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)

Smooth muscle cells are able to adapt rapidly to chemical and mechanical signals impinging on the cell surface. It has been suggested that dynamic changes in the actin cytoskeleton contribute to the processes of contractile activation and mechanical adaptation in smooth muscle. In this review, evidence for functionally important changes in actin polymerization during smooth muscle contraction is summarized. The functions and regulation of proteins associated with "focal adhesion complexes" (membrane-associated dense plaques) in differentiated smooth muscle, including integrins, focal adhesion kinase (FAK), c-Src, paxillin, and the 27-kDa small heat shock protein (HSP27) are described. Integrins in smooth muscles are key elements of mechanotransduction pathways that communicate with and are regulated by focal adhesion proteins that include FAK, c-Src, and paxillin as well as proteins known to mediate cytoskeletal remodeling. Evidence that functions of FAK and c-Src protein kinases are closely intertwined is discussed as well as evidence that focal adhesion proteins mediate key signal transduction events that regulate actin remodeling and contraction. HSP27 is reviewed as a potentially significant effector protein that may regulate actin dynamics and cross-bridge function in response to activation of p21-activated kinase and the p38 mitogen-activated protein kinase signaling pathway by signaling pathways linked to integrin proteins. These signaling pathways are only part of a large number of yet to be defined pathways that mediate acute adaptive responses of the cytoskeleton in smooth muscle to environmental stimuli.
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PMID:Invited review: focal adhesion and small heat shock proteins in the regulation of actin remodeling and contractility in smooth muscle. 1145 15

Inhibiting the mitogenic response of vascular endothelial cells may in part mediate the antiangiogenic and anticancer activity of supranutritional selenium supplements. Our previous work had shown that methylseleninic acid (MSeA), a precursor of the critical anticancer methylselenol metabolite pool, was a potent inhibitor of the growth and survival of human umbilical vein endothelial cells (HUVECs). Here we investigated the effects of MSeA on selected protein kinase signaling transduction pathways to characterize their role in methylselenium induction of HUVEC cell cycle arrest and apoptosis. Exposure of asynchronous HUVECs for 30 h to 3-5 microM MSeA led to a profound G(1) arrest, and exposure to higher levels of MSeA not only led to G(1) arrest but also to DNA fragmentation and caspase-mediated cleavage of poly(ADP-ribose)polymerase, both biochemical hallmarks of apoptosis. Immunoblot analyses indicated that G(1) arrest induced by the sublethal doses of MSeA was associated with dose-dependent reductions of the levels of phospho-protein kinase B (also known as AKT or PKB), phospho-extracellular signal regulated kinase (ERK) 1/2, and phospho-Jun NH(2)-terminal kinases 1/2 in the absence of any change in p38 mitogen-activated protein kinase (MAPK) phosphorylation. Apoptosis induced by MSeA was associated with an increased phosphorylation of p38 MAPK in addition to the dephosphorylation of the above kinases. In HUVECs deprived of endothelial cell growth supplement (ECGS) for 48 h, resumption of ECGS stimulation resulted in an approximately 10-fold increase in mitogenic response, as indicated by [(3)H]thymidine incorporation into DNA. The ECGS-stimulated mitogenic response was inhibited in a dose-dependent manner by MSeA exposure with a IC(50) approximately 1 microM and a complete blockage at 3 microM. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3K) upstream of AKT, potently inhibited the ECGS-stimulated DNA synthesis (IC(50), approximately 40 nM). Combining MSeA with Wortmannin showed an additive antimitogenic effect. An inhibitor of MAPK/ERK kinase 1, PD98059, also inhibited ECGS-stimulated DNA synthesis (IC(50), approximately 55 microM), but combining PD98059 with MSeA had an effect similar to that when PD98059 was used alone. A time-course experiment indicated that PI3K (AKT and ribosomal protein S6 kinase) activation occurred between 6 and 12 h of ECGS stimulation, and 3 microM MSeA exposure decreased AKT phosphorylation after 12 h of exposure, whereas no inhibitory effect was observed for ERK1/2 phosphorylation throughout the 30-h exposure duration. Additional experiments indicated that MSeA, Wortmannin, or a more specific PI3K inhibitor, LY294002, seemed to target, in the mid- to late-G(1) phase, a common mechanism(s) controlling G(1) progression to S while having no inhibitory effect on DNA synthesis once S-phase had initiated. Taken together, the results support a potent inhibitory activity at achievable serum levels of MSeA on ECGS-stimulated mitogenesis in the mid- to late-G(1) phase, and the target(s) of this inhibitory activity seems to be PI3K or components of this signal pathway. At pharmacological levels of exposure, modulation of ERK1/2 and other protein kinases may be relevant for the proapoptotic action of MSeA.
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PMID:Antimitogenic and proapoptotic activities of methylseleninic acid in vascular endothelial cells and associated effects on PI3K-AKT, ERK, JNK and p38 MAPK signaling. 1158 51

