Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A rare mRNA variant of the human lymphocyte-specific protein tyrosine kinase LCK gene that retains intron B and excludes exon 7 (B+7-) due to alternative splicing of the canonical LCK transcripts was identified and characterized. LCK B+7- mRNA is detected in all tested peripheral blood T lymphocytes total RNA samples but is apparently sequestered in the nucleus. The presence of intron B sequence does not disrupt the reading frame and results in the insertion of 58 aminoacids, containing a proline-rich region just upstream of p56lck SH3 domain. This putative isoform encodes an unstable 516 aminoacids protein (LckB+7-) which can be expressed in transfected COS-7 cells. Furthermore in Jurkat T cell extracts, a recombinant intron B plus SH3 p56lck domain fails to interact with some TCR-induced tyrosine phosphorylated polypeptides and known p56lck partners such as Sam68 and c-Cbl. The biological function of this rare messenger remains to be elucidated.
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PMID:A rare mRNA variant of the human lymphocyte-specific protein tyrosine kinase LCK gene with intron B retention and exon 7 skipping encodes a putative protein with altered SH3-dependent molecular interactions. 1610 3

Many B-lineage-specific genes are down-regulated in Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL). We investigated the involvement of epigenetic modifications in gene silencing in cHL cell lines and in microdissected primary HRS cells. We assessed the expression and methylation status of CD19, CD20, CD79B, SYK, PU.1, BOB.1/OBF.1, BCMA, and LCK, all of which are typically down-regulated in cHL. We could reactivate gene expression in cHL cell lines with the DNA demethylating agent 5-aza-deoxycytidine (5-aza-dC). Using methylation-specific polymerase chain reaction (MSP), bisulfite genomic sequencing, and digestion with methylation-sensitive endonuclease followed by polymerase chain reaction (PCR), we determined the methylation status of promoter regions of PU.1, BOB.1/OBF.1, CD19, SYK, and CD79B. Down-regulation of transcription typically correlated with hypermethylation. Using bisulfite genomic sequencing we found that in microdissected HRS cells of primary cHL SYK, BOB.1/OBF.1, and CD79B promoters were also hypermethylated. Ectopic expression of both Oct2 and PU.1 in a cHL cell line potentiated endogenous PU.1 and SYK expression after 5-aza-dC treatment. These observations indicate that silencing of the B-cell-specific genes in cHL may be the consequence of a compromised regulatory network where down-regulation of a few master transcription factors results in silencing of numerous genes.
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PMID:Epigenetic processes play a major role in B-cell-specific gene silencing in classical Hodgkin lymphoma. 1630 50

To glean biological differences and similarities of peripheral T-cell lymphoma-not otherwise specified [PTCL-NOS] to diffuse large B-cell lymphoma (DLBCL), a transcriptosome analysis was done on five PTCL-NOS and four DLBCL patients and validated by quantitative real-time reverse transcription-PCR on 10 selected genes. Normal peripheral blood T cells, peripheral blood B cells, and lymph node were used as controls. The resultant gene expression profile delineated distinct "tumor profile signatures" for PTCL-NOS and DLBCL. Several highly overexpressed genes in both PTCL-NOS and DLBCL involve the immune network, stroma, angiogenesis, and cell survival cascades that make important contributions to lymphomagenesis. Inflammatory chemokines and their receptors likely play a central role in these complex interrelated pathways: CCL2 and CXCR4 in PTCL-NOS and CCL5 and CCR1 in DLBCL. Highly overexpressed oncogenes unique to PTCL-NOS are SPI1, STK6, alpha-PDGFR, and SH2D1A, whereas in DLBCL they are PIM1, PIM2, LYN, BCL2A1, and RAB13. Oncogenes common to both lymphomas are MAFB, MET, NF-kappaB2, LCK, and LYN. Several tumor suppressors are also down-regulated (TPTE, MGC154, PTCH, ST5, and SUI1). This study illustrates the relevance of tumor-stroma immune trafficking and identified potential novel prognostic markers and targets for therapeutic intervention.
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PMID:Transcript profiling in peripheral T-cell lymphoma, not otherwise specified, and diffuse large B-cell lymphoma identifies distinct tumor profile signatures. 1637 2

