Lymphocyte cytosolic protein 2

Lymphocyte cytosolic protein 2 (SH2 domain containing leukocyte protein of 76kDa), also known as LCP2 or SLP-76, is a signal-transducing adaptor protein expressed in T cells and myeloid cells and is important in the signaling of T-cell receptors (TCRs).[5][6] As an adaptor protein, SLP-76 does not have catalytic functions, primarily binding other signaling proteins to form larger signaling complexes.[7] It is a key component of the signaling pathways of receptors with immunoreceptor tyrosine-based activation motifs (ITAMs) such as T-cell receptors, its precursors, and receptors for the Fc regions of certain antibodies.[7] SLP-76 is expressed in T-cells and related lymphocytes like natural killer cells.[8]

LCP2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesLCP2, SLP-76, SLP76, lymphocyte cytosolic protein 2, IMD81
External IDsOMIM: 601603 MGI: 1321402 HomoloGene: 4065 GeneCards: LCP2
Orthologs
SpeciesHumanMouse
Entrez

3937

16822

Ensembl

ENSG00000043462

ENSMUSG00000002699

UniProt

Q13094

Q60787

RefSeq (mRNA)

NM_005565

NM_010696

RefSeq (protein)

NP_005556

NP_034826

Location (UCSC)Chr 5: 170.25 – 170.3 MbChr 11: 34 – 34.04 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure and function

The amino acid sequence of the protein has a central domain with a high concentration of prolines, as well as domains at the amino-terminal and carboxy-terminal of the amino acid sequence. The PDB file 1H3H depicts the SH3 domain of GRAP2 in complex with an RSTK-containing peptide representing residues 226–235 of SLP-76. The human and murine cDNAs both encode 533 amino acid proteins that are 72% identical and composed of three modular domains.[5] The central domain binds SRC-Homology 3 (SH3) domains of other adaptor molecules such as Grb2 and Gads. The N-terminus has an acidic region with sections for SH2-domain binding and tyrosine residues that bind the proteins Vav and Nck when phosphorylated. The C-terminus region is itself a SH2 domain and binds FYB among other proteins.[6] SLP-76 is triggered when the TCR binds its ligand by the phosphorylation of tyrosines on the N-terminus by ZAP-70, a tyrosine kinase. Along with the LAT (linker for activation of T cells) adaptor protein, SLP-76 is essential to nearly all downstream effects from T-cell receptor signals. SLP-76, LAT, and Gads together combine into protein complexes, typically with LAT at the center and SLP-76 proteins on the outside. These complexes associate into larger microclusters that activate a multitude of signaling pathways.[9][10] The proteins that bind SLP-76 are essential to the production and secretion of interleukin 2 (IL-2) and rearrangement of the actin cytoskeleton in T-cells, which is an important part of T-cell division and proliferation.[6]

Studies using SLP-76-deficient T cell lines or mice have provided strong evidence that SLP-76 plays a positive role more generally in promoting T cell development and activation, as well as mast cell and platelet function. SLP-76 is critical in the signaling from the pre-TCR that shifts T-cell developing thymocytes from the double-negative (DN) stage to the double-positive (DP) stage. Allelic exclusion of the second locus of the TCRβ chain is also dependent on signaling from the TCRβ chain that is first expressed, involving SLP-76 as a key intermediate.[6]

SLP-76 is also important in natural killer (NK) cells, in the signaling pathways of the NK cell receptors (NKRs). The SH2 domain on the C-terminus binds HPK-1, a serine-threonine kinase, and the adhesion and degranulation-promoting adaptor protein (ADAP) also known as FYB. Both these proteins are common to regular T-cells as well, but have unique downstream signaling effects in NK cells relating to their distribution across different tissues. Studies using mutations in the SH2 domain of mice show that it produces an accumulation of invariant NK cells in primary lymphoid organs like the thymus and in peripheral lymph nodes, with a simultaneous reduction of these cells in the livers and spleens.[11]

Interactions

Lymphocyte cytosolic protein 2 has been shown to interact with:

