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)

Here, we report the identification of a new tensin family member, tensin3, and its role in epidermal growth factor (EGF) signaling pathway. Human tensin3 cDNA encodes a 1445 amino acid sequence that shares extensive homology with tensin1, tensin2, and COOH-terminal tensin-like protein. Tensin3 is expressed in various tissues and in different cell types such as endothelia, epithelia, and fibroblasts. The potential role of tensin3 in EGF-induced signaling pathway is explored. EGF induces tyrosine phosphorylation of tensin3 in MDA-MB-468 cells in a time- and dose-dependent manner, but it is independent of an intact actin cytoskeleton or phosphatidylinositol 3-kinase. Activation of EGF receptor is necessary but not sufficient for tyrosine phosphorylation of tensin3. It also requires Src family kinase activities. Furthermore, tensin3 forms a complex with focal adhesion kinase and p130Cas in MDA-MB-468 cells. Addition of EGF to the cells induces dephosphorylation of these two molecules, leads to disassociation of the tensin3-focal adhesion kinase-p130Cas complex, and enhances the interaction between tensin3 and EGF receptor. Our results demonstrate that tensin3 may function as a platform for the disassembly of EGF-related signaling complexes at focal adhesions.
 ...
PMID:Epidermal growth factor modulates tyrosine phosphorylation of a novel tensin family member, tensin3. 1514 Sep 44

The localization of the cyclin-dependent kinase inhibitor p27(kip1) is dependent on the phosphorylation of one of three key amino acid residues: S10, T157 and T198. However, it was unclear whether endogenous p27(kip1) is phosphorylated at T198 in the living cell. In the present work we describe the generation and characterization of a polyclonal antibody able to recognize recombinant, transfected as well as endogenous T198-phosphorylated p27(kip1). Using this antibody, we demonstrate that: (1) endogenous p27(kip1) is phosphorylated at T198 in 4 breast cancer cells lines (MCF7, MDA-MB231, MDA- MB436 and MDA-MB468); (2) T198 phosphorylation is increased in breast cancer cells compared with normal mammary epithelial cells (HMEC); (3) T198-phosphorylated p27(kip1) is exclusively cytoplasmic; (4) T198 phosphorylation is dependent on the activity of the PI3K-PKB/Akt pathway, being it drastically reduced by the pharmacological PI3K inhibitor LY294002 or stimulated by the constitutive activation of PKB/Akt. Finally, in primary human breast carcinomas, cytoplasmic accumulation of T198-phosphorylated p27(kip1) parallels Akt activation. We conclude that in breast cancer cells p27(kip1) is phosphorylated at T198 in a PI3K/Akt dependent manner and that this phosphorylation may contribute to p27(kip1) cytoplasmic mislocalization observed in breast cancer.
 ...
PMID:Akt-dependent T198 phosphorylation of cyclin-dependent kinase inhibitor p27kip1 in breast cancer. 1528 Jun 62

We have previously shown that novel protein kinase C (nPKC) isozymes, such as nPKCepsilon, negatively regulate TNF-induced apoptosis in breast cancer cells although the level on nPKCs did not correlate with cellular sensitivity to TNF. In the present study, we examined if the level/activation status of Akt/PKB influences antiapoptotic signaling by nPKCepsilon. While MCF-7 cells overexpressed PKB, BT-20 and SKBR-3 cells expressed constitutively phosphorylated PKB, and MDA-MB-231 cells expressed unphosphorylated PKB. Ly294002, an inhibitor of PI-3 kinase, induced cell death in SKBR-3 cells, which contained little nPKCs. Although Ly294002 by itself had only a modest effect on cell death in BT-20 and MCF-7 cells, it potentiated sensitivity of these cells to TNF. In contrast, Ly294002 either alone or in combination with TNF had little effect on cell death in MDA-MB-231 cells. These results suggest that the status of PKB in breast cancer cells influences antiapoptotic signaling by PKC.
 ...
PMID:Deregulation of PKB influences antiapoptotic signaling by PKC in breast cancer cells. 1528 68

We analysed breast tumors and breast cancer cell lines for the expression of beta-parvin (ParvB), an adaptor protein that binds to the integrin-linked kinase (ILK). Quantitative RT-PCR indicated that ParvB mRNA was downregulated, by at least 60%, in four of nine breast tumors, relative to patient-matched normal mammary gland tissue. We also found that ParvB protein levels were reduced by > or =90% in five of seven advanced tumors, relative to matched normal breast tissue. Conversely, ILK protein and kinase activity levels were elevated in these tumors, suggesting that downregulation of ParvB stimulates ILK signaling. Western blot analyses indicated very low levels of ParvB protein in MDA-MB-231 and MCF7 breast cancer cells, facilitating functional studies of the effects of ParvB on ILK signaling. Expression of ParvB in MDA-MB-231 and MCF7 cells increased cell adhesion to collagen. ParvB inhibited ILK kinase activity, anchorage-independent cell growth and in vitro matrigel invasion by MDA-MB-231 cells. EGF-induced phosphorylation of two ILK targets, PKB (Ser473) and glycogen synthase kinase 3beta (Ser9), was also inhibited by ParvB. These results indicated that ParvB inhibits ILK signaling downstream of receptor tyrosine kinases. Our results suggest that loss of ParvB expression is a novel mechanism for upregulating ILK activity in tumors.
 ...
PMID:Beta-parvin inhibits integrin-linked kinase signaling and is downregulated in breast cancer. 1546 40

