Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Engagement of the T cell receptor (TCR) by peptide antigen bound to the major histocompatibility complex molecules initiates a biochemical cascade involving protein tyrosine kinases (PTKs) such as Lck, ZAP70 and Csk, and protein tyrosine phosphatases (PTPases) such as CD45, SHP-1 and SHP-2. In the process of T cell activation, immune tyrosine-based activation motifs (ITAMs) and immune tyrosine-based inhibitory motifs(ITIMs) within the cytoplasmic region of CD3 and CD152 molecules play a key role in the activation of PTKs and PTPases. Consequently, Ras/MAP kinase and PLC gamma 1 pathways are activated to induce IL-2 gene transcription through AP-1 and NF-AT generation. Recent biochemical and genetic evidence has suggested that dysfunction in these TCR-related molecules resulted in immuno-deficiency, breakdown of tolerance and abnormal T cell development.
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PMID:[T cell receptor and its related molecules in signal transduction]. 1007 90

Latent membrane protein 1 (LMP1) acts like a permanently activated receptor of the tumor necrosis factor (TNF)-receptor superfamily and is absolutely required for B cell immortalization by Epstein-Barr virus. Molecular and biochemical approaches demonstrated that LMP1 usurps cellular signaling pathways resulting in the induction of NF-kappaB and AP-1 via two C-terminal activating regions. We demonstrate here that a third region encompassing a proline rich sequence within the 33 bp repetitive stretch of LMP1's C-terminus is required for the activation of Janus kinase 3 (JAK3). The interaction of LMP1 and JAK3 leads to the enhanced tyrosine auto/transphosphorylation of JAK3 within minutes after crosslinking of a conditional NGF-R:LMP1 chimera and is a prerequisite for the activation of STAT transcription factors. These results reveal a novel activating region in the LMP1 C-terminus and identify the JAK/STAT pathway as a target of this viral integral membrane protein in B cells.
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PMID:Latent membrane protein 1 of Epstein-Barr virus interacts with JAK3 and activates STAT proteins. 1035 18

CD40/CD40 ligand interactions play a key role in the immune responses of B lymphocytes, monocytes, and dendritic cells. The signal transduction events triggered by cross-linking of the CD40 receptor have been widely studied in B cell lines, but little is known about signaling following CD40 stimulation of monocytes and resting tonsillar B cells. Therefore, we studied the CD40 pathway in highly purified human monocytes and resting B cells. After CD40 triggering, a similar activation of the NF-kappaB (but not of the AP-1) transcription factor complex occurred in both cell preparations. However, the components of the NF-kappaB complexes were different in monocytes and B cells, because p50 is part of the NF-kappaB complex induced by CD40 triggering in both monocytes and B cells, whereas p65 was only induced in B cells. In contrast, although the Janus kinase 3 tyrosine kinase was associated with CD40 molecules in both monocytes and resting B cells, Janus kinase 3 phosphorylation induction was observed only in CD40-activated monocytes, with subsequent induction of STAT5a DNA binding activity in the nucleus. These results suggest that the activation signals in human B cells and monocytes differ following CD40 stimulation. This observation is consistent with the detection of normal CD40-induced monocyte activation in patients with CD40 ligand+ hyper IgM syndrome in whom a defect in CD40-induced B cell activation has been reported.
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PMID:Activation of the Janus kinase 3-STAT5a pathway after CD40 triggering of human monocytes but not of resting B cells. 1039 71

The murine DUB-1 gene is a hematopoietic-specific, immediate-early gene that encodes a growth-regulatory deubiquitinating enzyme. DUB-1 contains an IL-3-inducible enhancer element that is activated in a JAK2-dependent, STAT5-independent manner. In this study, we have further characterized this novel IL-3 response element. Transcriptional reporter assays in Ba/F3 cells revealed that two AP-1 sites, a GATA motif, and an Ets site are required for induction of DUB-1 enhancer activity. Gel shift assays indicated that IL-3 activates the binding of an AP-1 complex containing JunD to the AP-1 sites and the binding of another protein complex to the Ets motif. The latter complex was not detectable in Ba/F3 cells stably transfected with a dominant-negative mutant of JAK2. As previously shown, these cells do not express DUB-1 mRNA or protein. Furthermore, we demonstrated that GATA-1 constitutively binds to the DUB-1 enhancer element. The involvement of GATA-1 may be important for the hematopoietic-restricted expression pattern of DUB-1. This combination of inducible and constitutive elements of the DUB-1 enhancer appears to account for the unique STAT-independent expression characteristics of DUB-1.
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PMID:Analysis of cis-acting sequences and trans-acting factors regulating the interleukin-3 response element of the DUB-1 gene. 1052 5

