Lymphocyte cytosolic protein 2

LCP2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1H3H, 1YWO, 2EAP, 2ROR
Identifiers
Aliases	LCP2 , SLP-76, SLP76, lymphocyte cytosolic protein 2, IMD81
External IDs	OMIM: 601603; MGI: 1321402; HomoloGene: 4065; GeneCards: LCP2; OMA:LCP2 - orthologs
Gene location (Human) Chr. Chromosome 5 (human) [1] Band 5q35.1 Start 170,246,233 bp [1] End 170,297,815 bp [1]
Gene location (Mouse) Chr. Chromosome 11 (mouse) [2] Band 11|11 A4 Start 33,996,920 bp [2] End 34,042,295 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in monocyte granulocyte blood bone marrow cells spleen appendix lymph node upper lobe of left lung gallbladder thymus Top expressed in granulocyte thymus stroma of bone marrow mesenteric lymph nodes spleen blood zygote tibiofemoral joint secondary oocyte body of femur More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding Cellular component cytoplasm cytosol TCR signalosome cell-cell junction plasma membrane raft Biological process platelet activation mast cell activation Fc-epsilon receptor signaling pathway positive regulation of protein kinase activity intracellular signal transduction T cell receptor signaling pathway immune response transmembrane receptor protein tyrosine kinase signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 Mb Chr 11: 34 – 34.04 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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]

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. ^[9] 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. ^{[10] [11]} 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. ^[12]

Interactions

Lymphocyte cytosolic protein 2 has been shown to interact with:

• Cbl gene, ^{[13] [14]}
• GRAP2, ^{[15] [16] [17] [18]}
• Grb2, ^{[14] [18] [19] [20] [21]}
• ITK ^{[22] [23]}
• LYN, ^[24]
• NCK1, ^{[22] [25]}
• PIK3R1, ^[22]
• PLCG1, ^[26]
• PTPN6, ^{[27] [28]}
• SHB, ^[29] and
• VAV1. ^{[30] [31]}

See also

• Activation

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   978-0-12-022479-1. 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. Structural Basis for Specific Binding of the Gads SH3 Domain to an RxxK Motif-Containing SLP-76 Peptide https://doi.org/10.1016/S1097-2765(03)00046-7
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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. Bibcode:1999CBio....9...67L. doi: 10.1016/S0960-9822(99)80017-7 . PMID   10021361. S2CID   14131281.
18. 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.
19. 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.
20. 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.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.
26. 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.
27. 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.
28. 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.
29. 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.
30. Raab M, da Silva AJ, Findell PR, Rudd CE (February 1997). "Regulation of Vav-SLP-76 binding by ZAP-70 and its relevance to TCR zeta/CD3 induction of interleukin-2". Immunity. 6 (2): 155–164. doi: 10.1016/S1074-7613(00)80422-7 . PMID   9047237.
31. Onodera H, Motto DG, Koretzky GA, Rothstein DM (September 1996). "Differential regulation of activation-induced tyrosine phosphorylation and recruitment of SLP-76 to Vav by distinct isoforms of the CD45 protein-tyrosine phosphatase". The Journal of Biological Chemistry. 271 (36): 22225–22230. doi: 10.1074/jbc.271.36.22225 . PMID   8703037.

