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)

A novel neuronal model (PC12EN cells), obtained by somatic hybridization of rat adrenal medullary pheochromocytoma (PC12) and bovine adrenal medullary endothelial (BAME) cells, was developed. PC12EN cells maintained numerous neuronal characteristics: they expressed neuronal glycolipid conjugates, synthesized and secreted catecholamines, and responded to differentiative agents with neurite outgrowth. PC12EN lacked receptors for EGF and both the p75 and trk NGF receptors, while FGF receptor expression was maintained. Staurosporine (5-50 nM), but not other members of the K252a family of protein kinase inhibitors, rapidly induced neurite outgrowth in PC12EN, as also found in the parental PC12 cells, but not in BAME cells. Similarly, both acidic and basic FGF (1-100 ng/ml) were neurotropic in PC12EN. In contrast to the mechanism by which FGF promoted neurite outgrowth in PC12EN, the neurotropic effect of staurosporine did not involve activation of established signalling pathways, such as tyrosine phosphorylation of erk (ras pathway) or SNT (a specific target of neuronal differentiation). In addition, staurosporine induced the tyrosine phosphorylation of the focal adhesion kinase p125FAK. However, since the latter effect was also observed with other protein kinase inhibitors of the K252a family, which induced PC12EN cells flattening but no neurite extension, we propose that FAK tyrosine phosphorylation may be related to ubiquitous changes in cell shape. We anticipate that PC12EN neuronal hybrids will become useful models in neuroscience research for evaluating unique cellular signalling mechanisms of novel neurotropic compounds.
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PMID:Staurosporine induces neurite outgrowth in neuronal hybrids (PC12EN) lacking NGF receptors. 887 7

This review summarizes the evolution of ideas concerning insulin signal transduction, the current information on protein ser/thr kinase cascades as signalling intermediates, and their status as participants in insulin regulation of energy metabolism. Best characterized is the Ras-MAPK pathway, whose input is crucial to cell fate decisions, but relatively dispensable in metabolic regulation. By contrast the effectors downstream of PI-3 kinase, although less well elucidated, include elements indispensable for the insulin regulation of glucose transport, glycogen and cAMP metabolism. Considerable information has accrued on PKB/cAkt, a protein kinase that interacts directly with Ptd Ins 3'OH phosphorylated lipids, as well as some of the elements further downstream, such as glycogen synthase kinase-3 and the p70 S6 kinase. Finally, some information implicates other erk pathways (e.g. such as the SAPK/JNK pathway) and Nck/cdc42-regulated PAKs (homologs of the yeast Ste 20) as participants in the cellular response to insulin. Thus insulin recruits a broad array of protein (ser/thr) kinases in its target cells to effectuate its characteristic anabolic and anticatabolic programs.
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PMID:Insulin signal transduction through protein kinase cascades. 960 12

We previously demonstrated contrasting roles for integrin alpha subunits and their cytoplasmic domains in controlling cell cycle withdrawal and the onset of terminal differentiation (Sastry, S., M. Lakonishok, D. Thomas, J. Muschler, and A.F. Horwitz. 1996. J. Cell Biol. 133:169-184). Ectopic expression of the integrin alpha5 or alpha6A subunit in primary quail myoblasts either decreases or enhances the probability of cell cycle withdrawal, respectively. In this study, we addressed the mechanisms by which changes in integrin alpha subunit ratios regulate this decision. Ectopic expression of truncated alpha5 or alpha6A indicate that the alpha5 cytoplasmic domain is permissive for the proliferative pathway whereas the COOH-terminal 11 amino acids of alpha6A cytoplasmic domain inhibit proliferation and promote differentiation. The alpha5 and alpha6A cytoplasmic domains do not appear to initiate these signals directly, but instead regulate beta1 signaling. Ectopically expressed IL2R-alpha5 or IL2R-alpha6A have no detectable effect on the myoblast phenotype. However, ectopic expression of the beta1A integrin subunit or IL2R-beta1A, autonomously inhibits differentiation and maintains a proliferative state. Perturbing alpha5 or alpha6A ratios also significantly affects activation of beta1 integrin signaling pathways. Ectopic alpha5 expression enhances expression and activation of paxillin as well as mitogen-activated protein (MAP) kinase with little effect on focal adhesion kinase (FAK). In contrast, ectopic alpha6A expression suppresses FAK and MAP kinase activation with a lesser effect on paxillin. Ectopic expression of wild-type and mutant forms of FAK, paxillin, and MAP/erk kinase (MEK) confirm these correlations. These data demonstrate that (a) proliferative signaling (i.e., inhibition of cell cycle withdrawal and the onset of terminal differentiation) occurs through the beta1A subunit and is modulated by the alpha subunit cytoplasmic domains; (b) perturbing alpha subunit ratios alters paxillin expression and phosphorylation and FAK and MAP kinase activation; (c) quantitative changes in the level of adhesive signaling through integrins and focal adhesion components regulate the decision of myoblasts to withdraw from the cell cycle, in part via MAP kinase.
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PMID:Quantitative changes in integrin and focal adhesion signaling regulate myoblast cell cycle withdrawal. 1008 71

