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)

The urokinase-type plasminogen activator receptor (uPAR) is involved in several biological processes, including proteolysis, adhesion, migration and inflammation. Increased expression of uPAR is associated with metastasis in several tumor types. We studied the biological role of uPAR in melanoma and found that inhibition of uPAR via RNA interference induced massive death in three different metastatic cell lines. Annexin-V staining and caspase activation analysis revealed induction of the mitochondrial apoptotic pathway. The expression of members of the Bcl-2 family (Bax, Bcl-2, Bak and Bcl-x(L)) was changed in a pro-apoptotic manner. uPAR inhibition induced the expression of the tumor suppressor p53 and of its downstream target gene p21. Inhibition of p53 rescued cells from apoptosis indicating that p53 was critical for apoptosis induction. Apoptosis was observed in melanoma cells carrying activating BRAF mutations and occurred in the presence of extracellular signal-regulated kinase (ERK) phosphorylation. uPAR can activate focal adhesion kinase (FAK), which is implicated in adhesion-dependent tumor cell survival. However, inhibition of FAK did not induce apoptosis. Our data suggest a new function of uPAR acting as a survival factor for melanoma by downregulating p53. Inhibition of uPAR induces a pro-apoptotic signalling pathway via p53 that is independent of ERK or FAK signalling. These findings may offer new treatment strategies for metastatic melanoma.
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PMID:Inhibition of urokinase-type plasminogen activator receptor induces apoptosis in melanoma cells by activation of p53. 1711 Sep 57

The death of midbrain dopaminergic neurons in sporadic Parkinson disease is of unknown etiology but may involve altered growth factor signaling. The present study showed that leptin, a centrally acting hormone secreted by adipocytes, rescued dopaminergic neurons, reversed behavioral asymmetry, and restored striatal catecholamine levels in the unilateral 6-hydroxydopamine (6-OHDA) mouse model of dopaminergic cell death. In vitro studies using the murine dopaminergic cell line MN9D showed that leptin attenuated 6-OHDA-induced apoptotic markers, including caspase-9 and caspase-3 activation, internucleosomal DNA fragmentation, and cytochrome c release. ERK1/2 phosphorylation (pERK1/2) was found to be critical for mediating leptin-induced neuroprotection, because inhibition of the MEK pathway blocked both the pERK1/2 response and the pro-survival effect of leptin in cultures. Knockdown of the downstream messengers JAK2 or GRB2 precluded leptin-induced pERK1/2 activation and neuroprotection. Leptin/pERK1/2 signaling involved phosphorylation and nuclear localization of CREB (pCREB), a well known survival factor for dopaminergic neurons. Leptin induced a marked MEK-dependent increase in pCREB that was essential for neuroprotection following 6-OHDA toxicity. Transfection of a dominant negative MEK protein abolished leptin-enhanced pCREB formation, whereas a dominant negative CREB or decoy oligonucleotide diminished both pCREB binding to its target DNA sequence and MN9D survival against 6-OHDA toxicity. Moreover, in the substantia nigra of mice, leptin treatment increased the levels of pERK1/2, pCREB, and the downstream gene product BDNF, which were reversed by the MEK inhibitor PD98059. Collectively, these data provide evidence that leptin prevents the degeneration of dopaminergic neurons by 6-OHDA and may prove useful in the treatment of Parkinson disease.
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PMID:Leptin protects against 6-hydroxydopamine-induced dopaminergic cell death via mitogen-activated protein kinase signaling. 1789 42

Agglucetin, a platelet glycoprotein (GP)Ib binding protein from Formosan Agkistrodon acutus (A. acutus) venom, could sustain human umbilical vein endothelial cell (HUVEC) proliferation and HUVEC adhering to immobilized agglucetin showed extensive spreading, which was strongly abrogated by integrin antagonists 7E3 and triflavin. Flow cytometric analyses confirmed the expression of GPIb complex on HUVEC is absent and fluorescein isothiocyanate (FITC)-agglucetin binds to HUVEC in a dose-dependent and saturable manner. Furthermore, native agglucetin specifically and dose-dependently inhibited the binding of FITC-23C6, an anti-alphavbeta3 monoclonal antibody (mAb), but not antibodies against alpha2 and alpha5, toward HUVEC and purified alphavbeta3 also bound to immobilized agglucetin-beta in a dose-dependent manner. Moreover, agglucetin exhibited a pro-angiogenic effect in vitro, as well as the focal adhesion kinase (FAK)-associated signaling molecules responsible for HUVEC activation were initiated by agglucetin. In conclusion, agglucetin, acting as a survival factor, promotes endothelial adhesion and angiogenesis by triggering alphavbeta3 signaling through FAK/phosphatidylinositol 3-kinase (PI3K)/Akt pathway.
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PMID:Agglucetin, a tetrameric C-type lectin-like venom protein, regulates endothelial cell survival and promotes angiogenesis by activating integrin alphavbeta3 signaling. 1831 55

