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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adhesion of human neuroblastoma cells (SK-N-SH clone SY5Y) to laminin or collagen type IV promotes tyrosine phosphorylation of a group of proteins with molecular mass ranging from 100 to 130 kDa and of a protein of 180 kDa. The same pattern of tyrosine phosphorylation was observed when SY5Y cells were allowed to adhere to culture dishes coated with monoclonal antibodies directed to the integrin subunits expressed in the cells, alpha 1, alpha 3, and beta 1, indicating that these receptors are responsible for this signaling mechanism. Using specific antibodies we identified the focal adhesion kinase p125FAK as a component of the 100- to 130-kDa phosphoproteins. Treatment with genistein or herbimycin A, two specific tyrosine kinase inhibitors, greatly reduced the tyrosine phosphorylation of the 100- to 130- and the 180-kDa proteins in response to laminin or collagen IV. Concomitantly, neurite outgrowth on the matrix proteins was strongly inhibited. This effect was observed in two distinct neuroblastoma cell lines, SY5Y and SK-N-BE. Genistein and herbimycin A treatment did not affect cell viability nor cause retraction of preformed neurites. These data suggest that matrix-induced tyrosine phosphorylation events are involved in neurite extension.
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PMID:Role of tyrosine phosphorylation in matrix-induced neurite outgrowth in human neuroblastoma cells. 808 34

In the current studies, we examined whether focal adhesion kinase (FAK) and paxillin play a role in insulin-like growth factor-I (IGF-I)-stimulated morphological changes in neuronal cells. In SH-SY5Y human neuroblastoma cells, 10 nM IGF-I enhanced the extension of lamellipodia within 30 min. Scanning electron microscopy and staining with rhodamine-phalloidin showed that these lamellipodia displayed ruffles, filopodia, and a distinct meshwork of actin filaments. Immunofluorescent staining identified focal concentrations of FAK, paxillin, and phosphotyrosine within the lamellipodia. Immunoprecipitation experiments revealed that FAK and paxillin are tyrosine-phosphorylated during IGF-I-stimulated lamellipodial extension. Maximal phosphorylation of FAK and paxillin was observed 15-30 min after the addition of 10 nM IGF-I, whereas maximal IGF-I receptor phosphorylation occurred within 5 min. FAK, paxillin, and IGF-I receptor tyrosine phosphorylation had similar concentration-response curves and were inhibited by the receptor blocking antibody alphaIR-3. These results indicate that FAK and paxillin are tyrosine-phosphorylated during IGF-I-stimulated lamellipodial advance and suggest that the tyrosine phosphorylation of these two proteins helps mediate IGF-I-stimulated cell and growth cone motility. These responses contrast directly with recent reports showing insulin-stimulated dephosphorylation of FAK and paxillin.
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PMID:Tyrosine phosphorylation of paxillin and focal adhesion kinase during insulin-like growth factor-I-stimulated lamellipodial advance. 903 May 91

In the current studies, we investigated the relationship between tyrosine phosphorylation and neurite formation. In SH-SY5Y neuroblastoma cells, the tyrosine kinase inhibitor methyl 2, 5-dihydroxycinnimate blocked neurite formation on laminin. This corresponded with inhibition of paxillin and focal adhesion kinase tyrosine phosphorylation as well as a disruption of actin filament organization and actin polymerization. This suggests that tyrosine phosphorylation helps direct changes in the actin cytoskeleton required for neurite formation.
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PMID:The tyrosine kinase inhibitor methyl 2,5-dihydroxycinnimate disrupts changes in the actin cytoskeleton required for neurite formation. 903 51

Axonal growth cones respond to adhesion molecules and extracellular matrix components by rapid morphological changes and growth rate modification. Neurite outgrowth mediated by the neural cell adhesion molecule (NCAM) requires the src family tyrosine kinase p59(fyn) in nerve growth cones, but the molecular basis for this interaction has not been defined. The NCAM140 isoform, which is found in migrating growth cones, selectively co-immunoprecipitated with p59(fyn) from nonionic detergent (Brij 96) extracts of early postnatal mouse cerebellum and transfected rat B35 neuroblastoma and COS-7 cells. p59(fyn) did not associate significantly with the NCAM180 isoform, which is found at sites of stable neural cell contacts, or with the glycophosphatidylinositol-linked NCAM120 isoform. pp60(c-)src, a tyrosine kinase that promotes neurite growth on the neuronal cell adhesion molecule L1, did not interact with any NCAM isoform. Whereas p59(fyn) was constitutively associated with NCAM140, the focal adhesion kinase p125(fak), a nonreceptor tyrosine kinase known to mediate integrin-dependent signaling, became recruited to the NCAM140-p59(fyn) complex when cells were reacted with antibodies against the extracellular region of NCAM. Treatment of cells with a soluble NCAM fusion protein or with NCAM antibodies caused a rapid and transient increase in tyrosine phosphorylation of p125(fak) and p59(fyn). These results suggest that NCAM140 binding interactions at the cell surface induce the assembly of a molecular complex of NCAM140, p125(fak), and p59(fyn) and activate the catalytic function of these tyrosine kinases, initiating a signaling cascade that may modulate growth cone migration.
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PMID:NCAM140 interacts with the focal adhesion kinase p125(fak) and the SRC-related tyrosine kinase p59(fyn). 907 53

