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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the roles of adenomatous polyposis coli (APC) protein and glycogen synthase kinase 3beta (GSK3beta) of smoking murine model in the repair of the injured airway epithelial cells (AECs) in different stages, 30 male Kun-Ming mice were randomly divided into two groups, the control group and the smoking group. There were 24 mice in smoking group, and 6 animals were separately killed at the end of the 1st, 4th, 8th and 12th week after smoking. Then the following tests were undertaken: (1) HE staining of lung section to observe the morphological changes of the bronchi in the smoking mice. (2) Immunohistochemical staining of APC protein and GSK3beta in the AECs. (3) Western blot was used to detect the levels of APC protein, GSK3beta and phosphorated GSK3beta (p-GSK3beta) in pulmonary tissue. (4) Observing the localizations of APC protein and GSK3beta in the AECs by immunofluorescence technique. The results showed: (1) AECs showed changes of predominant injury (1-, 4-week), repair (8-week) and reinjury (12-week) along with smoking time prolonged. The experimental results indicated that the model of smoking mice was duplicated successfully. (2) Immunohistochemical results showed that the expression of APC protein in the AECs increased after 1-week smoking (0.458 +/- 0.062 vs 0.399 +/- 0.060, P< 0.05 vs control), but was significantly decreased at the end of the 4th week (0.339+/- 0.056, P<0.01 vs control) and increased at the end of the 8th and 12th week (0.387 +/- 0.041, 0.378 +/- 0.037, P<0.05 vs 4-week). The expression of GSK3beta in the AECs of smoking mice obviously decreased (P<0.01 or P<0.05 vs control). (3) Western blot showed that the expressions of APC protein and GSK3beta in lung tissue were consistent with the results of immunohistochemistry; and the levels of p-GSK3beta in all smoking models were higher than that in control. (4) The results of immunofluorescence showed that APC protein was localized mainly near the regions of epithelial cell membrane at the end of the 1st and 8th week after smoking, which were dissimilar with the localization in control, and this change was not seen in the location of GSK3beta. Taken together, these results demonstrate that the expressions and localizations of APC protein, GSK3beta and the activity of GSK3beta are dynamically changed in the AECs with experimental smoking injury at different phases, suggesting that APC protein and GSK3beta may be involved in the regulation of migration and proliferation of AECs, and play an important role in the process of repair of airway epithelium injury.
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PMID:[Dynamic changes of adenomatous polyposis coli protein and glycogen synthase kinase 3beta in the repair of the injured airway epithelial cells in smoking mice]. 1678 10

The Wnt gene family encodes secreted signaling molecules that play important roles in tumorgenesis and embryogenesis. The canonical Wnt signaling pathway regulates target gene expression via the stabilization and nuclear translocation of the cytoplasmic pool of beta-catenin. The activation of integrin-linked kinase (ILK) is also known to regulate the stabilization and subsequent nuclear translocation of beta-catenin in several epithelial cell models. We now report that molecular and pharmacological inhibition of ILK activity in mammalian cells directly modulates Wnt signaling by suppressing the stabilization and nuclear translocation of beta-catenin, as well as beta-catenin/Lef-mediated transcription. Inhibition of ILK activity, but not phosphatidylinositol-3 kinase (PI3K) or MEK activities suppresses nuclear beta-catenin stabilization in cells stably expressing Wnt3a as well as in cells exposed to either Wnt3a conditioned media or purified Wnt3a. Furthermore, ILK inhibition reverses the Wnt3a-induced suppression of beta-catenin phosphorylation that accompanies beta-catenin stabilization. In addition, we show that ILK can be identified in a complex with Wnt pathway components such as adenomatous polyposis coli and GSK-3. Upon treatment of L cells with Wnt3a-CM, glycogen synthase kinase-3 (GSK-3beta) becomes highly phosphorylated on Ser 9, which is completely abolished upon inhibition of ILK activity. However, acute exposure of L cells to purified Wnt3a does not result in the stimulation of GSK-3beta Ser 9 phosphorylation, despite beta-catenin stabilization. Together our data demonstrate that ILK activity can modulate acute Wnt3a mediated beta-catenin phosphorylation, stabilization and nuclear activation in a PI3K-independent manner, as well as the more prolonged PI3K-dependent secondary effects of Wnt signaling on GSK-3 phosphorylation. Finally, we suggest that a novel small molecule inhibitor of ILK, QLT-0267, may be a useful tool in the regulation of pathological Wnt signaling.
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PMID:Modulation of Wnt3a-mediated nuclear beta-catenin accumulation and activation by integrin-linked kinase in mammalian cells. 1679 42