Basic fibroblast growth factor (FGF-2) expression takes place during morphogenic differentiation of mammary ducts and is lost in breast cancer. Forced re-expression of FGF-2 in breast cancer cell lines induces a more differentiated phenotype and inhibits motility by unknown mechanisms. Here we demonstrate that MDA-MB-231 cells with encumbered motility due to forced re-expression of FGF-2 have activated focal complexes as determined by immunoprecipitation/western blotting and immunofluorescence staining with antibodies to FAK, p130Cas, paxillin, vinculin and phosphotyrosine. The activation of the focal adhesion complexes results in loss of stress fibers associated with malignant transformation of mammary epithelial cells and the formation of circumferentially-distributed actin bundles associated with non-transformed mammary epithelial cells. These effects require continuous FGF-2 expression, as the effects of exogenous recombinant FGF-2 are only small and transient. FGF-2 expression results in an increase in integrin alpha 3 expression and decreases in integrin beta 1 and beta 4 expression. These changes, however, induce only a small decrease in adhesion to uncoated and fibronectin-coated tissue culture dishes suggesting that the primary cause of impaired motility is due to intrinsic signaling. These data suggest that FGF-2-inhibits motility in breast cancer cells by stabilization of focal complexes and induction of a more differentiated phenotype with disruption of stress fiber formation and a characteristic cortical actin distribution.
 ...
PMID:Expression of FGF-2 alters focal adhesion dynamics in migration-restricted MDA-MB-231 breast cancer cells. 1553 42

We have shown that inhibition of polyamine biosynthesis with alpha-difluoromethylornithine (DFMO) reduces in vitro invasiveness and metastatic capacity of MDA-MB-435 breast cancer cells. These experiments investigated the mechanisms mediating the anti-invasive properties of DFMO. DFMO did not affect phosphorylation of FAK or Akt, but increased ERK phosphorylation by approximately threefold. To test the biologic significance of this finding, we tested the effect of the MEK inhibitor PD98059 on in vitro invasiveness of MDA-MB-435 breast cancer cells, both in the absence and in the presence of the proinvasive peptide hepatocyte growth factor (HGF) as a chemoattractant. We observed that PD98059 treatment reversed the anti-invasive effect of DFMO under both experimental conditions. Next, we tested the influence of DFMO on the production of the prometastatic peptide osteopontin (OPN) and the anti-metastatic protein thrombospondin-1 (TSP-1). DFMO treatment, while not affecting OPN production, markedly increased the TSP-1 level in the conditioned media. This effect was abolished by putrescine administration, thus indicating the specificity of the DFMO action through the polyamine pathway. PD98059 completely blocked the stimulatory effect of DFMO on TSP-1 production, which supports a mediatory role for activation of the MAPK pathway in the upregulation of this anti-metastatic peptide by DFMO. In summary, our results show that the increase in ERK phosphorylation induced by DFMO plays a critical role in the anti-invasive action of the drug and in its ability to upregulate TSP-1 production.
 ...
PMID:Cellular mechanisms mediating the anti-invasive properties of the ornithine decarboxylase inhibitor alpha-difluoromethylornithine (DFMO) in human breast cancer cells. 1567 71

Morphologic characteristics of the long-term denervated muscle in animals suggest that some original fibers are lost and some of those seen are the result of repeated cycles of fiber regeneration. Muscle biopsies from lower motoneuron denervated patients enrolled in the EU Project RISE show the characteristics of long-term denervation. They present a few atrophic or severely atrophic myofibers dispersed among adipocytes and connective tissue (denervated degenerated muscle, DDM). Monoclonal antibody for embryonic myosin shows that regenerative events are present from 1- to 37-years postspinal cord injury (SCI). After 2- to 10-years FES-training the muscle cryosections present mainly large round myofibers. In the FES-trained muscles the regenerative events are present, but at a lower rate than long-term denervated muscles (myofiber per mm2 of cryosection area: 0.8 +/- 1.3 in FES vs. 2.3 +/- 2.3 in DDM, mean +/- SD, P = 0.011). In our opinion this is a sound additional evidence of effectiveness of the Kern's electrical stimulation protocol for FES of DDM. In any case, the overall results demonstrate that the FES-training is safe: at least it does not induce more myofiber damage/regeneration than denervation per se.
 ...
PMID:Muscle fiber regeneration in human permanent lower motoneuron denervation: relevance to safety and effectiveness of FES-training, which induces muscle recovery in SCI subjects. 1572 14