Tyrosine kinase oncogenes such as p210BCR-ABL activate multiple signal pathways. As a result, it is difficult to infer the functional relevance of a pathway acting alone or in cooperation with another. One or 2 second-tier kinases represented in the p21ras and phosphatidylinositol-3-kinase (PI-3-kinase) pathways (activated RafCAAX and gag-akt, respectively) were expressed in parental H7 interleukin-3 (IL-3)-dependent myeloid cells. IL-3-dependent cells served, independently, as recipients of p210BCR-ABL, which activated p21ras and PI-3-kinase pathways, including raf/erk and akt, respectively, en route to transformation. By contrast, neither RafCAAX nor gag-akt when expressed in parental cells in isolation produced factor-independent cells. On the other hand, H7 cells expressing both RafCAAX and gag-akt (H7gag-akt/RafCAAX) were transformed. Such transformation in H7gag-akt/RafCAAX was accomplished in the absence of active versions of Shc or cbl, and there was no evidence of Stat activity and only modest amounts of bcl-xL, a Stat5 transcriptional target protein, all of which characterized the cells transformed by BCR-ABL. However, H7gag-akt/RafCAAX cells and H7BCR-ABL cells cultured in the absence of IL-3 shared strikingly increased p65 nuclear factor kappaB (NFkappaB) activity. Treatment of cells with a specific NFkappaB inhibitor, parthenolide, led to loss of NFkappaB activity and down-regulation of antiapoptotic c-IAP2. In cells with only gag-akt/RafCAAX, this was sufficient to allow polyADP ribosyltransferase (PARP)-degradative apoptosis, but in cells with p210BCR-ABL, apoptosis was blocked, possibly by a Stat5/bcl-xL-dependent mechanism. Therefore, one hematopoietic antiapoptotic program, among others, available to certain tyrosine kinase oncogenes involves a cooperative response between raf/erk and akt, unambiguous components of p21ras and PI-3-kinase pathways, to induce p65 NFkappaB and c-IAP2.
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PMID:Transformation of interleukin-3-dependent cells without participation of Stat5/bcl-xL: cooperation of akt with raf/erk leads to p65 nuclear factor kappaB-mediated antiapoptosis involving c-IAP2. 1158 49

During tumor metastasis, a fine-tuned balance between the formation and loosening of adhesive cell contacts has to occur, a process based on the regulated expression of integrins. Human ovarian OV-MZ-6 cancer cells express the integrin alpha(v)beta3, which associates with vitronectin (VN) and correlates with ovarian cancer progression. Adhesion and spreading of OV-MZ-6 cells on VN was accompanied by the formation of focal adhesion contacts and the recruitment of activated tyrosine-phosphorylated focal adhesion kinase. Cultivation of OV-MZ-6 cells on VN resulted in a significantly induced cell proliferation. This VN effect could be mimicked by cultivating cells on the immobilized alpha(v)beta3 directed peptide cyclo-Arg-Gly-Asp-D-Phe-Val (cRGDfV). VN-dependent OV-MZ-6 cell adhesion and proliferation was significantly enhanced by overexpression of alpha(v)beta3 and was accompanied by rapid and transient tyrosine-phosphorylation of p44(erk-1)/p42(erk-2) mitogen-activated protein kinase. Moreover, overexpression of alpha(v)beta3 and OV-MZ-6 cell attachment to VN increased cell motility up to 5-fold accompanied by prominent changes in cytoskeletal organization and cell morphology. Upon alpha(v)beta3/VN interaction, by cDNA expression microarray analysis we identified altered mRNA levels of c-myc, epidermal growth factor receptor (EGF-R), transcription factor Fra-1, prothymosin-alpha (PTMA), integrin-linked kinase (ILK), and the cell adhesion molecule SQM-1, candidates which are possibly involved in changes of the adhesive, migratory, and proliferative phenotype of human ovarian cancer cells.
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PMID:Ovarian cancer cell proliferation and motility is induced by engagement of integrin alpha(v)beta3/Vitronectin interaction. 1295 24

