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)

Activation of Akt/PKB by growth factors requires multiple phosphorylation events. Phosphorylation of Thr(308) and Ser(473) of Akt by its upstream kinase(s) or autophosphorylation is critical for optimal activation of its kinase activity. Here, we present evidence that tyrosine phosphorylation is required for Akt activation. Epidermal growth factor treatment induces tyrosine phosphorylation of Akt in COS1 and PC3M cells, which is abrogated by PP2, a selective inhibitor for Src family tyrosine kinases. Elevated Akt activity is observed in v-Src transformed NIH3T3 cells, which is accompanied with increased tyrosine phosphorylation of Akt. Akt activity induced by growth factors is significantly reduced in SYF cells lacking Src, Yes, and Fyn, which can be restored by introducing c-Src, but not the kinase-inactive Src, back to these cells. Furthermore, we have identified two tyrosine residues near the activation loop of Akt that are important for its activation. Substitution of these residues with phenylalanine abolishes Akt kinase activity stimulated by growth factors. These two YF mutants fail to block Forkhead transcription factor activity in 293 cells and are unable to prevent apoptosis induced by matrix detachment. Our data suggest that, in addition to phosphorylation of Thr(308) and Ser(473), tyrosine phosphorylation of Akt may be essential for its biological function.
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PMID:Regulation of Akt/PKB activation by tyrosine phosphorylation. 1144 57

Activation of phospholipase C-gamma2 (PLCgamma2) is the critical step in B cell antigen receptor (BCR)-coupled calcium signaling. Although genetic dissection experiments on B cells have demonstrated that Bruton's tyrosine kinase (Btk) and Syk are required for activating PLCgamma2, the exact activation mechanism of PLCgamma2 by these kinases has not been established. We identify the tyrosine residues 753, 759, 1197, and 1217 in rat PLCgamma2 as Btk-dependent phosphorylation sites by using an in vitro kinase assay. To evaluate the role of these tyrosine residues in phosphorylation-dependent activation of PLCgamma2, PLCgamma2-deficient DT40 cells were reconstituted with a series of mutant PLCgamma2s in which the phenylalanine was substituted for tyrosine. Substitution of all four tyrosine residues almost completely eliminated the BCR-induced PLCgamma2 phosphorylation, indicating that these residues include the major phosphorylation sites upon BCR engagement. Cells expressing PLCgamma2 with a single substitution exhibited some extent of reduction in calcium mobilization, whereas those expressing quadruple mutant PLCgamma2 showed greatly reduced calcium response. These findings indicate that the phosphorylations of the tyrosine residues 753, 759, 1197, and 1217, which have been identified as Btk-dependent phosphorylation sites in vitro, coordinately contribute to BCR-induced activation of PLCgamma2.
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PMID:Four tyrosine residues in phospholipase C-gamma 2, identified as Btk-dependent phosphorylation sites, are required for B cell antigen receptor-coupled calcium signaling. 1150 89

Prostate cancer is the second most common cause of cancer deaths among men in the United States. We have investigated the effect of cyclo-(Arg-Gly-Asp-D-Phe-Val; cRGDfV), Arg-Gly-Asp, or Arg-Gly-Asp-Ser, on survival of human prostate cancer (LNCaP and PC-3) and normal (HEL) cells in vitro. Addition of cRGDfV (20 microg/ml) but not the linear Arg-Gly-Asp or Arg-Gly-Asp-Ser peptide induced significant (approximately 84%) killing of LNCaP cells expressing alphavbeta3 integrins on their surfaces. In contrast, none of these peptides had any major effect on the growth of PC-3 or HEL cells, which express little alphavbeta3 integrin on their surfaces. Treatment of LNCaP but not of PC-3 or HEL cells with cRGDfV resulted in cleavage of focal adhesion kinase, a key player in integrin-mediated signal transduction pathway. The evidence we present here suggests that the killing of LNCaP cells after cRGDfV treatment was attributable to apoptosis or programmed cell death. This is evidenced by activation of at least two caspases (caspase-3 and caspase-9) as detected by cleavage of poly(ADP-ribose) polymerase and partial blocking of apoptosis by a selective inhibitor of caspase-9. Our results suggest that cRGDfV may be an effective treatment for some human prostate cancers by inducing apoptosis through interference with the regulation of integrin/focal adhesion kinase-mediated signal transduction pathway necessary for cell survival.
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PMID:Induction of apoptosis of integrin-expressing human prostate cancer cells by cyclic Arg-Gly-Asp peptides. 1159 88