Constitutive activation of the JAK/STAT3 pathway is a major contributor to oncogenesis. In the present study, structure-activity relationship (SAR) studies with five cucurbitacin (Cuc) analogs, A, B, E, I, and Q, led to the discovery of Cuc Q, which inhibits the activation of STAT3 but not JAK2; Cuc A which inhibits JAK2 but not STAT3 activation; and Cuc B, E, and I, which inhibit the activation of both. Furthermore, these SAR studies demonstrated that conversion of the C3 carbonyl of the cucurbitacins to a hydroxyl results in loss of anti-JAK2 activity, whereas addition of a hydroxyl group to C11 of the cucurbitacins results in loss of anti-STAT3 activity. Cuc Q inhibits selectively the activation of STAT3 and induces apoptosis without inhibition of JAK2, Src, Akt, Erk, or JNK activation. Furthermore, Cuc Q induces apoptosis more potently in human and murine tumors that contain constitutively activated STAT3 (i.e., A549, MDA-MB-435, and v-Src/NIH 3T3) as compared to those that do not (i.e., H-Ras/NIH 3T3, MDA-MB-453, and NIH 3T3 cells). Finally, in a nude mouse tumor xenograft model, Cuc Q, but not Cuc A, suppresses tumor growth indicating that JAK2 inhibition is not sufficient to inhibit tumor growth and suggesting that the ability of Cuc Q to inhibit tumor growth is related to its anti-STAT3 activity. These studies further validate STAT3 as a drug discovery target and provide evidence that pharmacological agents that can selectively reduce the P-STAT3 levels in human cancer cells result in tumor apoptosis and growth inhibition.
 ...
PMID:Cucurbitacin Q: a selective STAT3 activation inhibitor with potent antitumor activity. 1573 20

Resveratrol, a grape polyphenol, is thought to be a cancer preventive, yet its effects on metastatic breast cancer are relatively unknown. Since cancer cell invasion is dependent on cell migration, the chemotactic response of MDA-MB-231 metastatic human breast cancer cells to resveratrol, estradiol (E2), or epidermal growth factor (EGF) was investigated. Resveratrol decreased while E2 and EGF increased directed cell migration. Resveratrol may inhibit cell migration by altering the cytoskeleton. Resveratrol induced a rapid global array of filopodia and decreased focal adhesions and focal adhesion kinase (FAK) activity. E2 or EGF treatment did not affect filopodia extension but increased lamellipodia and associated focal adhesions that are integral for cell migration. Combined resveratrol and E2 treatment resulted in a filopodia and focal adhesion response similar to resveratrol alone. Combined resveratrol and EGF resulted in a lamellipodia and focal adhesion response similar to EGF alone. E2 and to a lesser extent resveratrol increased EGFR activity. The cytoskeletal changes and EGFR activity in response to E2 were blocked by EGFR1 inhibitor indicating that E2 may increase cell migration via crosstalk with EGFR signaling. These data suggest a promotional role for E2 in breast cancer cell migration but an antiestrogenic, preventative role for resveratrol.
 ...
PMID:Resveratrol and estradiol exert disparate effects on cell migration, cell surface actin structures, and focal adhesion assembly in MDA-MB-231 human breast cancer cells. 1580 18

Rho GTPases are overexpressed in human tumors and are involved in a variety of cellular processes such as organization of the actin cytoskeleton, cell-cell contact and malignant transformation. EGFR activation plays a key role in the acquisition of motile properties in carcinoma cells, and it has been proposed that downregulation of FAK activity is one of its most relevant consequences. In the present study, using mammary MCF-7 cells, we demonstrated that overexpression of the active form of the small GTPase RhoA induced the activation of EGFR by a phenomenon that depends on the activity of a metalloproteinase (MMP), which presumably cleaves a membrane-bound EGFR ligand. The EGFR tyrosine phosphorylation correlates with ERK1,2 activation and the stimulation of urokinase production. An aggressive mammary cell line (MDA-MB-231) that overexpresses both RhoA and EGFR in their active forms also displayed an MMP-dependent activation mechanism of EGFR. RhoA-GTP-transfected cells showed a cortical array of F-actin, rounded morphology, reduced spreading potential and a dephosphorylation of FAK that was released by integrin-dependent fibronectin adhesion and a specific EGFR tyrosine kinase inhibitor. Our results suggest that the MMP-dependent EGFR activation observed in V14 RhoA cells represents the starting point of a signaling route that promotes cell motility by activation of ERK1,2 and further enhancement of proteases production.
 ...
PMID:Overexpression of RhoA-GTP induces activation of the Epidermal Growth Factor Receptor, dephosphorylation of focal adhesion kinase and increased motility in breast cancer cells. 1596 82


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>