K-252a and staurosporine selectively block autophosphorylation of neurotrophin receptors and neurotrophin-mediated responses.

Nye, Steven H.; Squinto, Stephen P.; Glass, David J.; Stitt, Trevor N.; Hantzopoulos, Petros; Macchi, Mary J.; Lindsay, N S; Ip, Nancy Y.; Yancopouloš, George D.

doi:10.1091/mbc.3.6.677

Cited by 145 publications

(99 citation statements)

References 45 publications

(64 reference statements)

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“…However in MLP-29 cells the same concentration of K252a did not affect phosphorylation of the signaling molecules following an EGF stimulus. Results similar to ours were obtained by others using K252a to inhibit PDGF receptor signaling (Nye et al, 1992). Also in this case receptor phosphorylation was only partially blocked in conditions in which PDGF-dependent ERK2 phosphorylation was completely inhibited.…”

Section: Discussionsupporting

confidence: 90%

“…As a control for the specificity of the inhibitor we used EGF, a growth factor whose receptor was previously described as insensitive to K252a (Nye et al, 1992;Chin et al, 1997;Ruggeri et al, 1999). After stimulation, cells were lysed and analysed for phosphorylation of the RTKs and of downstream effectors.…”

Section: K252a Inhibits Metmentioning

confidence: 99%

“…It was originally described as a serine/threonine kinase inhibitor. Subsequently it was found to act as a potent and selective inhibitor of Trk family members (Tapley et al, 1992) and as a partial inhibitor of the PDGF receptor (IC 50 in the low versus high nanomolar range, respectively) (Nye et al, 1992). In this range of concentrations the compound was inactive on the EGF, FGF and IGF-1 receptors (Nye et al, 1992;Chin et al, 1997;Ruggeri et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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K252a inhibits the oncogenic properties of Met, the HGF receptor

et al. 2002

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The ATP analog K252a is a potent inhibitor for receptor tyrosine kinases of the Trk family. Here we show that nanomolar concentrations of K252a prevent HGFmediated scattering in MLP-29 cells (30 nM), reduce Met-driven proliferation in GTL-16 gastric carcinoma cells (100 nM), and cause reversion in NIH3T3 fibroblasts transformed by the oncogenic form of the receptor, TprMet (75 nM). K252a inhibits Met autophosphorylation in cultured cells and in immunoprecipitates and prevents activation of its downstream effectors MAPKinase and Akt. Interestingly, K252a seems to be more effective at inhibiting the mutated form of Met (M1268T) found in papillary carcinoma of the kidney than the wild type receptor. Pretreatment of both Tpr-Met-transformed NIH3T3 fibroblasts and of GTL-16 gastric carcinoma cells with K252a results in loss of their ability to form lung metastases in nude mice upon injection into the caudal vein. These observations suggest that K252a derivatives, which are active in vivo as anti-cancer drugs in models of Trk-driven malignancies, should also be effective for treatment of Met-mediated tumors.

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Section: Discussionsupporting

confidence: 90%

Section: K252a Inhibits Metmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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K252a inhibits the oncogenic properties of Met, the HGF receptor

et al. 2002

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“…This is a representative of several experiments (anti-trk and ab-1 antibodies have similar immunoprecipitation e ciencies shown to be phosphorylated in the absence of ligand stimulation . To determine whether the elevated levels of trk tyrosine phosphorylation in PC12trk ts p53 cells were responsible for the di erentiated phenotype, the cells were treated with 100 nM K252a, a speci®c inhibitor of trk tyrosine kinase activity in PC12 cells (Berg et al, 1992;Knusel et al, 1992;Nye et al, 1992;Tapley et al, 1992). K252a treatment inhibited the neuronal di erentiation of PC12trk ts p53 cells (data not shown), suggesting that the mechanism of neurite induction by p53 involves the activation of trk tyrosine kinase activity.…”

