Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies show that tyrosine phosphorylation by a number of neuropeptides may be an important intracellular pathway in mediating changes in cell function, particularly related to growth. Neuromedin B (NMB), a mammalian bombesin related peptide, functions through a distinct receptor, the neuromedin B receptor (NMB-R), of which little is known about its cellular basis of action. In the present study we explored the ability of NMB-R activation to cause tyrosine phosphorylation of focal adhesion kinase (p125(FAK)), an important substrate for tyrosine phosphorylation by other neuropeptides. NMB caused rapid increases in p125(FAK) phosphorylation which reached maximum at 2 min in both rat C6 glioblastoma cells which possess native NMB-Rs and rat neuromedin B receptor (rNMR-R) transfected BALB 3T3 cells. NMB had a half-maximal effect was at 0.4 nM and was 30-fold more potent than gastrin-releasing peptide (GRP). The stoichiometric relationships between increased p125(FAK) tyrosine phosphorylation and other cellular processes was similar in both C6 cells and rNMB-R transfected cells. TPA (1 microM) caused 45% and the calcium ionophore, A23187, 11% of maximal tyrosine phosphorylation of p125(FAK) seen with NMB. A23187 potentiated the effect of TPA. Pretreatment with the selective PKC inhibitor, GF109203X, inhibited TPA-induced p125(FAK) tyrosine phosphorylation, but it had no effect on the NMB stimulation. Pretreatment with thapsigargin completely inhibited NMB-stimulated increases in [Ca2+]i, but had no effect on NMB-stimulation of p125(FAK) phosphorylation either alone or with GF109203X. The tyrosine kinase inhibitor, tyrphostin A25, inhibited NMB-induced phosphorylation of p125(FAK) by 52%. However, tyrphostin A25 did not inhibit NMB-stimulated increases in [3H]inositol phosphates. Cytochalasin D, an agent which disrupts actin microfilaments, inhibited BN- and TPA-induced tyrosine phosphorylation of p125(FAK) completely. In contrast, colchicine, an agent which disrupts microtubules, had no effect. Pretreatment with Clostridium botulinum C3 exoenzyme which inactivates the small GTP-binding protein rho p21, also inhibited tyrosine phosphorylation of p125(FAK) by 55%. These results demonstrate that activation of NMB-R can cause rapid tyrosine phosphorylation of p125(FAK). NMB-induced tyrosine phosphorylation of p125(FAK) is independent of NMB-induced changes in [Ca2+]i or PKC. The integrity of the actin cytoskeleton but not of microtubules is necessary for NMB-stimulated phosphorylation of p125(FAK). The ras-related small GTP-binding protein rho p21 is at least partially involved in mediating NMB-induced tyrosine phosphorylation of p125(FAK). These results suggest that similar to some other neuropeptides, activation of this pathway may be an important mechanism in mediating cellular changes by this receptor such as growth.
 ...
PMID:Neuromedin B receptor activation causes tyrosine phosphorylation of p125FAK by a phospholipase C independent mechanism which requires p21rho and integrity of the actin cytoskeleton. 940 68

Protein tyrosine phosphorylation was examined on a human glioblastoma cell line, T98G, after exposure to oxidative stress in vitro. Hydrogen peroxide (1 mM) markedly induced tyrosine phosphorylation of a 125 kDa protein at 30 min after stimulation. The 125-kDa molecule phosphorylated was revealed to be a focal adhesion kinase (FAK). Tyrosine phosphorylation of p125FAK continued at least up to 5 h, and decreased after 8 h concomitant with apoptosis. Tyrosine phosphorylation of p125FAK was blocked by herbimycin A, a potent inhibitor of protein tyrosine kinases, while apoptosis was accelerated. When T98G cells were incubated with FAK antisense oligonucleotide, apoptosis was also accelerated. These results suggest that tyrosine phosphorylation of p125FAK plays a suppressive role in hydrogen peroxide-induced apoptosis.
 ...
PMID:A suppressive role of p125FAK protein tyrosine kinase in hydrogen peroxide-induced apoptosis of T98G cells. 943 84

The tumor suppressor PTEN dephosphorylates focal adhesion kinase (FAK) and inhibits integrin-mediated cell spreading and cell migration. We demonstrate here that expression of PTEN selectively inhibits activation of the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway. PTEN expression in glioblastoma cells lacking the protein resulted in inhibition of integrin-mediated MAP kinase activation. Epidermal growth factor (EGF) and platelet-derived growth factor (PDGF)- induced MAPK activation were also blocked. To determine the specific point of inhibition in the Ras/Raf/ MEK/ERK pathway, we examined these components after stimulation by fibronectin or growth factors. Shc phosphorylation and Ras activity were inhibited by expression of PTEN, whereas EGF receptor autophosphorylation was unaffected. The ability of cells to spread at normal rates was partially rescued by coexpression of constitutively activated MEK1, a downstream component of the pathway. In addition, focal contact formation was enhanced as indicated by paxillin staining. The phosphatase domain of PTEN was essential for all of these functions, because PTEN with an inactive phosphatase domain did not suppress MAP kinase or Ras activity. In contrast to its effects on ERK, PTEN expression did not affect c-Jun NH2-terminal kinase (JNK) or PDGF-stimulated Akt. Our data suggest that a general function of PTEN is to down-regulate FAK and Shc phosphorylation, Ras activity, downstream MAP kinase activation, and associated focal contact formation and cell spreading.
 ...
PMID:Tumor suppressor PTEN inhibits integrin- and growth factor-mediated mitogen-activated protein (MAP) kinase signaling pathways. 983 64