Further reading

• Jackman JK, Motto DG, Sun Q, Tanemoto M, Turck CW, Peltz GA, et al. (March 1995). "Molecular cloning of SLP-76, a 76-kDa tyrosine phosphoprotein associated with Grb2 in T cells". The Journal of Biological Chemistry. 270 (13): 7029–7032. doi: 10.1074/jbc.270.13.7029 . PMID   7706237.
• Sunden SL, Carr LL, Clements JL, Motto DG, Koretzky GA (July 1996). "Polymorphism in and localization of the gene LCP2 (SLP-76) to chromosome 5q33.1-qter". Genomics. 35 (1): 269–270. doi:10.1006/geno.1996.0354. PMID   8661136.
• Motto DG, Ross SE, Wu J, Hendricks-Taylor LR, Koretzky GA (April 1996). "Implication of the GRB2-associated phosphoprotein SLP-76 in T cell receptor-mediated interleukin 2 production". The Journal of Experimental Medicine. 183 (4): 1937–1943. doi:10.1084/jem.183.4.1937. PMC   2192521 . PMID   8666952.
• Bubeck Wardenburg J, Fu C, Jackman JK, Flotow H, Wilkinson SE, Williams DH, et al. (August 1996). "Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function". The Journal of Biological Chemistry. 271 (33): 19641–19644. doi: 10.1074/jbc.271.33.19641 . PMID   8702662.
• Onodera H, Motto DG, Koretzky GA, Rothstein DM (September 1996). "Differential regulation of activation-induced tyrosine phosphorylation and recruitment of SLP-76 to Vav by distinct isoforms of the CD45 protein-tyrosine phosphatase". The Journal of Biological Chemistry. 271 (36): 22225–22230. doi: 10.1074/jbc.271.36.22225 . PMID   8703037.
• 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.
• Raab M, da Silva AJ, Findell PR, Rudd CE (February 1997). "Regulation of Vav-SLP-76 binding by ZAP-70 and its relevance to TCR zeta/CD3 induction of interleukin-2". Immunity. 6 (2): 155–164. doi: 10.1016/S1074-7613(00)80422-7 . PMID   9047237.
• Musci MA, Hendricks-Taylor LR, Motto DG, Paskind M, Kamens J, Turck CW, Koretzky GA (May 1997). "Molecular cloning of SLAP-130, an SLP-76-associated substrate of the T cell antigen receptor-stimulated protein tyrosine kinases". The Journal of Biological Chemistry. 272 (18): 11674–11677. doi: 10.1074/jbc.272.18.11674 . PMID   9115214.
• da Silva AJ, Li Z, de Vera C, Canto E, Findell P, Rudd CE (July 1997). "Cloning of a novel T-cell protein FYB that binds FYN and SH2-domain-containing leukocyte protein 76 and modulates interleukin 2 production". Proceedings of the National Academy of Sciences of the United States of America. 94 (14): 7493–7498. Bibcode:1997PNAS...94.7493D. doi: 10.1073/pnas.94.14.7493 . PMC   23849 . PMID   9207119.
• Fu C, Chan AC (October 1997). "Identification of two tyrosine phosphoproteins, pp70 and pp68, which interact with phospholipase Cgamma, Grb2, and Vav after B cell antigen receptor activation". The Journal of Biological Chemistry. 272 (43): 27362–27368. doi: 10.1074/jbc.272.43.27362 . PMID   9341187.
• Zhang W, Sloan-Lancaster J, Kitchen J, Trible RP, Samelson LE (January 1998). "LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation". Cell. 92 (1): 83–92. doi: 10.1016/S0092-8674(00)80901-0 . PMID   9489702. S2CID   1806525.
• Fu C, Turck CW, Kurosaki T, Chan AC (July 1998). "BLNK: a central linker protein in B cell activation". Immunity. 9 (1): 93–103. doi: 10.1016/S1074-7613(00)80591-9 . PMID   9697839.
• Chu J, Liu Y, Koretzky GA, Durden DL (September 1998). "SLP-76-Cbl-Grb2-Shc interactions in FcgammaRI signaling". Blood. 92 (5): 1697–1706. doi:10.1182/blood.V92.5.1697. PMID   9716598.
• 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.
• 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. Bibcode:1999CBio....9...67L. doi: 10.1016/S0960-9822(99)80017-7 . PMID   10021361. S2CID   14131281.
• 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.
• 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.
• 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.
• 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.
• Gross BS, Melford SK, Watson SP (August 1999). "Evidence that phospholipase C-gamma2 interacts with SLP-76, Syk, Lyn, LAT and the Fc receptor gamma-chain after stimulation of the collagen receptor glycoprotein VI in human platelets". European Journal of Biochemistry. 263 (3): 612–623. doi: 10.1046/j.1432-1327.1999.00560.x . PMID   10469124.

External links

• SLP-76+signal+Transducing+adaptor+proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)