The nucleoporin gene, NUP98, has been reported to be fused to seven partner genes in hematological malignancies with 11p15 translocations. We report here a novel NUP98 partner gene, HOXD11, not HOXD13, in a pediatric patient with de novo AML having t(2;11)(q31;p15), using a cDNA panhandle PCR. The HOXD11 gene is one of the HOXD cluster genes and contains 2 exons, encoding a protein of 338 amino acids with a homeodomain. Reverse transcription (RT)-PCR analysis showed that two alternatively spliced 5'-NUP98 transcripts were fused in frame to the HOXD11 gene. Both proteins consist of an NH(2)-terminal phenylalanine-glycine repeat motif of NUP98 and COOH-terminal homeodomain of HOXD11. RT-PCR analysis in various leukemic cell lines showed that expression of the HOXD11 gene was significantly more frequent in BCR-ABL-positive than in BCR-ABL-negative leukemic cell lines (P = 0.028). Our results revealed that t(2;11)(q31;p15) was not a single chromosomal abnormality and that the NUP98-HOXD fusion genes encode similar fusion proteins, which suggests that the NUP98-HOXD11 as well as NUP98-HOXD13 fusion protein play a role in leukemogenesis through similar mechanisms.
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PMID:The HOXD11 gene is fused to the NUP98 gene in acute myeloid leukemia with t(2;11)(q31;p15). 1178 54

In the absence of survival-inducing cytokines activated T cells and neutrophils enter apoptosis spontaneously. Phosphatidylinositol 3-kinase (PI3 K) activation and signaling through PKB/AKT have been widely linked to the inhibition of apoptosis by cytokines. Here we have investigated the role of PKB in the inhibition of spontaneous apoptosis of activated human CD4+ T cells and neutrophils. We used a range of cytokines known to induce survival and/or activation of PKB. We found activation of PKB in T cells treated with IL-2 and insulin, and neutrophils cultured with N-formyl-Met-Leu-Phe (fMLP), insulin or granulocyte-macrophage colony-stimulating factor. Insulin did not inhibit apoptosis in neutrophils or T cells and fMLP did not delay neutrophil apoptosis. Intriguingly, IFN-beta induced PI3 K-dependent survival in both cell types, but did not activate PKB. IL-2 mediated rescue of T cells from apoptosis but no induction of proliferation occurred in thepresence of LY294002, an inhibitor of PI3 K, which also blocked subsequent PKB activation. The main role of PI3 K in IL-2-mediated signaling may therefore be in the regulation of proliferation. These findings suggest that activation of PKB and inhibition of apoptosis can be dissociated in cytokine-mediated rescue of non-transformed CD4+ T cells and neutrophils.
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PMID:Cytokine-mediated inhibition of apoptosis in non-transformed T cells and neutrophils can be dissociated from protein kinase B activation. 1182 65

Stats (signal transducer and activator of transcription) are latent transcription factors that translocate from the cytoplasm to the nucleus. Constitutive activation of Stat3 alpha by upstream oncoproteins and receptor tyrosine kinases has been found in many human tumors and tumor-derived cell lines. Constitutively activated Stat3 alpha is often correlated with the activation of ErbB-2, a member of the EGFR family. To explore the involvement of ErbB-2 in the activation of Stat3 and the mechanism underlying this event, an ErbB-2 point mutant was used as a model of constitutively activated receptor. Phenylalanine mutations (Y-->F) were made in the autophosphorylation sites of the receptor, and their ability to activate Stat3 alpha was evaluated. Our results suggest that Stat3 alpha and JAK2 associates with ErbB-2 prior to phosphorylation of the receptor and that full activation of Stat3 alpha by ErbB-2 requires the participation of other non-receptor tyrosine kinases. Both Src and Jak2 kinases contribute to the activation of Stat3 alpha but Src binds to ErbB-2 only when the receptor is phosphorylated. Our results also suggest that tyrosine 1139 may be important for Src homology 2 domain association because a mutant lacking this tyrosine reduces the ability of the Src homology 2 domain to bind to ErbB-2 and significantly decreases its ability to activate Stat3 alpha.
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PMID:ErbB-2 activates Stat3 alpha in a Src- and JAK2-dependent manner. 1194 May 72

Interleukin-2 induces heterodimerization of the IL-2 receptor beta and gamma subunits. This study addresses a role of the Shb adapter protein in IL-2 receptor signaling in T and NK cells. The IL-2Rbeta and gamma chains were found to co-immunoprecipitate with Shb, when each alone was co-expressed with Shb in COS cells. Using fusion proteins, the Shb SH2 domain was found to associate in a phosphotyrosine-dependent manner with the IL-2 receptor beta and gamma subunits upon IL-2 stimulation in primary T cells and the NK cell line NK-92. The main binding site of the Shb SH2 domain was phosphorylated Tyr-510 in the IL-2Rbeta chain. Shb was also phosphorylated upon IL-2 stimulation when overexpressed together with IL-2Rbeta (in pre-B cells, which express the gamma chain constitutively). These cells were also less apoptotic in the presence of IL-2 than cells overexpressing a mutant Shb (with a defect SH2 domain) or cells expressing a mutant IL-2Rbeta, with the Shb binding sites mutated to phenylalanine (Y392F, Y510F). JAK1 and JAK3 were also found to associate with Shb, but in contrast to the Shb-IL-2 receptor association, JAK1 and 3 appear to associate with the proline-rich regions of Shb. In conclusion, Shb links the IL-2 receptor to other signaling proteins and mediates the regulation of apoptosis in the presence of IL-2.
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PMID:IL-2 receptor signaling through the Shb adapter protein in T and NK cells. 1220 Jan 37