T cell-specific adapter protein (TSAd) is a SRC-homology-2 (SH2) domain-containing intracellular signaling molecule that is required for T cell antigen receptor (TCR)-induced cytokine synthesis in T cells. How TSAd functions in TCR signal transduction is not clear. Previous work has suggested a nuclear role for this adapter. However, other evidence suggests that TSAd also functions in the cytoplasm. Using T cells from TSAd-deficient mice, we now show that the major role of TSAd in the cytoplasm is in activation of the LCK protein tyrosine kinase at the outset of TCR signal transduction. Consequently, TSAd regulates several downstream signaling events, including intracellular calcium mobilization and activation of the Ras-extracellular signal-regulated kinase signaling pathway. TSAd regulates LCK activity directly through physical interaction with LCK SH3 and SH2 domains. These studies reveal TSAd as a positive regulator of proximal TCR signal transduction and provide important new information on the mechanism of TCR-induced LCK activation.
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PMID:Essential role of the T cell-specific adapter protein in the activation of LCK in peripheral T cells. 1644 80

CD40 promotes survival, proliferation, and differentiation of normal B cells but can cause activation-induced cell death in malignant B lymphocytes. CD40 ligand and anti-CD40 antibodies have been used successfully to induce apoptosis in lymphoma lines both in vitro and in xenograft tumor models. Although this makes CD40 an attractive target for antitumor therapies, the response of malignant B cells to CD40 signaling is variable, and CD40 stimulation can enhance proliferation and can increase chemoresistance in some cell lines. It would therefore be useful to identify markers that predict whether a specific cell line or tumor will undergo apoptosis when stimulated with CD40 and to identify targets downstream of CD40 that affect only the apoptotic arm of CD40 signaling. We have analyzed gene expression patterns in CD40-sensitive and CD40-resistant diffuse large B-cell lymphoma (DLBCL) cell lines to identify signaling pathways that are involved in CD40-mediated apoptosis. CD40-resistant lines expressed pre-B-cell markers, including RAG and VPREB, whereas CD40-sensitive cells resembled mature B cells and expressed higher levels of transcripts encoding several members of the CD40 signaling pathway, including LCK and VAV. In addition, CD40-sensitive DLBCL cell lines also displayed constitutive activation of extracellular signal-regulated kinase (ERK) and failed to undergo apoptosis when ERK phosphorylation was inhibited. In contrast, CD40-resistant lines showed no constitutive activation of ERK and no increase in ERK activity in response to CD40 stimulation. Our results suggest that constitutive activation of ERK may be required for death signaling by CD40.
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PMID:Constitutive activation of extracellular signal-regulated kinase predisposes diffuse large B-cell lymphoma cell lines to CD40-mediated cell death. 1658 79

Therapeutic success of TCR gene transfer to treat tumors depends on the ability of redirected T cells to become activated upon tumor recognition in vivo. Help provided by tumor-specific Th1 cells is reported to relieve T cells from an anergized state and to induce tumor regression. We recently demonstrated the ability to generate melanoma-specific Th1 cells by genetic introduction of both a CD8-dependent TCR and the CD8alpha coreceptor into CD4+ T cells. In this study, we analyzed a TCR that binds Ag independently of CD8, a property generally preferred to induce tumor-specific T cell responses, and addressed the contribution of CD8alpha following introduction into TCR-transduced CD4+ T cells. To this end, primary human CD4+ T cells were gene transferred with a high-avidity TCR, and were shown not only to bind peptide/MHC class I, but also to effectively kill Ag-positive tumor cells in the absence of CD8alpha. The introduction of CD8alpha up-regulates the tumor-specific production of TNF-alpha and IL-2 to some extent, but significantly down-regulates production of IL-4, IL-5, and IL-10 in CD4+ T cells. The introduction of a mutated cysteine motif in CD8alpha, which prevents its binding to LCK and linker for activation of T cells, did not adversely affect expression and T cell cytotoxicity, but counteracted the CD8alpha-mediated down-regulation of IL-4 and IL-5, but not IL-10. In conclusion, CD8alpha down-regulates the production of major Th2-type cytokines, in part mediated by LCK and/or linker for activation of T cells, and may induce differentiation of tumor-specific Th1 cells, which makes this coreceptor an interesting candidate to improve the clinical potential of TCR gene transfer to treat cancer.
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PMID:CD8 alpha coreceptor to improve TCR gene transfer to treat melanoma: down-regulation of tumor-specific production of IL-4, IL-5, and IL-10. 1681 55

Expression of the CD8 alpha alpha homodimer has been used to differentiate lymphoid (CD8alpha(+)) from myeloid (CD8alpha(-)) dendritic cells (DCs). We have reported that CD8alpha(+) and CD8alpha(-) DCs have differential abilities to stimulate proliferation in allogeneic T cells. However, no specific function has been attributed to DC-derived CD8alpha. The current study examines the hypothesis that CD8 alpha alpha expression on DCs regulates DC-induced T cell activation. CD8alpha(-) transduced bone marrow-derived DCs were more potent stimulators of T cell proliferation, and produced significantly greater quantities of IL-12 in co-culture with T cells. LCK, a kinase whose expression is reported to be T cell-restricted and known to bind to the cytoplasmic tail of CD8 alpha beta in T cells, was detected readily in primary CD8alpha(+) splenic DCs and at greater levels than CD8alpha(-) DCs from the same tissues. LCK also co-precipitated with CD8alpha on immunblots strongly suggesting its role in CD8alpha(+) DC-induced T cell activation. Collectively, these data show that CD8alpha expressed on DC may not only be a lineage/maturation marker but also contribute to DC function.
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PMID:Dendritic cell-T cell interactions: CD8 alpha alpha expressed on dendritic cells regulates T cell proliferation. 1722 89