The oncogenic latent membrane protein 1 (LMP1) of the Epstein-Barr virus recruits tumor necrosis factor-receptor (TNFR)-associated factors (TRAFs), the TNFR-associated death domain protein (TRADD) and JAK3 to induce intracellular signaling pathways. LMP1 serves as the prototype of a TRADD-binding receptor that transforms cells but does not induce apoptosis. Here we show that TRAF6 critically mediates LMP1 signaling to p38 mitogen-activated protein kinase (MAPK) via a MAPK kinase 6-dependent pathway. In addition, NF-kappaB but not c-Jun N-terminal kinase 1 (JNK1) induction by LMP1 involves TRAF6. The PxQxT motif of the LMP1 C-terminal activator region 1 (CTAR1) and tyrosine 384 of CTAR2 together are essential for full p38 MAPK activation and for TRAF6 recruitment to the LMP1 signaling complex. Dominant-negative TRADD blocks p38 MAPK activation by LMP1. The data suggest that entry of TRAF6 into the LMP1 complex is mediated by TRADD and TRAF2. In TRAF6-knockout fibroblasts, significant induction of p38 MAPK by LMP1 is dependent on the ectopic expression of TRAF6. We describe a novel role of TRAF6 as an essential signaling mediator of a transforming oncogene, downstream of TRADD and TRAF2.
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PMID:TRAF6 is a critical mediator of signal transduction by the viral oncogene latent membrane protein 1. 1159 11

Phosphatidylinositol 3-kinase (PI3-K) is a growth factor-activated transforming lipid (and protein) kinase, involved in cell motility and invasion, that has multiple effectors. Relatively little is known about its expression and enzymatic activity in human breast cancer. Since growth factor receptors are amplified in breast cancer, and the tumor suppressor PTEN may be mutated in human breast cancer, it was hypothesized that PI3-K and its downstream effectors would be activated in this disease. In 11 resected tumors analyzed for expression of this kinase, a mean 3-fold increase in protein expression was observed over the corresponding adjacent control tissue. Using an in vitro lipid kinase assay of the immunoprecipitated PI3-K protein, a greater than 2-fold increase in activation was observed. These changes were observed in the absence of an activation of either protein kinase B (PKB, akt1) or p70 S6 kinase (p70 S6K). However, p21-activated kinase (Pak), p38 mitogen-activated protein kinase (p38 MAPK) and mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK 2) were all overexpressed and demonstrated increased enzyme activity. It may be concluded that aberrant mitogenic signaling in human breast cancer in vivo involves Pak, p38 MAPK and MAPKAPK2 downstream of PI3-K, but neither of PKB or p70 S6K. It is proposed that this pathway may serve as a useful targeting nexus for investigation of small molecule inhibitors in human breast cancer.
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PMID:Dysregulation of phosphatidylinositol 3-kinase and downstream effectors in human breast cancer. 1185 99

Acute BCR-ABL expression during in vitro hematopoietic development of embryonic stem (ES) cells causes expansion of multipotent and myeloid progenitors with a concomitant reduction in differentiation toward erythroblasts. Progenitor cell expansion is due to a rapid, cell autonomous, suppression of programmed cell death with an increase in expression of the antiapoptotic molecule BCL-X(L). Other antiapoptotic effectors, including AKT, STAT5, and BCL-2 are not up-regulated by BCR-ABL in this system. In addition, the proapoptotic p38 mitogen-activated protein kinase (MAPK) pathway is suppressed by BCR-ABL expression in ES-derived hematopoietic progenitors. Inhibition of p38 MAPK by the small molecule inhibitor SB203580 expanded ES-derived hematopoietic progenitors by an antiapoptotic mechanism and is sufficient to expand ES-derived hematopoietic progenitors to levels approaching 80% of that seen following BCR-ABL expression. In the cellular context of ES-derived hematopoietic progenitors, BCR-ABL expression expands cells by suppressing programmed cell death with a set of antiapoptotic pathways distinct from those previously reported in continuous cell line studies.
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PMID:Cell context-specific effects of the BCR-ABL oncogene monitored in hematopoietic progenitors. 1252 91