Our laboratories have previously identified the alpha7 nAChR-JAK2 pathway as playing a central role in nicotine-induced neuroprotection. We have also reported that the angiotensin II (Ang II) AT(2) receptor induced activation of SHP-1 induces the tyrosine dephosphorylation of JAK2 that results in a complete neutralization of the alpha7 nAChR-JAK2 pro-survival cascade. In this study, we investigated the effects of inhibiting the alpha7 nAChR-JAK2 pro-survival cascade on the nicotine-induced production of the survival factor Bcl-2 and the transcriptional activation of NF-kappaB, AP-1, STAT1, STAT3, and STAT5. We report that nicotine induced the production of Bcl-2 and increased the transcriptional activation of NF-kappaB, AP-1, STAT1, and STAT3, and with the exception of AP-1, the other transcription factors (NF-kappaB, STAT1, and STAT3) were significantly reduced by JAK2 inhibition. We also demonstrate that, via transfection of either Bcl-2 antisense or NF-kappaB, STAT1 and STAT3 transcription factor decoys oligodeoxyribonucleotides into PC12 cells, nicotine induces its neuroprotection in PC12 cells via activation of the alpha7 nAChR-JAK2-(NF-kappaB; STAT3)-Bcl-2 pro-survival pathway. Finally, the neuroprotective nicotine-induced production of Bcl-2 appears to fully counteract the Abeta (1-42)-induced apoptosis of PC12 cells by blocking Abeta (1-42)-induced mitochondrial release of cytosolic cytochrome C.
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PMID:Convergence of alpha 7 nicotinic acetylcholine receptor-activated pathways for anti-apoptosis and anti-inflammation: central role for JAK2 activation of STAT3 and NF-kappaB. 1906 68

Maintenance of E-cadherin mediated cell-cell contacts is often required for the survival of epithelial cells and tissues. Here we report that oncogenic activation of H-Ras in murine keratinocytes can prevent cell death induced by immunological disruption of E-cadherin adhesion. A similar situation was observed in cells showing constitutive activation of the p110 alpha catalytic subunit of class IA PI3K. This protective effect is associated with beta-catenin-dependent transcription and with activation of survival factor Akt/PKB. In addition, we induced cell death by employing photodynamic therapy, using Zn-phthalocyanine as a photosensitizer that targets E-cadherin adhesion complexes. We have found that cell death based on this photodynamic action is also bypassed in cells showing constitutive activation of H-Ras and p110 alpha. Taken together, these results indicate that H-Ras/PI3K/Akt signaling plays a key role in cell survival mediated by E-cadherin cell-cell contacts.
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PMID:Oncogenic H-Ras and PI3K signaling can inhibit E-cadherin-dependent apoptosis and promote cell survival after photodynamic therapy in mouse keratinocytes. 1906 34

CNTF is a cytokine that promotes survival and/or differentiation in many cell types, including rat pancreatic islets. In this work, we studied the mechanism of CNTF signal in neonatal rats pancreatic islets isolated by the collagenase method and cultured for 3 days in RPMI medium without (CTL) or with 1 nM of CNTF. The medium contained, when necessary, specific inhibitors of the PI3K, MAPK and JAK/STAT3 pathways. mRNA expression (RT-PCR) and protein phosphorylation (Western blot) of Akt, ERK1/2 and STAT3, and SOCS-3 (RT-PCR and Western blot), as well as glucose-stimulated insulin secretion (GSIS) (Radioimmunoassay), were analyzed. Our results showed that Akt, ERK1 and STAT3 mRNA expression, as well as phosphorylated Akt and ERK1/2, was not affected by CNTF treatment. CNTF increased cytoplasmatic and nuclear phosphorylated STAT3, and the SOCS3 mRNA and protein expression. In addition, CNTF lowered apoptosis and impaired GSIS. These effects were blocked by the JAK inhibitor, AG490 and by the STAT3 inhibitor Curcumin, but not by the MAPK inhibitor, PD98059, nor by the PI3K inhibitor, Wortmannin. In conclusion, CNTF signals through the JAK2/STAT3 cascade, increases SOCS3 expression, impairs GSIS and protects neonatal pancreatic rat islets from cytokine-induced apoptosis. These findings indicate that CNTF may be a potential therapeutic tool against Type 1 and/or Type 2 diabetes.
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PMID:Ciliary neurotrophic factor (CNTF) signals through STAT3-SOCS3 pathway and protects rat pancreatic islets from cytokine-induced apoptosis. 1927 93

Myeloid cell leukemia-1 (Mcl-1), a member of the B-cell lymphoma-2 (Bcl-2) family, has been reported to be a critical survival factor in hematopoietic cells, yet little data exists for a role of Mcl-1 in human oral squamous cell carcinoma (SCC). A high level expression of Mcl-1 was observed in tumor cells of human primary SCC, lymph node metastasis tissues, and SCC cell lines. We manipulated expression of Mcl-1 protein in SCC cells by small interfering RNA (siRNA) for Mcl-1 and observed that Mcl-1 siRNA inhibited the growth of SCCs accompanied with apoptosis. Combination therapy of Mcl-1 siRNA and anti-tumor drug drastically inhibited the cell growth in comparison to that in each single treatment. In addition, phosphorylation of focal adhesion kinase (FAK) was decreased by treatment with Mcl-1 siRNA, resulting in decreases in phosphorylation of MEK1/2 and MAPK. The cell growth inhibition caused by knockdown of Mcl-1 was suggested to be mainly a result of suppression of proliferation via the inhibition of intracellular FAK/MAPK signaling pathways. These results imply a potentially important and novel role of the inhibition of Mcl-1 function by the use of specific siRNA in the treatment of SCC.
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PMID:Role of myeloid cell leukemia-1 in cell growth of squamous cell carcinoma. 1957 64