See also

References
  1. GRCh38: Ensembl release 89: ENSG00000043462 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000002699 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Entrez Gene: LCP2 lymphocyte cytosolic protein 2 (SH2 domain containing leukocyte protein of 76kDa)".
  6. Pivniouk VI, Geha RS (April 2000). "The role of SLP-76 and LAT in lymphocyte development". Current Opinion in Immunology. 12 (2): 173–178. doi:10.1016/S0952-7915(99)00068-0. PMID 10712938.
  7. Yablonski D, Weiss A (2001). Mechanisms of signaling by the hematopoietic-specific adaptor proteins, SLP-76 and LAT and their B cell counterpart, BLNK/SLP-65. Advances in Immunology. Vol. 79. pp. 93–128. doi:10.1016/S0065-2776(01)79003-7. ISBN 9780120224791. PMID 11680012.
  8. Kim HS, Long EO (July 2012). "Complementary phosphorylation sites in the adaptor protein SLP-76 promote synergistic activation of natural killer cells". Science Signaling. 5 (232): ra49. doi:10.1126/scisignal.2002754. PMC 3842037. PMID 22786724.
  9. Yablonski D (July 2019). "Bridging the Gap: Modulatory Roles of the Grb2-Family Adaptor, Gads, in Cellular and Allergic Immune Responses". Frontiers in Immunology. 10: 1704. doi:10.3389/fimmu.2019.01704. PMC 6669380. PMID 31402911.
  10. Balagopalan L, Raychaudhuri K, Samelson LE (January 2021). "Microclusters as T Cell Signaling Hubs: Structure, Kinetics, and Regulation". Frontiers in Cell and Developmental Biology. 8: 608530. doi:10.3389/fcell.2020.608530. PMC 7870797. PMID 33575254.
  11. Gerth E, Mattner J (June 2019). "The Role of Adaptor Proteins in the Biology of Natural Killer T (NKT) Cells". Frontiers in Immunology. 10: 1449. doi:10.3389/fimmu.2019.01449. PMC 6603179. PMID 31293596.
  12. Park RK, Izadi KD, Deo YM, Durden DL (September 1999). "Role of Src in the modulation of multiple adaptor proteins in FcalphaRI oxidant signaling". Blood. 94 (6): 2112–2120. doi:10.1182/blood.V94.6.2112. PMID 10477741.
  13. Erdreich-Epstein A, Liu M, Kant AM, Izadi KD, Nolta JA, Durden DL (April 1999). "Cbl functions downstream of Src kinases in Fc gamma RI signaling in primary human macrophages". Journal of Leukocyte Biology. 65 (4): 523–534. doi:10.1002/jlb.65.4.523. PMID 10204582. S2CID 18340540.
  14. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, et al. (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–1178. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514. S2CID 4427026.
  15. Ellis JH, Ashman C, Burden MN, Kilpatrick KE, Morse MA, Hamblin PA (June 2000). "GRID: a novel Grb-2-related adapter protein that interacts with the activated T cell costimulatory receptor CD28". Journal of Immunology. 164 (11): 5805–5814. doi:10.4049/jimmunol.164.11.5805. PMID 10820259.
  16. Liu SK, Fang N, Koretzky GA, McGlade CJ (January 1999). "The hematopoietic-specific adaptor protein gads functions in T-cell signaling via interactions with the SLP-76 and LAT adaptors". Current Biology. 9 (2): 67–75. doi:10.1016/S0960-9822(99)80017-7. PMID 10021361. S2CID 14131281.
  17. Asada H, Ishii N, Sasaki Y, Endo K, Kasai H, Tanaka N, et al. (May 1999). "Grf40, A novel Grb2 family member, is involved in T cell signaling through interaction with SLP-76 and LAT". The Journal of Experimental Medicine. 189 (9): 1383–1390. doi:10.1084/jem.189.9.1383. PMC 2193052. PMID 10224278.