Beta-catenin plays multiple roles in cell-cell adhesion and Wnt signal transduction. Through the Wnt signal, the cellular level of beta-catenin is constitutively regulated by the multicomponent destruction complex containing glycogen synthase kinase 3beta, axin, and adenomatous polyposis coli. Here, we present multiple lines of evidence to demonstrate that LZTS2 (lucine zipper tumor suppressor 2) interacts with beta-catenin, represses the transactivation of beta-catenin, and affects the subcellular localization of beta-catenin. The LZTS2 gene is located at 10q24.3, which is frequently lost in a variety of human tumors. A functional nuclear export signal (NES) was identified in the C terminus of the protein (amino acids 631 to 641). Appending this motif to green fluorescent protein (GFP) induced nuclear exclusion of the GFP fusion protein. However, introducing point mutations in either one or two leucine residues of this NES sequence abolished the nuclear exclusion of the LZTS2 protein. The nuclear export of LZTS2 can be blocked by leptomycin B (LMB), an inhibitor of the CRM1/exportin-alpha pathway. Intriguingly, beta-catenin colocalizes with LZTS2 in the cytoplasm of cells in the absence of LMB but in the nuclei of cells in the presence of LMB. Increasing the LZTS2 protein in cells reduces the level of nuclear beta-catenin in SW480 cells. Taken together, these data demonstrate that LZTS2 is a beta-catenin-interacting protein that can modulate beta-catenin signaling and localization.
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PMID:LZTS2 is a novel beta-catenin-interacting protein and regulates the nuclear export of beta-catenin. 1700 Jul 60

Increased expression of casein kinase 2 (CK2) is associated with hyperproliferation and suppression of apoptosis in cancer. Mutations in the tumor suppressor APC (adenomatous polyposis coli) are frequent in colon cancer and often augment beta-catenin-T cell factor (Tcf)/lymphoid enhancer binding factor (Lef)-dependent transcription of genes such as c-myc and cyclin-D1. CK2 has also been implicated recently in the regulation of beta-catenin stability. To identify mechanisms by which CK2 promotes survival, effects of the specific CK2 inhibitors 4,5,6,7-tetrabromobenzotriazole (TBB) and 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole were assessed. TBB and 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole significantly decreased proliferation and increased apoptosis of HT29(US) colon cancer cells. RT-PCR and immunoblot analysis revealed that both inhibitors decreased survivin mRNA and protein levels in HT29(US) cells. Similar effects were observed with TBB in human DLD-1 and SW-480 colorectal cells as well as ZR-75 breast cancer cells and HEK-293T embryonic kidney cells. Expression of GFP-CK2alpha in HEK-293T cells resulted in beta-catenin-Tcf/Lef-dependent up-regulation of survivin and increased resistance to anticancer drugs. Augmented beta-catenin-Tcf/Lef-dependent transcription and resistance to apoptosis observed upon GFP-CK2alpha expression were abolished by TBB. Alternatively, HEK-293T cells expressing GFP-survivin were resistant to TBB-induced apoptosis. Finally, siRNA-mediated down-regulation of CK2alpha in HEK-293T cells coincided with reduced beta-catenin and survivin levels. Taken together, these results suggest that CK2 kinase activity promotes survival by increasing survivin expression via beta-catenin-Tcf/Lef-mediated transcription. Hence, selective CK2 inhibition or down-regulation in tumors may provide an attractive opportunity for the development of novel cancer therapies.
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PMID:Casein kinase 2 (CK2) increases survivin expression via enhanced beta-catenin-T cell factor/lymphoid enhancer binding factor-dependent transcription. 1700 22

