009) BioGPS: An extensible and customizable portal for querying and organizing gene annotation resources. Genome Biol. 10, R130. PubMed PMC

Benita Y., Cao Z., Giallourakis C., Li C., Gardet A., Xavier R. J. (2010) Gene enrichment profiles reveal T-cell development, differentiation, and lineage-specific transcription factors including ZBTB25 as a novel NF-AT repressor. Blood 115, 5376–5384 PubMed PMC

Paul S. P., Taylor L. S., Stansbury E. K., McVicar D. W. (2000) Myeloid-specific human CD33 is an inhibitory receptor with differential ITIM function in recruiting the phosphatases SHP-1 and SHP-2. Blood 96, 483–490 PubMed

Avril T., Floyd H., Lopez F., Vivier E., Crocker P. R. (2004) The membrane-proximal immunoreceptor tyrosine-based inhibitory motif is critical for the inhibitory signaling mediated by Siglecs-7 and -9, CD33-related Siglecs expressed on human monocytes and NK cells. J. Immunol. 173, 6841–6849 PubMed

Ulyanova T., Shah D. D., Thomas M. L. (2001) Molecular cloning of MIS, a myeloid inhibitory siglec, that binds protein-tyrosine phosphatases SHP-1 and SHP-2. J. Biol. Chem. 276, 14451–14458 PubMed

Angelisová P., Hilgert I., Horejsí V. (1994) Association of four antigens of the tetraspans family (CD37, CD53, TAPA-1, and R2/C33) with MHC class II glycoproteins. Immunogenetics 39, 249–256 PubMed

Yunta M., Lazo P. A. (2003) Tetraspanin proteins as organizers of membrane microdomains and signaling complexes. Cell Signal. 15, 559–564 PubMed

Chong Z. Z., Maiese K. (2007) The Src homology 2 domain tyrosine phosphatases SHP-1 and SHP-2: Diversified control of cell growth, inflammation, and injury. Histol. Histopathol. 22, 1251–1267 PubMed PMC

Tsui H. W., Siminovitch K. A., de Souza L., Tsui F. W. (1993) Motheaten and viable motheaten mice have mutations in the haematopoietic cell phosphatase gene. Nat. Genet. 4, 124–129 PubMed

Croker B. A., Lawson B. R., Rutschmann S., Berger M., Eidenschenk C., Blasius A. L., Moresco E. M., Sovath S., Cengia L., Shultz L. D., Theofilopoulos A. N., Pettersson S., Beutler B. A. (2008) Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88, and a microbial trigger. Proc. Natl. Acad. Sci. U.S.A. 105, 15028–15033 PubMed PMC

Tsui F. W., Martin A., Wang J., Tsui H. W. (2006) Investigations into the regulation and function of the SH2 domain-containing protein-tyrosine phosphatase, SHP-1. Immunol. Res. 35, 127–136 PubMed

Yu C. C., Tsui H. W., Ngan B. Y., Shulman M. J., Wu G. E., Tsui F. W. (1996) B and T cells are not required for the viable motheaten phenotype. J. Exp. Med. 183, 371–380 PubMed PMC

Chan R. J., Leedy M. B., Munugalavadla V., Voorhorst C. S., Li Y., Yu M., Kapur R. (2005) Human somatic PTPN11 mutations induce hematopoietic-cell hypersensitivity to granulocyte-macrophage colony-stimulating factor. Blood 105, 3737–3742 PubMed PMC

Bauler T. J., Kamiya N., Lapinski P. E., Langewisch E., Mishina Y., Wilkinson J. E., Feng G. S., King P. D. (2011) Development of severe skeletal defects in induced SHP-2-deficient adult mice: A model of skeletal malformation in humans with SHP-2 mutations. Dis. Model. Mech. 4, 228–239 PubMed PMC

An H., Zhao W., Hou J., Zhang Y., Xie Y., Zheng Y., Xu H., Qian C., Zhou J., Yu Y., Liu S., Feng G., Cao X. (2006) SHP-2 phosphatase negatively regulates the TRIF adaptor protein-dependent type I interferon and proinflammatory cytokine production. Immunity 25, 919–928 PubMed

You M., Yu D. H., Feng G. S. (1999) Shp-2 tyrosine phosphatase functions as a negative regulator of the interferon-stimulated Jak/STAT pathway. Mol. Cell. Biol. 19, 2416–2424 PubMed PMC

An alternative downstream translation start site in the non-TIR adaptor Scimp enables selective amplification of CpG DNA responses in mouse macrophages

Regulation of Inflammatory Response by Transmembrane Adaptor Protein LST1

Tetraspanins and Transmembrane Adaptor Proteins As Plasma Membrane Organizers-Mast Cell Case