In our present study we focused on soluble VCAM-1 (sVCAM-1)/alpha(4) integrin-induced angiogenesis and found that this type of angiogenesis was mediated through p38 mitogen-activated protein kinase and focal adhesion kinase (FAK). HUVEC expressed both alpha(4) and beta(1) integrins, and it was reported that expression of alpha(4) integrin and its counterreceptor, sVCAM-1/VCAM-1, was enhanced in response to an inflammatory cytokine, TNF-alpha. In endothelial cells phosphorylation of p38 and FAK, but not that of extracellular signal-regulated kinase 1/2 was induced by sVCAM-1. Migration of endothelial cells was stimulated in response to sVCAM-1 at similar levels as those induced by vascular endothelial growth factor, and sVCAM-1-induced migration was almost completely blocked by neutralizing Ab against alpha(4) integrin, by either an inhibitor of p38 (SB203580), or by adenovirus containing FAK-related nonkinase. sVCAM-1 also induced the formation of blood vessels in Matrigel plug assay in vivo, and this neovascularization was blocked by SB203580 or neutralizing Ab against alpha(4) integrin. Moreover, we also confirmed that both TNF-alpha and sVCAM-1 could synergistically induce angiogenesis in the corneas of mice when each factor at used dose could not induce. This angiogenesis by TNF-alpha and sVCAM-1 was almost completely blocked by coadministration of SB203580 and also by neutralizing Ab against alpha(4) integrin. These results suggest that sVCAM-1/alpha(4) integrin induces angiogenesis through p38 and FAK signaling pathways.
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PMID:Synergistic effect of TNF-alpha in soluble VCAM-1-induced angiogenesis through alpha 4 integrins. 1275 53

The EBV latent membrane protein 1 (LMP1) is an integral membrane protein that acts like a constitutively activated receptor. LMP1 interacts with members of the tumor necrosis factor receptor-associated factor family, as well as with tumor necrosis factor receptor-associated death domain, resulting in induction of nuclear factor-kappaB, the p38 mitogen-activated protein kinase pathway, and the c-Jun NH(2)-terminal kinase activator protein 1-signaling cascade. The binding of Janus kinase 3 results in activation of signal transducers and activators of transcription. The domain structure of LMP1 has been mapped extensively, but the quantitative contribution of distinct LMP1 domains to the efficiency of B-cell proliferation by EBV has not been determined. On the basis of the maxi-EBV system, which allows us to introduce and study mutations in the context of the complete EBV genome, a panel of 10 EBV mutants with alterations in the LMP1 gene locus was established. The mutant EBVs were tested for their efficiency to induce and maintain proliferation of clonal B-cell lines in vitro. Surprisingly and with reduced frequency, EBV mutants which deleted LMP1's COOH terminus, transmembrane domains, or the entire open reading frame were able to generate proliferating B-cell clones that were dependent on the presence of human fibroblast feeder cells. A B-cell clone carrying the LMP1-null mutant EBV genome was also analyzed for oncogenicity in severe combined immunodeficiency mice. Our results demonstrate that LMP1 is critical but not mandatory for the generation of proliferating B cells in vitro. LMP1 functions greatly contribute to EBV's transformation potential and appear essential for its oncogenicity in severe combined immunodeficiency mice.
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PMID:Latent membrane protein 1 is critical for efficient growth transformation of human B cells by epstein-barr virus. 1278 7

