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 actincytoskeleton 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:
^ abcdPivniouk 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. PMID10712938.
^ abYablonski 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. ISBN978-0-12-022479-1. PMID11680012.
^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. PMID10477741.
^ abErdreich-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. PMID10204582. S2CID18340540.
^ abcShim 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. PMID15388330. S2CID24678709.
^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. PMID12084069.
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. PMID8661136.
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. PMID10204582. S2CID18340540.