PTEN/MMAC1 is a major new tumor suppressor gene that encodes a dual-specificity phosphatase with sequence similarity to the cytoskeletal protein tensin. Recently, we reported that PTEN dephosphorylates focal adhesion kinase (FAK) and inhibits cell migration, spreading, and focal adhesion formation. Here, the effects of PTEN on cell invasion, migration, and growth as well as the involvement of FAK and p130 Crk-associated substrate (p130Cas) were investigated in U87MG glioblastoma cells missing PTEN. Cell invasion, migration, and growth were down-regulated by expression of phosphatase-active forms of PTEN but not by PTEN with an inactive phosphatase domain; these effects were correlated with decreased tyrosine phosphorylation levels of FAK and p130Cas. Overexpression of FAK concomitant with PTEN resulted in increased total tyrosine phosphorylation levels of FAK and p130Cas and effectively antagonized the effects of PTEN on cell invasion and migration and partially on cell growth. Overexpression of p130Cas increased total tyrosine phosphorylation levels of p130Cas without affecting those of FAK; however, although p130Cas could reverse PTEN inhibition of cell invasion and migration, it did not rescue cell growth in U87MG cells. In contrast to FAK, p130Cas could not be shown to interact with PTEN in cells, and it was not dephosphorylated directly by PTEN in vitro. These results suggest important roles of PTEN in the phenotype of tumor progression, and that the effects of PTEN on cell invasion, migration, and growth are mediated by distinct downstream pathways that diverge at the level of FAK.
 ...
PMID:Tumor suppressor PTEN inhibition of cell invasion, migration, and growth: differential involvement of focal adhesion kinase and p130Cas. 992 60

Protein phosphorylation in a human glioblastoma cell line, T98G, was examined after exposure to oxidative stress in vitro. Hydrogen peroxide (1 mM) markedly induced tyrosine phosphorylation of focal adhesion kinase (FAK) and serine phosphorylation of Akt at 1 h after stimulation. Concommitantly, the association of FAK with phosphatidylinositide 3'-OH-kinase (PI 3-kinase) was also observed by the hydrogen peroxide stimulation. When T98G cells were incubated with wortmannin, a PI 3-kinase inhibitor, both PI 3-kinase activity and phosphorylation of Akt were inhibited, whereas apoptosis by oxidative stress was accelerated. Concomitant with apoptosis, elevated level of CPP32 protease activity (caspase-3) was observed, with decreases in Bcl-2 protein and increases in Bax protein. These results suggested that in the signal transduction pathway from FAK to PI 3-kinase, Akt promotes survival. Thus, it became apparent that FAK is the upstream signal protein of the PI 3-kinase-Akt survival pathway in hydrogen peroxide-induced apoptosis in T98G cells.
 ...
PMID:FAK is the upstream signal protein of the phosphatidylinositol 3-kinase-Akt survival pathway in hydrogen peroxide-induced apoptosis of a human glioblastoma cell line. 1018 51

The tumor suppressor PTEN is a phosphatase with sequence homology to tensin. PTEN dephosphorylates phosphatidylinositol 3,4, 5-trisphosphate (PIP3) and focal adhesion kinase (FAK), and it can inhibit cell growth, invasion, migration, and focal adhesions. We investigated molecular interactions of PTEN and FAK in glioblastoma and breast cancer cells lacking PTEN. The PTEN trapping mutant D92A bound wild-type FAK, requiring FAK autophosphorylation site Tyr397. In PTEN-mutated cancer cells, FAK phosphorylation was retained even in suspension after detachment from extracellular matrix, accompanied by enhanced PI 3-K association with FAK and sustained PI 3-K activity, PIP3 levels, and Akt phosphorylation; expression of exogenous PTEN suppressed all five properties. PTEN-mutated cells were resistant to apoptosis in suspension, but most of the cells entered apoptosis after expression of exogenous PTEN or wortmannin treatment. Moreover, overexpression of FAK in PTEN-transfected cells reversed the decreased FAK phosphorylation and PI 3-K activity, and it partially rescued PIP3 levels, Akt phosphorylation, and PTEN-induced apoptosis. Our results show that FAK Tyr397 is important in PTEN interactions with FAK, that PTEN regulates FAK phosphorylation and molecular associations after detachment from matrix, and that PTEN negatively regulates the extracellular matrix-dependent PI 3-K/Akt cell survival pathway in a process that can include FAK.
 ...
PMID:PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway. 1040 Jul 3