The mechanism whereby agonist occupancy of muscarinic cholinergic receptors elicits an increased tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin has been examined. Addition of oxotremorine-M to SH-SY5Y neuroblastoma cells resulted in rapid increases in the phosphorylation of FAK (t(1/2) = 2 min) and paxillin that were independent of integrin-extracellular matrix interactions, cell attachment, and the production of phosphoinositide-derived second messengers. In contrast, the increased tyrosine phosphorylations of FAK and paxillin were inhibited by inclusion of either cytochalasin D or mevastatin, agents that disrupt the cytoskeleton. Furthermore, phosphorylation of FAK and paxillin could be prevented by addition of either wortmannin or LY-294002, under conditions in which the synthesis of phosphatidylinositol 4-phosphate was markedly attenuated. These results indicate that muscarinic receptor-mediated increases in the tyrosine phosphorylation of FAK and paxillin in SH-SY5Y neuroblastoma cells depend on both the maintenance of an actin cytoskeleton and the ability of these cells to synthesize phosphoinositides.
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PMID:Cytoskeletal and phosphoinositide requirements for muscarinic receptor signaling to focal adhesion kinase and paxillin. 948 13

Peroxynitrite may contribute to oxidative stress involving neurodegeneration in several disorders, including Alzheimer's disease. As with other reactive oxygen species, peroxynitrite might affect neuronal signalling systems, actions that could contribute to adaptive or deleterious cellular outcomes, but such effects have not previously been studied. To address this issue directly, peroxynitrite (50-500 microM) was administered to human neuroblastoma SH-SY5Y cells to assess its effects on protein tyrosine nitration, phosphoinositide signalling and protein tyrosine phosphorylation. Peroxynitrite rapidly increased the nitrotyrosine immunoreactivity of numerous proteins, primarily in the cytosol. Peroxynitrite inhibited, in a concentration-dependent manner, phosphoinositide hydrolysis stimulated by activation of muscarinic receptors with carbachol and the inhibition was greater after the depletion of cellular glutathione. In comparison, muscarinic receptor-stimulated phosphoinositide hydrolysis in human astrocytoma 1321N1 cells was less vulnerable to inhibition by peroxynitrite either without or with prior depletion of glutathione. There was a large, rapid and reversible increase in the tyrosine phosphorylation of the p120 Src substrate in peroxynitrite-treated SH-SY5Y cells, a response that was potentiated by glutathione depletion; in contrast, peroxynitrite decreased the tyrosine phosphorylation of focal adhesion kinase and paxillin. Tyrosine phosphorylation of p120 in 1321N1 astrocytoma cells was less sensitive to modulation by peroxynitrite. Thus alterations in phosphoinositide signalling and protein tyrosine phosphorylation were greater in neuroblastoma than astrocytoma cells, and modulation of these signalling processes probably contributes to neuronal mechanisms of the response to peroxynitrite.
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PMID:Peroxynitrite modulates tyrosine phosphorylation and phosphoinositide signalling in human neuroblastoma SH-SY5Y cells: attenuated effects in human 1321N1 astrocytoma cells. 953 3

In SH-SY5Y human neuroblastoma cells, insulin-like growth factor (IGF)-I mediates membrane ruffling and growth cone extension. We have previously shown that IGF-I activates the tyrosine phosphorylation of focal adhesion kinase (FAK) and extracellular signal-regulated protein kinase (ERK) 2. In the current study, we examined which signaling pathway underlies IGF-I-mediated FAK phosphorylation and cytoskeletal changes and determined if an intact cytoskeleton was required for IGF-I signaling. Treatment of SH-SY5Y cells with cytochalasin D disrupted the actin cytoskeleton and prevented any morphological changes induced by IGF-I. Inhibitors of phosphatidylinositol 3-kinase (PI 3-K) blocked IGF-I-mediated changes in the actin cytoskeleton as measured by membrane ruffling. In contrast, PD98059, a selective inhibitor of ERK kinase, had no effect on IGF-I-induced membrane ruffling. In parallel with effects on the actin cytoskeleton, cytochalasin D and PI 3-K inhibitors blocked IGF-I-induced FAK tyrosine phosphorylation, whereas PD98059 had no effect. It is interesting that cytochalasin D did not block IGF-I-induced ERK2 tyrosine phosphorylation. Therefore, it is likely that FAK and ERK2 tyrosine phosphorylations are regulated by separate pathways during IGF-I signaling. Our study suggests that integrity as well as dynamic motility of the actin cytoskeleton mediated by PI 3-K is required for IGF-I-induced FAK tyrosine phosphorylation, but not for ERK2 activation.
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PMID:Differential regulation of focal adhesion kinase and mitogen-activated protein kinase tyrosine phosphorylation during insulin-like growth factor-I-mediated cytoskeletal reorganization. 972 62