  18. Lewitzky M, Kardinal C, Gehring NH, Schmidt EK, Konkol B, Eulitz M, et al. (March 2001). "The C-terminal SH3 domain of the adapter protein Grb2 binds with high affinity to sequences in Gab1 and SLP-76 which lack the SH3-typical P-x-x-P core motif". Oncogene. 20 (9): 1052–1062. doi:10.1038/sj.onc.1204202. PMID 11314042.
  19. Robinson A, Gibbins J, Rodríguez-Liñares B, Finan PM, Wilson L, Kellie S, et al. (July 1996). "Characterization of Grb2-binding proteins in human platelets activated by Fc gamma RIIA cross-linking". Blood. 88 (2): 522–530. doi:10.1182/blood.V88.2.522.bloodjournal882522. PMID 8695800.
  20. Hendricks-Taylor LR, Motto DG, Zhang J, Siraganian RP, Koretzky GA (January 1997). "SLP-76 is a substrate of the high affinity IgE receptor-stimulated protein tyrosine kinases in rat basophilic leukemia cells". The Journal of Biological Chemistry. 272 (2): 1363–1367. doi:10.1074/jbc.272.2.1363. PMID 8995445.
  21. Shim EK, Moon CS, Lee GY, Ha YJ, Chae SK, Lee JR (September 2004). "Association of the Src homology 2 domain-containing leukocyte phosphoprotein of 76 kD (SLP-76) with the p85 subunit of phosphoinositide 3-kinase". FEBS Letters. 575 (1–3): 35–40. doi:10.1016/j.febslet.2004.07.090. PMID 15388330. S2CID 24678709.
  22. Bunnell SC, Diehn M, Yaffe MB, Findell PR, Cantley LC, Berg LJ (January 2000). "Biochemical interactions integrating Itk with the T cell receptor-initiated signaling cascade". The Journal of Biological Chemistry. 275 (3): 2219–2230. doi:10.1074/jbc.275.3.2219. PMID 10636929.
  23. Gross BS, Lee JR, Clements JL, Turner M, Tybulewicz VL, Findell PR, et al. (February 1999). "Tyrosine phosphorylation of SLP-76 is downstream of Syk following stimulation of the collagen receptor in platelets". The Journal of Biological Chemistry. 274 (9): 5963–5971. doi:10.1074/jbc.274.9.5963. PMID 10026222.
  24. Wunderlich L, Faragó A, Downward J, Buday L (April 1999). "Association of Nck with tyrosine-phosphorylated SLP-76 in activated T lymphocytes". European Journal of Immunology. 29 (4): 1068–1075. doi:10.1002/(SICI)1521-4141(199904)29:04<1068::AID-IMMU1068>3.0.CO;2-P. PMID 10229072.
  25. Yablonski D, Kadlecek T, Weiss A (July 2001). "Identification of a phospholipase C-gamma1 (PLC-gamma1) SH3 domain-binding site in SLP-76 required for T-cell receptor-mediated activation of PLC-gamma1 and NFAT". Molecular and Cellular Biology. 21 (13): 4208–4218. doi:10.1128/MCB.21.13.4208-4218.2001. PMC 87082. PMID 11390650.
  26. Binstadt BA, Billadeau DD, Jevremović D, Williams BL, Fang N, Yi T, et al. (October 1998). "SLP-76 is a direct substrate of SHP-1 recruited to killer cell inhibitory receptors". The Journal of Biological Chemistry. 273 (42): 27518–27523. doi:10.1074/jbc.273.42.27518. PMID 9765283.
  27. Mizuno K, Katagiri T, Hasegawa K, Ogimoto M, Yakura H (August 1996). "Hematopoietic cell phosphatase, SHP-1, is constitutively associated with the SH2 domain-containing leukocyte protein, SLP-76, in B cells". The Journal of Experimental Medicine. 184 (2): 457–463. doi:10.1084/jem.184.2.457. PMC 2192711. PMID 8760799.
  28. Lindholm CK, Henriksson ML, Hallberg B, Welsh M (July 2002). "Shb links SLP-76 and Vav with the CD3 complex in Jurkat T cells". European Journal of Biochemistry. 269 (13): 3279–3288. doi:10.1046/j.1432-1033.2002.03008.x. PMID 12084069.
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Further reading
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