Rlk/Txk is a T-cell-specific member of the Btk/Tec family of tyrosine kinases, whereas SLP-76 is a lymphoid adaptor that is essential for pre-TcR and mature TcR signaling. Although Rlk deficient T-cells show partial defects in T-cell proliferation, Rlk can complement ITK-/- cells with multiple defects in TcR initiated early events and interleukin (IL)-2 production. A key question is the nature of the target of Rlk responsible for bridging the TcR with the activation of IL-2 transcription. In this study, we identify a pathway in which Rlk phosphorylates SLP-76 leading to the phosphorylation of PLCgamma1, activation of ERKs, and the synergistic up-regulation of TcR-driven IL-2 NFAT/AP-1 transcription. Rlk phosphorylated the N-terminal region of SLP-76, a region that has been previously shown to serve as a target for ZAP-70. Loss of N-terminal YESP/YEPP sites of SLP-76 or the Rlk kinase activity attenuated cooperativity between Rlk and SLP-76. These observations support a model where the TcR can utilize Rlk (as well as ZAP-70) in the phosphorylation of key sites in SLP-76 leading to the up-regulation of Th1 preferred cytokine IL-2.
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PMID:Resting lymphocyte kinase (Rlk/Txk) targets lymphoid adaptor SLP-76 in the cooperative activation of interleukin-2 transcription in T-cells. 1066 May 34

Cross-linking of FcepsilonRI induces the activation of three protein tyrosine kinases, Lyn, Syk, and Bruton's tyrosine kinase (Btk), leading to the secretion of a panel of proinflammatory mediators from mast cells. This study showed phosphorylation at Ser-473 and enzymatic activation of Akt/protein kinase B, the crucial survival kinase, upon FcepsilonRI stimulation in mouse mast cells. Phosphorylation of Akt is regulated positively by Btk and Syk and negatively by Lyn. Akt in turn can regulate positively the transcriptional activity of interleukin (IL)-2 and tumor necrosis factor (TNF)-alpha promoters. Transcription from the nuclear factor kappaB (NF-kappaB), nuclear factor of activated T cells (NF-AT), and activator protein 1 (AP-1) sites within these promoters is under the control of Akt activity. Accordingly, the signaling pathway involving IkappaB-alpha, a cytoplasmic protein that binds NF-kappaB and inhibits its nuclear translocation, appears to be regulated by Akt in mast cells. Catalytic activity of glycogen synthase kinase (GSK)-3beta, a serine/threonine kinase that phosphorylates NF-AT and promotes its nuclear export, seems to be inhibited by Akt. Importantly, Akt regulates the production and secretion of IL-2 and TNF-alpha in FcepsilonRI-stimulated mast cells. Altogether, these results revealed a novel function of Akt in transcriptional activation of cytokine genes via NF-kappaB, NF-AT, and AP-1 that contributes to the production of cytokines.
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PMID:Akt-dependent cytokine production in mast cells. 1097 38

Multiple endocrine neoplasia 2A (MEN 2A) is an inherited disease caused by mutations of the Ret proto-oncogene. Although many different Ret mutations have been described, little is known about the signaling pathways triggered by the Ret oncogene. In this study, we have determined the signaling properties of a Ret-9bp duplication encoding amino acids 634-636, which was recently identified in a patient with all clinical features of the MEN 2A syndrome. The Ret-9bp duplication leads to constitutive activation of the Ret tyrosine kinase. Furthermore, Ret-9bp increased mitogenic and transforming activity demonstrated by thymidine incorporation as well as colony formation in soft agar. Studying intracellular signaling pathways, which may be involved in malignant transformation of Ret-9bp expressing NIH3T3 cells, we could demonstrate Ret-9bp dependent phosphorylation of insulin receptor substrate-2 (IRS-2) with consecutive activation of phosphatidylinositol 3-kinase (PI 3-kinase) and protein kinase B (PKB/AKT). Moreover, Ret-9bp induces phosphorylation of SHC resulting in growth factor receptor binding protein-2 (Grb-2) binding and activation of the mitogen activating protein (MAP) kinase pathway. In addition to these postreceptor cytoplasmic signaling events, we have studied nuclear signal by Ret-9bp and found activation of c-jun and jun-D, two members of the jun/AP-1 family of transcription factors. In summary, an oncogenic 9bp duplication of Ret causes Ret dimer formation and ligand independent activation of the tyrosine kinase. Besides the signaling steps leading to MAPK activation, we could demonstrate that Ret-9bp induced constitutive activation of a signaling pathway involving IRS-2, PI 3-kinase and PKB/AKT which could transduce the oncogenic Ret signal to increased gene transcription via activation of the jun/AP-1 transcription factor family.
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PMID:Ret oncogene signal transduction via a IRS-2/PI 3-kinase/PKB and a SHC/Grb-2 dependent pathway: possible implication for transforming activity in NIH3T3 cells. 1100 May 21