The influence of single-walled carbon nanotubes (SWCNTs) on human HEK293 cells is investigated with the aim of exploring SWCNTs biocompatibility. Results showed that SWCNTs can inhibit HEK293 cell proliferation, decrease cell adhesive ability in a dose- and time-dependent manner. HEK293 cells exhibit active responses to SWCNTs such as secretion of some 20-30 kd proteins to wrap SWCNTs, aggregation of cells attached by SWCNTs and formation of nodular structures. Cell cycle analysis showed that 25 microg/ml SWCNTs in medium induced G1 arrest and cell apoptosis in HEK293 cells. Biochip analysis showed that SWCNTs can induce up-regulation expression of cell cycle-associated genes such as p16, bax, p57, hrk, cdc42 and cdc37, down-regulation expression of cell cycle genes such as cdk2, cdk4, cdk6 and cyclin D3, and down-regulation expression of signal transduction-associated genes such as mad2, jak1, ttk, pcdha9 and erk. Western blot analysis showed that SWCNTs can induce down-regulation expression of adhesion-associated proteins such as laminin, fibronectin, cadherin, FAK and collagen IV. These results suggest that down-regulation of G1-associated cdks and cyclins and upregulation of apoptosis-associated genes may contribute to SWCNTs induced G1 phase arrest and cell apoptosis. In conclusion, SWCNTs can inhibit HEK293 cells growth by inducing cell apoptosis and decreasing cellular adhesion ability.
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PMID:Effect of single wall carbon nanotubes on human HEK293 cells. 1558 62

This study was designed to investigate Bad phosphorylation at several of its key regulatory Ser residues in cytokine-dependent hemopoietic cells. These studies were initiated in light of numerous studies that have reported a key role for phosphorylated Bad in preventing apoptosis. One key question is whether the survival signaling effect of the PI 3-kinase pathway is mediated by PKB phosphorylation of Bad. We confirm previous reports that if Bad is overexpressed or if active PKB is overexpressed, then the increased phosphorylation of Bad at Ser136 is apparent. However, we were unable to detect phosphorylation of endogenous Bad at Ser136 in the MC/9 mast cell line or in murine bone marrow-derived macrophages. On the other hand, phosphorylation of Bad at Ser112 and Ser155 was observed in response to IL-3 or GM-CSF, which activate the MEK/erk pathway, but not with IL-4, which activates the PI 3-kinase, but not the MEK/erk pathway, and also promotes cell survival. In contrast to previous reports, we found that ceramide had no effect on the phosphorylation status of Bad. In summary, our results suggest that Bad phosphorylation at any of the three major sites is not a required event for cytokine-dependent cell survival, and in particular, the activation of PI 3-kinase/PKB pathway can be dissociated from phosphorylation of Bad at Ser136.
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PMID:Phosphorylation of Bad is not essential for PKB-mediated survival signaling in hemopoietic cells. 1584 95