We characterized the overall rate of F-actin polymerization in the pseudopod region by measuring the rate of extension of single pseudopods stimulated by f-Met-Leu-Phe. The rate of pseudopod extension was measured in the presence of inhibitors for signaling molecules that are known to be involved in motility. Our data show the existence of 2 distinct signaling pathways of actin polymerization in the pseudopod region: a phosphoinositide 3-kinase gamma (PI3Kgamma)-dependent and -independent pathway. The PI3Kgamma dependent signaling of F-actin polymerization also depends on protein kinase C zeta and protein kinase B (Akt/PKB). The PI3Kgamma-independent pathway depends on GTPase RhoA, the RhoA ROCK kinase, Src family tyrosine kinases, and NADPH, and is modulated by cAMP.
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PMID:Chemoattractant receptor-stimulated F-actin polymerization in the human neutrophil is signaled by 2 distinct pathways. 1239 89

Myofibroblast differentiation and activation by transforming growth factor-beta1 (TGF-beta1) is a critical event in the pathogenesis of human fibrotic diseases, but regulatory mechanisms for this effect are unclear. In this report, we demonstrate that stable expression of the myofibroblast phenotype requires both TGF-beta1 and adhesion-dependent signals. TGF-beta1-induced myofibroblast differentiation of lung fibroblasts is blocked in non-adherent cells despite the preservation of TGF-beta receptor(s)-mediated signaling of Smad2 phosphorylation. TGF-beta1 induces tyrosine phosphorylation of focal adhesion kinase (FAK) including that of its autophosphorylation site, Tyr-397, an effect that is dependent on cell adhesion and is delayed relative to early Smad signaling. Pharmacologic inhibition of FAK or expression of kinase-deficient FAK, mutated by substituting Tyr-397 with Phe, inhibit TGF-beta1-induced alpha-smooth muscle actin expression, stress fiber formation, and cellular hypertrophy. Basal expression of alpha-smooth muscle actin is elevated in cells grown on fibronectin-coated dishes but is decreased on laminin and poly-d-lysine, a non-integrin binding polypeptide. TGF-beta1 up-regulates expression of integrins and fibronectin, an effect that is associated with autophosphorylation/activation of FAK. Thus, a safer and more effective therapeutic strategy for fibrotic diseases characterized by persistent myofibroblast activation may be to target this integrin/FAK pathway while not interfering with tumor-suppressive functions of TGF-beta1/Smad signaling.
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PMID:Myofibroblast differentiation by transforming growth factor-beta1 is dependent on cell adhesion and integrin signaling via focal adhesion kinase. 1253 88

1. The human orphan G-protein coupled receptor bombesin receptor subtype 3 (hBRS-3) was screened for peptide ligands by a Ca(2+)mobilization assay resulting in the purification and identification of two specific ligands, the naturally occurring VV-hemorphin-7 (VV-H-7) and LVV-hemorphin-7 (LVV-H-7), from human placental tissue. These peptides were functionally characterized as full agonists with unique specificity albeit low affinity for hBRS-3 compared to other bombesin receptors. 2. VV-H-7 and LVV-H-7 induced a dose-dependent response in hBRS-3 overexpressing CHO cells, as well as in NCI-N417 cells expressing the hBRS-3 endogenously. The affinity of VV-H-7 was higher in NCI-N417 cells compared to overexpressing CHO cells. In detail, the EC(50) values were 45+/-15 microM for VV-H-7 and 183+/-60 microM for LVV-H-7 in CHO cells, and 19+/-6 microM for VV-H-7 and 38+/-18 microM for LVV-H-7 in NCI-N417 cells. Other hemorphins had no effect. Gastrin-releasing peptide (GRP) and neuromedin B (NMB) showed similar EC(50) values of 13-20 microM (GRP) and of 1-2 microM (NMB) on both cell lines. 3. Structure-function analysis revealed that both the N-terminal valine and the C-terminal phenylalanine residues of VV-H-7 are critical for the ligand-receptor interaction. 4. Endogenous hBRS-3 in NCI-N417 activated by VV-H-7 couples to phospholipase C resulting in changes of intracellular calcium, which is initially released from an inositol trisphosphate (IP(3))-sensitive store followed by a capacitive calcium entry from extracellular space. 5. VV-H-7-induced hBRS-3 activation led to phosphorylation of p42/p44-MAP kinase in NCI-N417 cells, but did not stimulate cell proliferation. In contrast, phosphorylation of focal adhesion kinase (p125(FAK)) was not observed.
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PMID:Identification and functional characterization of hemorphins VV-H-7 and LVV-H-7 as low-affinity agonists for the orphan bombesin receptor subtype 3. 1272 Oct 98


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