Lymphocyte cytosolic protein 2

Last updated
LCP2
PDB 1h3h EBI.jpg
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases LCP2 , SLP-76, SLP76, lymphocyte cytosolic protein 2, IMD81
External IDs OMIM: 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 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]

Contents

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.[ citation needed ] 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

Related Research Articles

<span class="mw-page-title-main">Platelet-derived growth factor receptor</span> Cell surface receptors

Platelet-derived growth factor receptors (PDGF-R) are cell surface tyrosine kinase receptors for members of the platelet-derived growth factor (PDGF) family. PDGF subunits -A and -B are important factors regulating cell proliferation, cellular differentiation, cell growth, development and many diseases including cancer. There are two forms of the PDGF-R, alpha and beta each encoded by a different gene. Depending on which growth factor is bound, PDGF-R homo- or heterodimerizes.

<span class="mw-page-title-main">GRB2</span> Protein-coding gene in the species Homo sapiens

Growth factor receptor-bound protein 2, also known as Grb2, is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene.

<span class="mw-page-title-main">ZAP70</span> Protein-coding gene in the species Homo sapiens

ZAP-70 is a protein normally expressed near the surface membrane of lymphocytes. It is most prominently known to be recruited upon antigen binding to the T cell receptor (TCR), and it plays a critical role in T cell signaling.

<span class="mw-page-title-main">Tyrosine-protein kinase SYK</span>

Tyrosine-protein kinase SYK, also known as spleen tyrosine kinase, is an enzyme which in humans is encoded by the SYK gene.

<span class="mw-page-title-main">ITK (gene)</span> Protein-coding gene in the species Homo sapiens

Tyrosine-protein kinase ITK/TSK also known as interleukin-2-inducible T-cell kinase or simply ITK, is a protein that in humans is encoded by the ITK gene. ITK is a member of the TEC family of kinases and is highly expressed in T cells.

<span class="mw-page-title-main">Linker for activation of T cells</span> Protein-coding gene in the species Homo sapiens

The Linker for activation of T cells, also known as linker of activated T cells or LAT, is a protein involved in the T-cell antigen receptor signal transduction pathway which in humans is encoded by the LAT gene. Alternative splicing results in multiple transcript variants encoding different isoforms.

<span class="mw-page-title-main">PIK3R1</span> Protein-coding gene in the species Homo sapiens

Phosphatidylinositol 3-kinase regulatory subunit alpha is an enzyme that in humans is encoded by the PIK3R1 gene.

<span class="mw-page-title-main">PTPN6</span> Protein-coding gene in humans

Tyrosine-protein phosphatase non-receptor type 6, also known as Src homology region 2 domain-containing phosphatase-1 (SHP-1), is an enzyme that in humans is encoded by the PTPN6 gene.

<span class="mw-page-title-main">PLCG1</span> Protein-coding gene in the species Homo sapiens

Phospholipase C, gamma 1, also known as PLCG1 and PLCgamma1, is a protein that in humans involved in cell growth, migration, apoptosis, and proliferation. It is encoded by the PLCG1 gene and is part of the PLC superfamily.

<span class="mw-page-title-main">CRKL</span> Protein-coding gene in the species Homo sapiens

Crk-like protein is a protein that in humans is encoded by the CRKL gene.

<span class="mw-page-title-main">GRB2-associated-binding protein 1</span> Protein-coding gene in the species Homo sapiens

GRB2-associated-binding protein 1 is a protein that in humans is encoded by the GAB1 gene.

<span class="mw-page-title-main">RAPGEF1</span> Protein-coding gene in the species Homo sapiens

Rap guanine nucleotide exchange factor 1 is a protein that in humans is encoded by the RAPGEF1 gene.

<span class="mw-page-title-main">VAV1</span> Human protein and coding gene

Proto-oncogene vav is a protein that in humans is encoded by the VAV1 gene.

<span class="mw-page-title-main">NCK1</span> Protein-coding gene in the species Homo sapiens

Cytoplasmic protein NCK1 is a protein that in humans is encoded by the NCK1 gene.

<span class="mw-page-title-main">B-cell linker</span> Mammalian protein found in Homo sapiens

B-cell linker (BLNK) protein is expressed in B cells and macrophages and plays a large role in B cell receptor signaling. Like all adaptor proteins, BLNK has no known intrinsic enzymatic activity. Its function is to temporally and spatially coordinate and regulate downstream signaling effectors in B cell receptor (BCR) signaling, which is important in B cell development. Binding of these downstream effectors is dependent on BLNK phosphorylation. BLNK is encoded by the BLNK gene and is also known as SLP-65, BASH, and BCA.

<span class="mw-page-title-main">GRAP2</span> Protein-coding gene in the species Homo sapiens

GRB2-related adapter protein 2 also known as GRB2-related adaptor downstream of Shc (GADS) is a 37 kDa protein that in humans is encoded by the GRAP2 gene.

<span class="mw-page-title-main">SHB (gene)</span> Protein-coding gene in the species Homo sapiens

SH2 domain-containing adapter protein B is a protein that in humans is encoded by the SHB gene.

<span class="mw-page-title-main">FYB</span> Protein-coding gene in the species Homo sapiens

FYN binding protein (FYB-120/130), also known as FYB, ADAP, and SLAP-130 is a protein that is encoded by the FYB gene in humans. The protein is expressed in T cells, monocytes, mast cells, macrophages, NK cells, but not B cells. FYB is a multifunctional protein involved in post-activation T cell signaling, lymphocyte cytokine production, cell adhesion, and actin remodeling.

<span class="mw-page-title-main">GRAP</span> Protein-coding gene in humans

GRB2-related adapter protein is a protein that in humans is encoded by the GRAP gene.

<span class="mw-page-title-main">SCIMP protein</span>

SLP65/SLP76, Csk-interacting membrane protein, termed SCIMP, belongs to family of transmembrane adaptor proteins (TRAP) which do not directly associate with a receptor, such as LAT, NTAL, LIME or LAX. SCIMP is expressed in antigen-presenting cells (APC), namely B cells, bone marrow-derived dendritic cells and macrophages.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000043462 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 "Entrez Gene: LCP2 lymphocyte cytosolic protein 2 (SH2 domain containing leukocyte protein of 76kDa)".
  6. 1 2 3 4 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. 1 2 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. ↑ 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. 1 2 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. Bibcode:1999CBio....9...67L. doi: 10.1016/S0960-9822(99)80017-7 . PMID   10021361. S2CID   14131281.
  17. 1 2 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. 1 2 3 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.
  29. ↑ 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.
  30. ↑ 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.

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