Upon overexpression of integrin alphavbeta3 and its engagement by vitronectin, we previously showed enhanced adhesion, proliferation, and motility of human ovarian cancer cells. By studying differential expression of genes possibly related to these tumor biological events, we identified the epidermal growth-factor receptor (EGF-R) to be under control of alphavbeta3 expression levels. Thus in the present study we characterized alphavbeta3-dependent changes of EGF-R and found significant upregulation of its expression and activity which was reflected by prominent changes of EGF-R promoter activity. Upon disruption of DNA-binding motifs for the transcription factors p53, ETF, the repressor ETR, p50, and c-rel, respectively, we sought to identify DNA elements contributing to alphavbeta3-mediated EGF-R promoter induction. Both, the p53- and ETF-mutant, while exhibiting considerably lower EGF-R promoter activity than the wild type promoter, retained inducibility by alphavbeta3. Mutation of the repressor motif ETR, as expected, enhanced EGF-R promoter activity with a further moderate increase upon alphavbeta3 elevation. The p50-mutant displayed EGF-R promoter activity almost comparable to that of the wild type promoter with no impairment of induction by alphavbeta3. However, the activity of an EGF-R promoter mutant displaying a disrupted c-rel-binding motif did not only prominently decline, but, moreover, was not longer responsive to enhanced alphavbeta3, involving this DNA element in alphavbeta3-dependent EGF-R upregulation. Moreover, alphavbeta3 did not only increase the EGF-R but, moreover, also led to obvious co-clustering on the cancer cell surface. By studying alphavbeta3/EGF-R-effects on the focal adhesion kinase (FAK) and the mitogen activated protein kinases (MAPK) p44/42 (erk(-1)/erk(-2)), having important functions in synergistic crosstalk between integrins and growth-factor receptors, we found for both significant enhancement of expression and activity upon alphavbeta3/VN interaction and cell stimulation by EGF. Upregulation of the EGF-R by integrin alphavbeta3, both receptor molecules with a well-defined role as targets for cancer treatment, might represent an additional mechanism to adapt synergistic receptor signaling and crosstalk in response to an altered tumor cell microenvironment during ovarian cancer progression.
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PMID:Integrin alphavbeta3 mediates upregulation of epidermal growth-factor receptor expression and activity in human ovarian cancer cells. 1857 66

MicroRNA-375 is involved in many types of alimentary system cancers. Our previous studies showed that microRNA-375 was significantly down-regulated in carcinoma tissues compared with para-carcinoma tissues, which strongly indicates that microRNA-375 might suppress the occurrence and development of colorectal cancer. However, the mechanism underlying the microRNA-375 regulation in colorectal cancer remains unclear. In this study, we first sorted out jak2, map3k8 and atg7 as microRNA-375 targeted genes from multiple databases, and found that jak2, map3k8 and their downstream genes stat3 and erk were up-regulated in carcinoma tissues. Secondly, we over-expressed microRNA-375 in colorectal cancer cell lines (HCT116, Caco2 and HT29). Our results showed that in microRNA-375 over-expressing cells, JAK2/STAT3 and MAP3K8/ERK proteins were down-regulated, cell proliferation was inhibited, cell migration rate did not change. There was no significant difference on ATG7 expression between the control group and microRNA-375 over-expressing HT29/Caco2 cells, whereas microRNA-375 down-regulated ATG7 specifically in HCT116 cells. Finally, we demonstrated that expressing microRNA-375 suppressed tumor formation in nude mice. In conclusion, microRNA-375 might function as a tumor-repressive gene to inhibit cell proliferation, mainly through targeting both JAK2/STAT3 and MAP3K8/ERK signaling pathways in colorectal cancer. These findings suggest miR-375 as a promising diagnostic marker and a therapeutic drug for colorectal cancer.
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PMID:microRNA-375 inhibits colorectal cancer cells proliferation by downregulating JAK2/STAT3 and MAP3K8/ERK signaling pathways. 2818 62

It is well known that Rho family small GTPases (Rho GTPase) has a role of molecular switch in intracellular signal transduction. The switch cycle between GTP-bound and GDP-bound state of Rho GTPase regulates various cell responses such as gene transcription, cytoskeletal rearrangements, and vesicular trafficking. Rho GTPase-specific guanine nucleotide exchange factors (RhoGEFs) are regulated by various extracellular stimuli and activates Rho GTPase such as RhoA, Rac1, and Cdc42. The molecular mechanisms that regulate RhoGEFs are poorly understood. Our studies reveal that Dbl's big sister (DBS), a RhoGEF for Cdc42 and RhoA, is phosphorylated at least on tyrosine residues at 479, 660, 727, and 926 upon stimulation by SRC signaling and that the phosphorylation at Tyr-660 is particularly critical for the serum response factor (SRF)-dependent transcriptional activation of DBS by Ephrin type-B receptor 2 (EPHB2)/SRC signaling. In addition, our studies also reveal that the phosphorylation of Tyr-479 and Tyr-660 on DBS leads to the actin cytoskeletal reorganization by EPHB2/SRC signaling. These findings are thought to be useful for understanding pathological conditions related to DBS such as cancer and non-syndromic autism in future.
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PMID:DBS is activated by EPHB2/SRC signaling-mediated tyrosine phosphorylation in HEK293 cells. 3108 35


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