It has been shown that accumulation of free beta-catenin leads to mobility shift of adenomatous polyposis coli (APC) protein and that Axin facilitates this process. Here we show that the beta-catenin-mediated mobility shift of APC is due to phosphorylation of two domains of APC by casein kinase 1epsilon/glycogen synthase kinase 3beta and unknown kinase(s), respectively. Interestingly, our results suggest that this process does not require Axin. The phosphorylated APC showed higher affinity to beta-catenin in vivo, and fragments of APC containing the phosphorylated domains can inhibit beta-catenin/Tcf-mediated reporter activity regardless of their ability to reduce the level of beta-catenin. From our data we propose a new role of APC: accumulation of excessive cytoplasmic beta-catenin induces phosphorylation of APC and the phosphorylated APC retains beta-catenin in cytoplasm to prevent excessive beta-catenin signaling. The retained beta-catenin in cytoplasm by APC may be down-regulated by Axin 2, which is induced by beta-catenin/Tcf signaling.
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PMID:Axin-independent phosphorylation of APC controls beta-catenin signaling via cytoplasmic retention of beta-catenin. 1741 91

To investigate the roles of glycogen synthase kinase 3beta (GSK3beta) and adenomatous polyposis coli (APC) protein in wound repair of airway epithelial cells (AECs), we established a wound model of airway epithelium in vitro. Then the following tests were undertaken: (1) Western blot was used to detect the levels of total GSK3beta and phosphorylated GSK3beta in human bronchial epithelial (16HBE) cells; (2) The localizations of APC protein was observed by using immunofluorescence technique; (3) Immunoprecipitation was used to investigate the relationship between APC protein and GSK3beta during the repair of 16HBE cells. The results were as follows: (1) The level of phosphorylated GSK3beta increased 0.5 h after scratching (P<0.05), reached a maximum at 6 h (P<0.05), and maintained until 12 h, while the total level of GSK3beta remained constant; (2) Results of immunofluorescence study showed that APC protein clustered with tubulin in the region of the migrating leading cells 6 h after scratching, which was dissimilar with that in the cells 0 h after scratching; (3) GSK3beta and APC protein were immunoprecipitated and analysed on SDS-PAGE. We found that GSK3beta and APC protein were precipitated, indicating that the two proteins existed in a complex. After scratching, dissociation of the two proteins occurred. Taken together, we conclude that scratching caused a decrease in phosphorylation of GSK3beta, and that reduced phosphorylation of GSK3beta promoted APC protein to bind to the plus ends of microtubules and stabilize the growing ends. These observations suggest that APC protein and GSK3beta may synergistically play an important role in the repair of airway epithelium.
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PMID:[Spatial-temporal distribution of glycogen synthase kinase 3beta and adenomatous polyposis coli protein are involved in the injury and repair of airway epithelial cells induced by scratching]. 1743 43

The RET receptor tyrosine kinase has essential roles in cell survival, differentiation, and proliferation. Oncogenic activation of RET causes the cancer syndrome multiple endocrine neoplasia type 2 (MEN 2) and is a frequent event in sporadic thyroid carcinomas. However, the molecular mechanisms underlying RET's potent transforming and mitogenic signals are still not clear. Here, we show that nuclear localization of beta-catenin is frequent in both thyroid tumors and their metastases from MEN 2 patients, suggesting a novel mechanism of RET-mediated function through the beta-catenin signaling pathway. We show that RET binds to, and tyrosine phosphorylates, beta-catenin and show that the interaction between RET and beta-catenin can be direct and independent of cytoplasmic kinases, such as SRC. As a result of RET-mediated tyrosine phosphorylation, beta-catenin escapes cytosolic down-regulation by the adenomatous polyposis coli/Axin/glycogen synthase kinase-3 complex and accumulates in the nucleus, where it can stimulate beta-catenin-specific transcriptional programs in a RET-dependent fashion. We show that down-regulation of beta-catenin activity decreases RET-mediated cell proliferation, colony formation, and tumor growth in nude mice. Together, our data show that a beta-catenin-RET kinase pathway is a critical contributor to the development and metastasis of human thyroid carcinoma.
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PMID:A novel RET kinase-beta-catenin signaling pathway contributes to tumorigenesis in thyroid carcinoma. 1831 96