GCET2 (Germinal centre B-cell expressed transcript 2; also named HGAL) is a newly cloned gene that has been shown to be a useful marker for germinal centre (GC) B cells and GC B-cell derived malignancies, including follicular lymphomas and germinal centre B cell-like diffuse large B-cell lymphomas (GCB-DLBCLs), and is a useful prognosticator for DLBCLs. We report here the biochemical and biological properties of GCET2, which may help to determine its role in the GC reaction. GCET2 is constitutively localised in the plasma membrane but is excluded from lipid rafts. GCET2 does not have a transmembrane domain, and its membrane localisation is mediated by myristoylation and palmitoylation. GCET2 has five conserved putative tyrosine phosphorylation sites, and it can be phosphorylated following pervanadate treatment in B cells. By serially mutating the five tyrosines, the third and fourth tyrosines were found to be essential for GCET2 phosphorylation. GCET2 was phosphorylated when co-transfected into COS7 cells with protein tyrosine kinases (PTKs) LYN, LCK or SYK, and therefore it could be a substrate of these kinases in B cells. The third tyrosine site ((107)YENV) of GCET2 is a consensus GRB2 binding site, and GCET2 was found to associate with GRB2 through the third tyrosine following phosphorylation. Our data suggests that GCET2 may be an adaptor protein in GC B cells that transduces signals from GC B-cell membrane to the cytosol via its association with GRB2.
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PMID:Studies of a germinal centre B-cell expressed gene, GCET2, suggest its role as a membrane associated adapter protein. 1748 82

The T-cell leukemia 1 (TCL1) oncoprotein is overexpressed by chromosomal rearrangement in the majority of cases of T-cell prolymphocytic leukemia (T-PLL). In vitro, TCL1 can modulate the activity of the serine-threonine kinase AKT, a downstream effector of T-cell receptor (TCR) signaling. In a series of 86 T-PLL tumors, we show that expression of TCR, and levels of TCL1 and activated AKT are adverse prognostic markers. High-level TCL1 in TCR-expressing T-PLL is associated with higher presenting white blood cell counts, faster tumor cell doubling, and enhanced in vitro growth response to TCR engagement. In primary tumors and TCL1-transfected T-cell lines, TCR engagement leads to rapid recruitment of TCL1 and AKT to transient membrane activation complexes that include TCR-associated tyrosine kinases, including LCK. Pharmacologic inhibition of AKT activation alters the localization, stability, and levels of these transient TCL1-AKT complexes and reduces tumor cell growth. Experimental introduction and knockdown of TCL1 influence the kinetics and strength of TCR-mediated AKT activation. We propose that in T-PLL, TCL1 represents a highly regulated, targetable modulator of TCR-mediated AKT growth signaling.
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PMID:High TCL1 expression and intact T-cell receptor signaling define a hyperproliferative subset of T-cell prolymphocytic leukemia. 1789 Apr 51

The neoplastic Reed-Sternberg cells characteristic of classical Hodgkin's lymphoma (cHL) are of B-cell origin but they almost always show striking loss of a range of B-cell-associated molecules. In contrast, the neoplastic cells found in lymphocyte predominant Hodgkin's lymphoma (LPHL) (L&H cells) are traditionally thought of as possessing the full repertoire of features associated with germinal centre B cells (eg BCL-6 expression, 'ongoing' Ig gene mutation). In the present paper, we report an extensive phenotypic analysis of L&H cells which revealed down-regulation of a number of markers associated with the B-cell lineage (eg CD19, CD37) and with the germinal centre maturation stage (eg PAG, LCK). The promoter methylation status of three of these down-regulated genes (CD10, CD19, and LCK) was further studied in microdissected L&H cells, and this revealed that their promoters were unmethylated. In contrast, these genes showed promoter methylation in cell lines derived from CHL. Further investigation of the mechanisms responsible for the deregulation of these molecules in L&H cells may provide new insights into the genetic abnormalities underlying LPHL.
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PMID:Selective loss of B-cell phenotype in lymphocyte predominant Hodgkin lymphoma. 1793 42


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