Angiogenesis depends on proper collagen biosynthesis and cross-linking, and type I collagen is an ideal angiogenic scaffold, although its mechanism is unknown. We examined angiogenesis using an assay wherein confluent monolayers of human umbilical vein endothelial cells were overlain with collagen in a serum-free defined medium. Small spaces formed in the cell layer by 2 h, and cells formed net-like arrays by 6-8 h and capillary-like lumens by 24 h. Blocking of alpha2beta1, but not alpha1 or alpha(v)beta3 integrin function halted morphogenesis. We found that a triple-helical, homotrimeric peptide mimetic of a putative alpha2beta1 binding site: alpha1(I)496-507 GARGERGFP*GER (where single-letter amino acid nomenclature is used, P* = hydroxyproline) inhibited tube formation, whereas a peptide carrying another putative site: alpha1(I)127-138 GLP*GERGRP*GAP* or control peptides did not. A chemical inhibitor of p38 mitogen-activated protein kinase (p38 MAPK), SB202190, blocked tube formation, and p38 MAPK activity was increased in collagen-treated cultures, whereas targeting MAPK kinase (MEK), focal adhesion kinase (FAK), or phosphatidylinositol 3-kinase (PI3K) had little effect. Collagen-treated cells had fewer focal adhesions and 3- to 5-fold less activated FAK. Thus capillary morphogenesis requires endothelial alpha2beta1 integrin engagement of a single type I collagen integrin-binding site, possibly signaling via p38 MAPK and focal adhesion disassembly/FAK inactivation.
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PMID:Angiogenesis in collagen I requires alpha2beta1 ligation of a GFP*GER sequence and possibly p38 MAPK activation and focal adhesion disassembly. 1278 34

Epigallocatechin gallate (EGCG), a major component of green tea, has been previously shown to inhibit platelet aggregation. The effects of other green tea catechins on platelet function are not known. Pre-incubation with EGCG concentration-dependently inhibited thrombin-induced aggregation and phosphorylation of p38 mitogen-activated protein kinase and extracellular signal-regulated kinases-1/2. In contrast EGCG stimulated tyrosine phosphorylation of platelet proteins, including Syk and SLP-76 but inhibited phosphorylation of focal adhesion kinase. Other catechins did not inhibit platelet aggregation. Interestingly, when EGCG was added to stirred platelets, a tyrosine kinase-dependent stimulation of platelet aggregation was observed. The two other catechins containing a galloyl group in the 3' position (catechin gallate, epicatechin gallate) also stimulated platelet aggregation, while catechins without a galloyl group (catechin, epicatechin) or the catechin with a galloyl group in the 2' position (epigallocatechin) did not.
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PMID:Complex effects of different green tea catechins on human platelets. 1283 52

IL-12 is a key immunoregulatory cytokine that promotes Th1 differentiation and cell-mediated immune responses. IL-12 stimulation results in the activation of Janus kinase 2 and tyrosine kinase 2 and, subsequently, STAT4 and STAT3. In addition, mitogen-activated protein kinase kinase 6/p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt pathways have been recently demonstrated to be activated by IL-12 and play an important role in IL-12 signaling. To further elucidate the molecular mechanism underlying IL-12 signaling, we have performed a yeast two-hybrid screening and identified mouse sphingosine kinase 2 (SPHK2) as a molecule associating with the mouse IL-12Rbeta1 cytoplasmic region. Analyses of various mutants of each molecule revealed that the region including the proline-rich domain in SPHK2 is probably responsible for the binding to IL-12Rbeta1, while the regions including the carboxyl terminus and Box II in the IL-12Rbeta1 cytoplasmic region appear to be involved in the binding to SPHK2. Transient expression of wild-type SPHK2 in T cell hybridoma augmented IL-12-induced STAT4-mediated transcriptional activation. Ectopic expression of dominant-negative SPHK2 in Th1 cell clone significantly reduced IL-12-induced IFN-gamma production, while that of wild-type SPHK2 enhanced it. In contrast, the expression minimally affected IL-12-induced proliferation. A similar decrease in IL-12-induced IFN-gamma production was observed when dominant-negative SPHK2 was expressed in activated primary T cells using a retroviral expression system. These results suggest that SPHK2 associates with the IL-12Rbeta1 cytoplasmic region and probably plays a role in modulating IL-12 signaling.
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PMID:Positive modulation of IL-12 signaling by sphingosine kinase 2 associating with the IL-12 receptor beta 1 cytoplasmic region. 1287 25


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