Disease relevance of Lsp1

• This study examines LSP1-deficient (Lsp1(-/-)) mice for the development of myeloid and lymphocytic cell populations and their response to the development of peritonitis induced by thioglycollate (TG) and to a T-dependent antigen [1].
• When the putative coding region of p50 cDNA was expressed in E. coli, the product showed an apparent molecular mass of 50 kDa on SDS-PAGE [2].
• A lymphocyte-specific protein-tyrosine kinase gene is rearranged and overexpressed in the murine T cell lymphoma LSTRA [3].
• SAP (SLAM-associated protein) is a small lymphocyte-specific signalling molecule that is defective or absent in patients with X-linked lymphoproliferative syndrome (XLP) [4].
• The MPC11 LTRs were five- to sixfold more active than an LS cDNA LTR when tested for promoter activity by transfection into plasmacytoma cells [5].

High impact information on Lsp1

• Ikaros proteins are required for normal T, B, and NK cell development and are postulated to activate lymphocyte-specific gene expression [6].
• Thus, there are lymphocyte-specific, developmentally regulated requirements for alpha4 integrins in hematopoiesis in the bone marrow [7].
• p56lck, a lymphocyte-specific member of the src family of cytoplasmic protein-tyrosine kinases, is associated noncovalently with the cell surface glycoproteins CD4 and CD8, which are expressed on functionally distinct subpopulations of T cells [8].
• We report our evaluation of the possible involvement of the lymphocyte-specific tyrosine kinase p56lck in these transduction pathways [9].
• Replacing the lymphocyte-specific IgH enhancer with a viral enhancer did not affect tissue specificity of mu Ig gene expression [10].

Chemical compound and disease context of Lsp1

• Studies with three independent sets of well-characterized parental CD45+, mutant CD45-, and revertant CD45+ lymphoma cell lines indicate that loss of CD45 increases the phosphorylation of the src-related leukocyte-specific tyrosine protein kinase p56lck on tyrosine-505, a putative negative regulatory site [11].
• Here we report that approximately 10% of the total intracellular LSP1 protein is associated with the Nonidet P-40 insoluble cytoskeleton of the mIgM+, mIgD+ B lymphoma cell line BAL17 [12].
• Here we develop a novel high-throughput assay by allowing a chemical library to compete with phage display peptide binding and identify a novel small-molecule ligand to the leukocyte-specific alpha(M)beta(2) integrin [13].
• Earlier studies from this laboratory suggested that higher homologues in a series could have greater affinity for system L. A higher homologue of BCH, 2-aminobicyclo[3.2.1]octane-2-carboxylic acid (ABOCA), has been synthesized and studied as a substrate and competitor for amino acid transport systems of the sarcoma 37 (S37) ascites cell [14].
• Preabsorption of the cell extract prior to immunoprecipitation with an excess of formalin-fixed Staphylococcus aureus, complexed with preimmune normal rabbit serum IgG, specifically removed the kinase phosphorylating p50 [15].

Biological context of Lsp1

• Consistent with altered endothelial function was a reduction in vascular permeability to histamine in Lsp1-/- animals [16].
• On injection of TG, the Lsp1(-/-) mice exhibit an accelerated kinetics of changes in peritoneal macrophage and neutrophil numbers as compared to wt including increased influx of these cells [1].
• In vitro chemotaxis experiments performed by time-lapse videomicroscopy showed that purified Lsp1(-/-) bone-marrow neutrophils exhibit an increased migration rate toward a gradient of fMLP as compared with wild-type neutrophils [17].
• Here we report the genomic organization of the Lsp1 gene and show that the distinct N termini of LSP1 and S37 are encoded by two alternatively used exons, each containing a translational start codon [18].
• The mouse Lsp1 and Tnnt3 genes are 4.3 kb apart on distal mouse chromosome 7 [19].