In response to extracellular signals during embryonic development, cells undergo directional movements to specific sites and establish proper connections to other cells to form organs and tissues. Cell extension and migration in the direction of extracellular cues is mediated by the actin and microtubule cytoskeletons, and recent results have shed new light on how these pathways are activated by neurotrophins, Wnt or extracellular matrix. These signals lead to modifications of microtubule-associated proteins (MAPs) and point to glycogen synthase kinase (GSK) 3beta as a key regulator of microtubule function during directional migration. This review will summarize these results and then focus on the role of microtubule-binding protein adenomatous polyposis coli (APC) in neuronal polarization and directed migration, and on its regulation by GSK3beta.
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PMID:Role of adenomatous polyposis coli (APC) and microtubules in directional cell migration and neuronal polarization. 1838 24

The adenomatous polyposis coli (APC) tumour suppressor is a multifunctional protein involved in the regulation of Wnt signalling and cytoskeletal dynamics. Little is known about how APC controls these disparate functions. In this study, we have used APC- and axin-fluorescent fusion proteins to examine the interactions between these proteins and show that the functionally distinct populations of APC are also spatially separate. Axin-RFP forms cytoplasmic punctate structures, similar to endogenous axin puncta. Axin-RFP recruits beta-catenin destruction complex proteins, including APC, beta-catenin, glycogen synthase kinase-3-beta (GSK3-beta) and casein kinase-1-alpha (CK1-alpha). Recruitment into axin-RFP puncta sequesters APC from clusters at cell extensions and this prevents its microtubule-associated functions. The interaction between APC-GFP and axin-RFP within the cytoplasmic puncta is direct and dramatically alters the dynamic properties of APC-GFP. However, recruitment of APC to axin puncta is not absolutely required for beta-catenin degradation. Instead, formation of axin puncta, mediated by the DIX domain, is required for beta-catenin degradation. An axinDeltaDIX mutant did not form puncta, but still mediated recruitment of destruction complex proteins and phosphorylation of beta-catenin. We conclude that there are distinct pools of APC and that the formation of axin puncta, rather than the axin/APC complex, is essential for beta-catenin destruction.
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PMID:Recruitment of adenomatous polyposis coli and beta-catenin to axin-puncta. 1859 34

The E2F1 transcription factor can promote proliferation or apoptosis when activated, and is a key downstream target of the retinoblastoma tumour suppressor protein (pRB). Here we show that E2F1 is a potent and specific inhibitor of beta-catenin/T-cell factor (TCF)-dependent transcription, and that this function contributes to E2F1-induced apoptosis. E2F1 deregulation suppresses beta-catenin activity in an adenomatous polyposis coli (APC)/glycogen synthase kinase-3 (GSK3)-independent manner, reducing the expression of key beta-catenin targets including c-MYC. This interaction explains why colorectal tumours, which depend on beta-catenin transcription for their abnormal proliferation, keep RB1 intact. Remarkably, E2F1 activity is also repressed by cyclin-dependent kinase-8 (CDK8), a colorectal oncoprotein. Elevated levels of CDK8 protect beta-catenin/TCF-dependent transcription from inhibition by E2F1. Thus, by retaining RB1 and amplifying CDK8, colorectal tumour cells select conditions that collectively suppress E2F1 and enhance the activity of beta-catenin.
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PMID:E2F1 represses beta-catenin transcription and is antagonized by both pRB and CDK8. 1881 47


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