Since osteoblast proliferation is critical for bone development, the effect of bone extracellular matrix (ECM) proteins on osteoblast signaling and proliferation in serum-free medium was investigated. Proliferation was highest in primary rat calvarial osteoblasts cells grown on fibronectin but less on type I collagen; osteonectin and poly-L-lysine did not support early proliferation. Fibronectin and type I collagen binding requires integrins, whereas cell adhesion to osteonectin or poly-L-lysine does not involve integrins. Therefore, the role of integrins in osteoblast signaling, leading to the induction of AP-1 transcription factors (c-fos and c-jun) which are important in cell proliferation, was studied. c-fos and c-jun message levels were increased at 60 min in osteoblasts plated onto fibronectin or collagen, but not in cells on osteonectin or poly-L-lysine. Protein synthesis was not required for c-fos mRNA expression; however, kinase activity was necessary for c-fos induction. In cells plated onto fibronectin, c-fos mRNA levels were controlled by protein kinase C and phosphotyrosine kinase signaling pathways. In contrast, c-fos levels in collagen-adhering cells may involve protein kinase A. The signaling pathway involving the phosphorylation of focal adhesion kinase and mitogen-activated kinases was also shown to be transiently increased in osteoblasts on fibronectin and type I collagen, but not in cells on poly-L-lysine. These results demonstrate that osteoblast binding to the extracellular matrix through integrins induces c-fos and c-jun, and that both fibronectin and collagen affect these AP-1 transcription factors through protein kinase-sensitive pathways. Thus, osteoblast proliferation is modulated differentially by specific ECM components.
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PMID:Integrin-mediated signaling regulates AP-1 transcription factors and proliferation in osteoblasts. 1103 56

The intracellular signaling pathway for osteoblast adhesion to the orthopedic implant material Ti6Al4V (TIV) was investigated and compared to integrin-mediated adhesion to extracellular matrix proteins. Primary osteoblasts from fetal rat calvaria were plated onto TIV, fibronectin (FN), and poly-L-lysine (PLL) and the levels of focal adhesion kinase (FAK), mitogen-activated protein kinase (MAPK), and AP-1 transcription factors, c-fos and c-jun, were compared by Western and Northern blots. Cells on all substrates showed maximum FAK phosphorylation within 60 min and then a decrease at 2 and 24 h. However, the subsequent signal transduction pathway differed on PLL compared to TIV and FN. MAPK was phosphorylated similarly in osteoblasts attached to FN and TIV, whereas cells on PLL demonstrated no MAPK phosphorylation. On TIV and FN, c-fos and c-jun mRNA levels were maximal within 1 h and then plateaued or declined by 2 h. On PLL, they increased at 2 h. Within 1 h, c-fos protein was stimulated in cells attached to TIV and FN and decreased in cells on PLL. c-jun protein increased on all substrates compared to unplated cells. Cytoskeletal changes visualized by phalloidin fluorescence microscopy at 4 h of culture were delayed on TIV compared to FN. In addition, approximately 50% fewer cells adhered to TIV compared to FN or PLL. By 24 h, a well-spread cytoskeleton with focal adhesion sites was apparent on TIV and FN, but cells on PLL were rounded with minimal cell spreading. During 6 days of culture, cells on FN and TIV proliferated, whereas the number of cells on PLL remained the same or decreased, depending on the initial plating density. We conclude that osteoblast adhesion to TIV implants is similar to osteoblast adhesion to FN and leads to osteoblast proliferation. These data provide evidence for the biocompatibility of TIV at a molecular level.
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PMID:Integrin-mediated signaling in osteoblasts on titanium implant materials. 1103 57

BCR/ABL, the oncoprotein responsible for chronic myeloid leukemia (CML), transforms hematopoietic cells through both Ras-dependent and -independent mechanisms. Farnesyl protein transferase inhibitors (FTIs) were designed to block mutant Ras signaling, but they also inhibit the growth of transformed cells with wild-type Ras, implying that other farnesylated targets contribute to FTI action. In the current study, the clinical candidate FTI SCH66336 was characterized for its ability to inhibit BCR/ABL transformation. When tested against BCR/ABL-BaF3 cells, a murine cell line that is leukemogenic in mice, SCH66336 potently inhibited soft agar colony formation, slowed proliferation, and sensitized cells to apoptotic stimuli. Quantification of activated guanosine triphosphate (GTP)-bound Ras protein and electrophoretic mobility shift assays for AP-1 DNA binding showed that Ras effector pathways are inhibited by SCH66336. However, SCH66336 was more inhibitory than dominant-negative Ras in assays of soft agar colony formation and cell proliferation, suggesting activity against targets other than Ras. Cell cycle analysis of BCR/ABL-BaF3 cells treated with SCH66336 revealed G2/M blockade, consistent with recent reports that centromeric proteins that regulate the G2/M checkpoint are critical farnesylated targets of FTI action. Mice injected intravenously with BCR/ABL-BaF3 cells developed acute leukemia and died within 4 weeks with massive splenomegaly, elevated white blood cell counts, and anemia. In contrast, nearly all mice treated with SCH66336 survived and have remained disease-free for more than a year. Furthermore, SCH66336 selectively inhibited the hematopoietic colony formation of primary human CML cells. As an oral, nontoxic compound with a mechanism of action distinct from that of ABL tyrosine kinase inhibition, FTI SCH66336 shows promise for the treatment of BCR/ABL-induced leukemia.
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PMID:Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia. 1122 87


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