Anatomical context of Lsp1

• The level of peritoneal lymphocytes is decreased in Lsp1(-/-) mice without affecting a particular lymphocytic subset [1].
• Lsp1(-/-) mice exhibit significantly higher levels of resident macrophages in the peritoneum compared to wild-type (wt) mice, whereas the development of myeloid cells is normal [1].
• Using LSP1-deficient (Lsp1(-/-)) mice, we show increased neutrophil migration into mouse knee joints during zymosan-induced acute inflammation, an inflammatory model in which the number of resident synoviocytes are not affected by LSP1-deficiency [17].
• We used the LSP1+ B-lymphoma cell line WEHI-231/89 and normal lipopolysaccharide treated immature B-cells from Lsp1-/- and wild type mice to determine a role for LSP1 in signaling through membrane IgM [20].
• A new lymphocyte-specific gene which encodes a putative Ca2+-binding protein is not expressed in transformed T lymphocyte lines [21].

Associations of Lsp1 with chemical compounds

• These results suggest that p50 may have some function, which is regulated through serine/threonine phosphorylation and the intracellular Ca2+ concentration, downstream of the phosphoinositide signaling system in the T cell activation cascade [22].
• The phosphorylation of p50 was also stimulated by a protein kinase C activator, phorbol myristate acetate (PMA), but not by a calcium ionophore, A23187 [22].
• The recombinant p50 was phosphorylated in vitro by rabbit protein kinase C (PKC) and by murine cytosolic protein kinase, that was activated by a combination of phosphatidylserine and diacylglycerol [2].
• Low expression of the Lsp1 gene in early mouse T-lymphomas induced by N-methyl-N-nitrosourea [23].
• LSP1(-) neutrophils demonstrate an enhanced chemotactic response in vitro to N-formyl methionyl-leucyl-phenylalanine (FMLP) and to the C-X-C chemokine, KC, indicating that their enhanced influx into the peritoneum may be a result of increased motility [1].

Physical interactions of Lsp1

• B lymphocyte-specific protein binding near an immunoglobulin kappa-chain gene J segment [24].
• The lymphocyte-specific protein tyrosine kinase p56lck participates in T cell signaling through functional interactions with components of the T cell antigen receptor complex and the interleukin-2 receptor [25].

Regulatory relationships of Lsp1

• In adult mice, Ets-1 is expressed predominantly in lymphoid cells where it has been implicated in regulating transcription of lymphocyte-specific genes [26].
• Gads functions to couple the activated TCR to distal signaling events through its interactions with the leukocyte-specific signaling proteins SLP-76 (SH2 domain-containing leukocyte protein of 76 kDa) and LAT (linker for activated T cells) [27].

Other interactions of Lsp1

• Modulation of Mac-1 (CD11b/CD18)-mediated adhesion by the leukocyte-specific protein 1 is key to its role in neutrophil polarization and chemotaxis [17].
• This difference was observed when cells migrated on fibrinogen, but not fibronectin, suggesting a role for LSP1 in modulating neutrophil adhesion by specific integrins [17].
• Leukocyte-specific gene 1 protein (LSP1) is involved in chemokine KC-activated cytoskeletal reorganization in murine neutrophils in vitro [28].
• A study of the regulation of the mouse RAG-2 promoter showed that the lymphocyte-specific promoter activity is conferred 80 nucleotide (nt) upstream of RAG-2 [29].
• The B lymphocyte-specific coactivator BOB.1/OBF.1 is required at multiple stages of B-cell development [30].

Analytical, diagnostic and therapeutic context of Lsp1

• By in situ hybridization analysis we show that the S37 isoforms are expressed in mesenchymal tissue, but not in adjacent epithelial tissue, of several developing organs during mouse embryogenesis [18].
• Purification and protein sequence analysis of p50 enabled us to identify it as a lymphocyte-specific putative Ca(2+)-binding protein (LSP-1) [22].
• On subcellular fractionation followed by immunoblotting analysis, membrane-bound p50 was shown to be released from the membrane following activation of PKC in T cells [2].
• Western blot analysis and immunofluorescence microscopy examination confirmed the presence of LSP1 in wild-type but not in Lsp1-/- mouse microvascular endothelial cells [16].
• We have used molecular cloning strategies to characterize a lymphocyte-specific protein-tyrosine kinase gene distinct from but closely related to src and yes [3].

References