Adiponectin is believed to exert hepatoprotective effects and induces CXCL8, a chemokine that functions as a survival factor, in vascular cells. In the current study, it is demonstrated that adiponectin also induces CXCL8 expression in primary human hepatocytes but not in hepatocellular carcinoma cell lines. Knock down of the adiponectin receptor (AdipoR) 1 or AdipoR2 by small-interfering RNA indicates that AdipoR1 is involved in adiponectin-stimulated CXCL8 release. Adiponectin activates nuclear factor (NF)-kappaB in primary hepatocytes and pharmacological inhibition of NF-kappaB, the p38 mitogen-activated protein kinase, and extracellular signal-regulated kinase (ERK) 1/ERK2 reduces adiponectin-mediated CXCL8 secretion. Furthermore, adiponectin also activates STAT3 involved in interleukin (IL)-6 and leptin-mediated CXCL8 induction in primary hepatocytes. Inhibition of JAK2 by AG-490 does not abolish adiponectin-stimulated CXCL8, indicating that this kinase is not involved. Pretreatment of primary cells with "STAT3 Inhibitor VI," however, elevates hepatocytic CXCL8 secretion, demonstrating that STAT3 is a negative regulator of CXCL8 in these cells. In accordance with this assumption, IL-6, a well-characterized activator of STAT3, reduces hepatocytic CXCL8. Therefore, adiponectin-stimulated induction of CXCL8 seems to be tightly controlled in primary human hepatocytes, whereas neither NF-kappaB, STAT3, nor CXCL8 are influenced in hepatocytic cell lines. CXCL8 is a survival factor, and its upregulation by adiponectin may contribute to the hepatoprotective effects of this adipokine.
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PMID:Adiponectin-stimulated CXCL8 release in primary human hepatocytes is regulated by ERK1/ERK2, p38 MAPK, NF-kappaB, and STAT3 signaling pathways. 1960 29

Targeted antibody-based therapy has been used successfully to treat cancers. Recent studies have demonstrated that tumor cells treated with antibodies specific for beta(2)-microglobulin (beta(2)M) or major histocompatibility complex (MHC) class I molecules undergo apoptosis in vitro and in vivo (mouse models). Antibodies against beta(2)M or MHC class I induce tumor cell apoptosis by 1) recruiting MHC class I molecules to lipid rafts and activating LYN kinase and the signal-transducing enzyme phospholipase C-gamma2-dependent c-Jun N-terminal kinase signaling pathway and 2) expelling interleukin 6 and insulin-like growth factor 1 receptors out of lipid rafts and inhibiting the growth and survival factor-induced activation of the phosphatidylinositol 3-kinase/Akt and extracellular signal-related kinase pathways. Consequently, mitochondrial integrity is compromised, and the caspase-9-dependent cascade is activated in treated tumor cells. However, although beta(2)M and MHC class I are expressed on normal hematopoietic cells, which is a potential safety concern, the monoclonal antibodies were selective to tumor cells and did not damage normal cells in vitro or in human-like mouse models. These findings suggest that targeting beta(2)M or MHC class I by using antibodies or other agents offers a potential therapeutic approach for beta(2)M/MHC class I-expressing malignancies. Cancer 2010. (c) 2010 American Cancer Society.
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PMID:Killing tumor cells through their surface beta(2)-microglobulin or major histocompatibility complex class I molecules. 2014 45

Signal transduction therapy for cancer targets signaling elements with key roles in cancer cell survival and proliferation, but with more minor roles in the survival of healthy cells. Cancer cells have shrunken signaling networks, and therefore tend to be dependent on fewer signaling modules than non-cancerous cells. Thus, targeted therapy holds the promise of efficacy with minimal toxicity. Yet, with the notable exception of Gleevec for the treatment of early chronic myelogenous leukemia (CML), targeted therapies have so far had minimal success. Unlike early CML, which is dependent upon BCR-ABL, most cancers are not dependent on a single survival factor. Furthermore, tumors are constantly evolving entities, and are heterogeneous in their cellular makeup, compounding the challenge. "Smart cocktails", comprising rational combinations of therapies, need to be developed to meet this challenge. What are the best pathways to target, and why? What types of molecules can be developed into effective therapeutics? What combinations are likely to be successful? Here we present an overview of the principles that need to be considered in designing effective targeted therapy for cancer.
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PMID:Signal transduction therapy of cancer. 2045 49


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