Cell-matrix interactions exert a profound influence on cell function and behavior. Our earlier observations suggested that disruption of the actin cytoskeleton results in the inhibition of phorbol ester-induced matrix metalloproteinase (MMP)-9 expression. In this study, to understand the role of protein tyrosine phosphatases in matrix metalloproteinase-9 expression, we treated glioblastoma cells with vanadate and phenylarsine oxide (PAO), which are inhibitors of protein tyrosine phosphatases. Vanadate and PAO inhibited expression of phorbol ester-induced MMP-9 as well as constitutive expression of matrix metalloproteinase-2 in a dose- and time-dependent fashion. An assay of the activity of phosphotyrosine phosphatase (PTPase) indicated that vanadate-treated cells had reduced PTPase activity compared with that of untreated controls. Vanadate and PAO also inhibited actin polymerization, cell spreading, migration, and invasion of glioma cells. Furthermore, elevated levels of protein tyrosine phosphorylation were observed in vanadate- and PAO-treated cells in both a concentration- and time-dependent fashion and were seen to have an inverse correlation with focal adhesion kinase protein expression. These results suggest that vanadate and PAO inhibited migration and invasion of glioma cells by their effect on the cytoskeleton and inhibition of MMP expression.
 ...
PMID:Altered actin cytoskeleton and inhibition of matrix metalloproteinase expression by vanadate and phenylarsine oxide, inhibitors of phosphotyrosine phosphatases: modulation of migration and invasion of human malignant glioma cells. 1056 4

In glioblastoma cells, inhibition of focal adhesion kinase (FAK) by the focal adhesion targeting domain attenuated epidermal growth factor receptor (EGFR) signaling, inhibiting epidermal growth factor-dependent migration. Although the EGFR-specific antagonist PD153035 increased caspase-3 activity, this was independent of FAK activity. Instead, the increase in apoptosis upon inhibition of FAK induced the aggregation of an NH(2)-terminal FAK fragment normally present in the nucleus. A recombinant NH(2)-terminal FAK construct was also targeted to the nucleus and aggregated in apoptotic cells upon coexpression with the focal adhesion targeting domain. Therefore, loss of FAK from the focal adhesions inhibits EGFR signaling at the cell membrane and transmits a proapoptotic signal to an NH(2)-terminal variant of FAK present in the nucleus.
 ...
PMID:Loss of focal adhesion kinase (FAK) inhibits epidermal growth factor receptor-dependent migration and induces aggregation of nh(2)-terminal FAK in the nuclei of apoptotic glioblastoma cells. 1143 28

Increased expression of focal adhesion kinase (FAK) was consistently observed in low- and high-grade astrocytomas and during glioblastoma progression after radiotherapy, but not in the more benign oligodendroglioma. In glioblastoma cell lines deficient for p53, p16(INK4A), and p14(ARF), FAK was inhibited in a dominant-negative manner by the focal adhesion targeting (FAT) domain, reducing invasion. In addition, caspase-3 activity was increased after serum withdrawal, or by cisplatin in the presence of serum, or upon loss of substrate attachment, and was in each case independent of PTEN status. Our results identify FAK as a potential target for anti-invasive strategies against infiltrating glioma cells.
 ...
PMID:PTEN-independent induction of caspase-mediated cell death and reduced invasion by the focal adhesion targeting domain (FAT) in human astrocytic brain tumors which highly express focal adhesion kinase (FAK). 1147 98

We have examined the role of the protein CD151 in cell motility, invasion and metastasis of cancer cells by using CD151-overexpressing cells prepared by transfection of CD151 cDNA into three cancer cell lines established from different origins; a human colon cancer RPMI4788, a human glioblastoma A172 and a human fibrosarcoma HT1080. Invasion into Matrigel and cell motility of all 3 CD151-overexpressing cancer cells were enhanced significantly when compared to control parental cells. Pulmonary metastasis of 2 metastatic CD151-overexpressing cancer cell lines, RPMI4788/CD151 and HT1080/CD151, was higher than that of control parental cells and was markedly inhibited by anti-CD151 monoclonal antibody (MAb), SFA1.2B4. To examine whether focal adhesion kinase (FAK) is associated with promotion of cell motility and invasion of cancer cells through CD151, we transfected human CD151 cDNA into FAK (+/+) or FAK (-/-) fibroblasts that were isolated from embryos in FAK-deficient mice and compared invasion into Matrigel and cell motility between each CD151-transfected cells and controls. The invasion into Matrigel and cell motility of CD151-transfected FAK (+/+) fibroblasts increased significantly above those of parental cells and were inhibited by anti-CD151 MAb, whereas those of CD151-transfected FAK (-/-) fibroblasts were not enhanced at all and were not blocked by anti-CD151 MAb. These findings indicate that the CD151 molecule enhances cell motility, invasion and metastasis of cancer cells and that FAK is needed for these events through CD151.
 ...
PMID:CD151 enhances cell motility and metastasis of cancer cells in the presence of focal adhesion kinase. 1177 85


1 2 3 4 5 6 7 8 Next >>