Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.108 (TAT)
 2,389 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Met receptor tyrosine kinase is known to be overexpressed in many solid tumors and plays a crucial role in tumor invasive growth and metastasis. In this study, we showed that hepatocyte growth factor-induced Met activation as well as Met-dependent downstream signaling of AKT and p44/42 mitogen-activated protein kinase (MAPK) could be efficiently blocked by TAT-coupled carboxyl-terminal tail peptide of Met receptor (TCTP), and inactivation of Met signaling significantly enhanced the sensitivity of T98G and U251 glioma cells to cis-diaminedichloroplatinum (CDDP, cisplatin). However, neither phosphoinositide 3-kinase/AKT inhibitor LY294002 nor p44/42 MAPK inhibitor PD98059 alone or combined could imitate the effect of TCTP on chemosensitivity enhancement of T98G cells to CDDP, indicating that Met-dependent inactivation of AKT and p44/42 MAPK signaling was not the main cause for the increased chemosensitivity to CDDP. Further studies revealed that TCTP significantly activated p38 MAPK in T98G and U251 cell lines. Activation of p38 MAPK by sorbitol pretreatment resembled the sensitization effects, whereas inhibition of p38 MAPK activation by its inhibitor SB202190 counteracted the sensitization effects induced by TCTP. Therefore, p38 MAPK activation was one of the major causes for the increased chemosensitivity to CDDP induced by Met inactivation. Taken together, the study indicated that Met receptor played an important role in regulating cell response to chemotherapy and suggested that inhibition of Met signaling could be used in combination with other chemotherapeutic regimens in treatment of tumor patients.
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PMID:Inhibition of the met receptor tyrosine kinase signaling enhances the chemosensitivity of glioma cell lines to CDDP through activation of p38 MAPK pathway. 1943 73

Epidermal growth factor receptor (EGFR) and other receptor tyrosine kinases (RTKs) are overexpressed and/or mutated in various cancers and their abnormal activation is implicated in carcinogenesis. We explored the possibility of generating an imaging probe for RTK activation using the SH2 domain of Grb2 for cancer characterization. For cell penetration, molecular analysis and radiolabeling, the SH2 domain was fused with TAT, flag and tyrosine residue, respectively (termed TSF). We analyzed TSF characteristics in cells such as cellular uptake, stability and localization. After uptake into EGFR-expressing cells, TSF was found to be binding to phosphorylated-EGFR, which increased by stimulation with EGF. TSF was co-localized with EGFR in EGFR-activated cells, while it was localized as dots in cytosol in EGFR-non-activated cells. Cellular retention time of TSF was significantly extended under EGFR activation with EGF stimuli and reduced under the treatment with a tyrosine kinase inhibitor, Tyrphostin AG1478. In conclusion, the SH2 domain of Grb2 has the potential to be used as a binding component of a probe to detect activated-RTK and to evaluate the effect of kinase inhibitors on RTK activation.
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PMID:Basic study on SH2 domain of Grb2 as a molecular probe for detection of RTK activation. 2059 55

Sprouty negatively regulates receptor tyrosine kinase signals by inhibiting Ras/extracellular signal-regulated kinase (ERK) pathways. Sprouty is downregulated in breast, prostate and liver cancers and appears to function as a tumor suppressor. The role of sprouty in colonic neoplasia, however, has not been investigated. Sprouty-2 protein and mRNA transcripts were significantly upregulated in human colonic adenocarcinomas. Strikingly, the c-Met receptor was also upregulated in tumors with increased sprouty-2. To delineate a potential causal relationship between sprouty-2 and c-Met, K-ras mutant HCT-116 colon cancer cells were transduced with purified TAT-sprouty-2 protein or stably transfected with full-length human sprouty-2 gene. Sprouty-2 upregulation significantly increased cell proliferation by accelerating cell cycle transition. Sprouty-2 transfectants showed strong upregulation of c-Met protein and mRNA transcripts and hepatocyte growth factor-stimulated ERK and Akt phosphorylation and enhanced cell migration and invasion. In contrast, knockdown of c-Met by small interfering RNA (siRNA) significantly decreased cell proliferation, migration and invasion in sprouty-2 transfectants. Further, knockdown of sprouty-2 by siRNA in parental HT-29 and LS-174T colon cancer cells also decreased cell invasion. Sprouty-2 transfectants formed significantly larger tumor xenografts and showed increased proliferation and angiogenesis and suppressed apoptosis. Sprouty-2 tumors metastasized to the liver from cecal orthotopic implants, suggesting that sprouty-2 might also enhance metastatic signals. Thus, in colon cancer sprouty functions as an oncogene and its effects are mediated in part by c-Met upregulation.
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PMID:Sprouty-2 controls c-Met expression and metastatic potential of colon cancer cells: sprouty/c-Met upregulation in human colonic adenocarcinomas. 2066 Dec 23

The non-receptor tyrosine kinase c-Src is an important mediator in several signaling pathways related to neuroinflammation. Our previous study showed that cortical injection of kainic acid (KA) promoted a transient increase in c-Src activity in reactive astrocytes surrounding the neuronal lesion. As a cell-penetrating peptide based on connexin43 (Cx43), specifically TAT-Cx43266-283, inhibits Src activity, we investigated the effect of TAT-Cx43266-283 on neuronal death promoted by cortical KA injections in adult mice. As expected, KA promoted neuronal death, estimated by the reduction in NeuN-positive cells and reactive gliosis, characterized by the increase in glial fibrillary acidic protein (GFAP) expression. Interestingly, TAT-Cx43266-283 injected with KA diminished neuronal death and reactive gliosis compared to KA or KA+TAT injections. In order to gain insight into the neuroprotective mechanism, we used in vitro models. In primary cultured neurons, TAT-Cx43266-283 did not prevent neuronal death promoted by KA, but when neurons were grown on top of astrocytes, TAT-Cx43266-283 prevented neuronal death promoted by KA. These observations demonstrate the participation of astrocytes in the neuroprotective effect of TAT-Cx43266-283. Furthermore, the neuroprotective effect was also present in non-contact co-cultures, suggesting the contribution of soluble factors released by astrocytes. As glial hemichannel activity is associated with the release of several factors, such as ATP and glutamate, that cause neuronal death, we explored the participation of these channels on the neuroprotective effect of TAT-Cx43266-283. Our results confirmed that inhibitors of ATP and NMDA receptors prevented neuronal death in co-cultures treated with KA, suggesting the participation of astrocyte hemichannels in neurotoxicity. Furthermore, TAT-Cx43266-283 reduced hemichannel activity promoted by KA in neuron-astrocyte co-cultures as assessed by ethidium bromide (EtBr) uptake assay. In fact, TAT-Cx43266-283 and dasatinib, a potent c-Src inhibitor, strongly reduced the activation of astrocyte hemichannels. In conclusion, our results suggest that TAT-Cx43266-283 exerts a neuroprotective effect through the reduction of hemichannel activity likely mediated by c-Src in astrocytes. These data unveil a new role of c-Src in the regulation of Cx43-hemichannel activity that could be part of the mechanism by which astroglial c-Src participates in neuroinflammation.
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PMID:A c-Src Inhibitor Peptide Based on Connexin43 Exerts Neuroprotective Effects through the Inhibition of Glial Hemichannel Activity. 2932 48