Regulatory interactions among individual receptor-coupled signal transduction systems are critically important for establishing cellular responses in the face of multiple stimuli. In this study, potential regulatory interactions between signal transduction systems activated by growth factor receptors and by G-protein-coupled receptors were examined using human neuroblastoma SH-SY5Y cells which express endogenous epidermal growth factor (EGF) and muscarinic M3 receptors. Activation of muscarinic receptors with carbachol was found to inhibit EGF-induced signaling, including tyrosine phosphorylation of the adaptor protein Cbl and of the EGF receptor, and complex formation between Shc proteins and the EGF receptor and Grb2. Protein kinase C, which is activated by muscarinic M3 receptors, mediated this inhibitory cross-talk. Activation of EGF receptors was found to inhibit muscarinic receptor-induced tyrosine phosphorylation of focal adhesion kinase and paxillin. Reactive oxygen species, which are formed as components of the EGF signaling cascade, mediated this inhibitory cross-talk. These mutual inhibitory interactions demonstrate novel mechanisms for neuronal integration of multiple signals generated by activation of receptors by neurotransmitters and growth factors.
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PMID:Muscarinic M3 and epidermal growth factor receptors activate mutually inhibitory signaling cascades in human neuroblastoma SH-SY5Y cells. 1004 86

Glial cell line-derived neurotrophic factor (GDNF) signals through a unique receptor system that includes Ret receptor tyrosine kinase and a glycosyl-phosphatidylinositol-linked cell surface protein. In the present study, we have identified several proteins in neuroblastoma cells that are phosphorylated on tyrosine in response to GDNF. The phosphorylated proteins include focal adhesion kinase (FAK), paxillin and Crk-associated substrate, p130Cas, all of which are known to be associated with focal adhesions. Of these, paxillin and p130Cas interacted with Crk proteins in GDNF-treated neuroblastoma cells. GDNF also induced reorganization of the actin cytoskelton. Tyrosine phosphorylation of FAK, paxillin and p130Cas was inhibited by cytochalasin D or two specific inhibitors of phosphatidylinositol-3' kinase (PI-3' kinase), wortmannin and LY294002, indicating that their tyrosine phosphorylation depends on the formation of actin stress fiber and activation of PI-3' kinase. In addition, phosphorylation of FAK but not of paxillin and p130Cas was markedly impaired by the Clostridium botulinum C3 exoenzyme that specifically ADP-ribosylates and inactivates Rho. These results suggested the presence of Rho-dependent and -independent signaling pathways downstream of PI-3' kinase that mediate tyrosine phosphorylation of FAK, paxillin and p130Cas through Ret kinase.
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PMID:Rho-dependent and -independent tyrosine phosphorylation of focal adhesion kinase, paxillin and p130Cas mediated by Ret kinase. 1020 19

Paxillin is a focal adhesion adaptor protein involved in the integration of growth factor- and adhesion-mediated signal transduction pathways. Repeats of a leucine-rich sequence named paxillin LD motifs (Brown M.C., M.S. Curtis, and C.E. Turner. 1998. Nature Struct. Biol. 5:677-678) have been implicated in paxillin binding to focal adhesion kinase (FAK) and vinculin. Here we demonstrate that the individual paxillin LD motifs function as discrete and selective protein binding interfaces. A novel scaffolding function is described for paxillin LD4 in the binding of a complex of proteins containing active p21 GTPase-activated kinase (PAK), Nck, and the guanine nucleotide exchange factor, PIX. The association of this complex with paxillin is mediated by a new 95-kD protein, p95PKL (paxillin-kinase linker), which binds directly to paxillin LD4 and PIX. This protein complex also binds to Hic-5, suggesting a conservation of LD function across the paxillin superfamily. Cloning of p95PKL revealed a multidomain protein containing an NH2-terminal ARF-GAP domain, three ankyrin-like repeats, a potential calcium-binding EF hand, calmodulin-binding IQ motifs, a myosin homology domain, and two paxillin-binding subdomains (PBS). Green fluorescent protein- (GFP-) tagged p95PKL localized to focal adhesions/complexes in CHO.K1 cells. Overexpression in neuroblastoma cells of a paxillin LD4 deletion mutant inhibited lamellipodia formation in response to insulin-like growth fac- tor-1. Microinjection of GST-LD4 into NIH3T3 cells significantly decreased cell migration into a wound. These data implicate paxillin as a mediator of p21 GTPase-regulated actin cytoskeletal reorganization through the recruitment to nascent focal adhesion structures of an active PAK/PIX complex potentially via interactions with p95PKL.
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PMID:Paxillin LD4 motif binds PAK and PIX through a novel 95-kD ankyrin repeat, ARF-GAP protein: A role in cytoskeletal remodeling. 1033 Apr 11


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