Section: Pc12trkmentioning

confidence: 99%

p53 associates with trk tyrosine kinase

Montano

1997

Oncogene

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The p53 tumor suppressor gene encodes a phosphoprotein which when overexpressed can induce growth arrest at the G1 and G2/M phases of the cell cycle, promote di erentiation and apoptosis. This paper demonstrates that p53 can associate with trk tyrosine kinase. Expression of a murine temperature-sensitive (ts) p53 mutant in PC12 cells overexpressing trk (a model system to analyse cellular di erentiation and signal transduction induced by NGF) induces morphological changes in the absence of NGF stimulation at 328C but not at 378C. In cells di erentiated by p53, trk, but not EGFr, was hyperphosphorylated on tyrosine. Furthermore trk was not phosphorylated when expressed in Saos-2 cells (human osteosarcoma cells that lack expression of both endogenous trk and p53) at either temperature. However, transfection of ts p53 into these cells induces trk phosphorylation at 328C in the absence of NGF stimulation. Association of trk and p53 can be detected in NIH3T3 and PC12 cells co-expressing trk and the ts p53 mutant, in NIH3T3 and PC12 cells transfected with trk alone, and in untransfected PC12 cells, showing that overexpressed and/or endogenous trk associates with endogenous, low levels of p53. These data suggest a novel function for p53 which involves the stimulation of signal transduction pathways (mediating morphological properties of cells), possibly through association with and hyperphosphorylation of trk.

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“…NGF binding stimulates the tyrosine kinase activity of trkA (Bothwell, 1991;Kaplan et al, 1991;Klein et al, 1991;Ebendal, 1992;Jing et al, 1992;Parada et al, 1992). Inactivation, removal, or functional inhibition of the tyrosine kinase domain (Ferrari et al, 1992;Jing et al, 1992;Knusel and Hefti, 1992;Nye et al, 1992;Ohmichi et al, 1992;Tapley et al, 1992) results in the loss of NGF actions. Although the precise CNS cell groups containing trkA is not clearly defined, it is known that cholinergic neurons of the striatum and basal forebrain express trkA mRNA (Lu et al, 1989;Kokaia et al, 1993;Miranda et al, 1993) and protein (Steininger et al, 1993).…”

mentioning

confidence: 99%

TrkA‐immunoreactive profiles in the central nervous system: Colocalization with neurons containing p75 nerve growth factor receptor, choline acetyltransferase, and serotonin

Sobreviela

Clary

Reichardt

et al. 1994

J of Comparative Neurology

306

197

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The present investigation used an antibody directed against the extracellular domain of the signal transducing nerve growth factor receptor, trkA, to reveal immunoreactive perikarya or fibers within the olfactory bulb and tubercle, cingulate cortex, nucleus accumbens, striatum, endopiriform nucleus, septal/diagonal band complex, nucleus basalis, hippocampal complex, thalamic paraventricular and reunions nuclei, periventricular hypothalamus, interpeduncular nucleus, mesencephalic nucleus of the fifth nerve, dorsal nucleus of the lateral lemniscus, prepositus hypoglossal nucleus, ventral cochlear nucleus, ventral lateral tegmentum, medial vestibular nucleus, spinal trigeminal nucleus oralis, nucleus of the solitary tract, raphe nuclei, and spinal cord. Colocalization experiments revealed that virtually all striatal trkA-immunoreactive neurons (> 99%) coexpressed choline acetyltransferase (ChAT) but not p75 nerve growth factor receptor (NGFR). Within the septal/diagonal band complex virtually all trkA neurons (>95%) coexpressed both ChAT and p75 NGFR. More caudally, dual stained sections revealed numerous trkA/ChAT (> 80%) and trkA/p75 NGFR (> 95%) immunoreactive neurons within the nucleus basalis. In the brainstem, raphe serotonergic neurons (45%) coexpressed trkA. Sections stained with a pan-trk antibody that recognizes primarily trkA, as well as trkB and trkC, labeled neurons within all of these regions as well as within the hypothalamic arcuate, supramammilary, and supraoptic nuclei, hippocampus, inferior and superior colliculus, substantia nigra, ventral tegmental area of T'sai, and cerebellar Purkinje cells. Virtually all of these other regions with the exception of the cerebellum also expressed pan-trk immunoreactivity in the monkey. The widespread expression of trkA throughout the central neural axis suggests that this receptor may play a role in signal transduction mechanisms linked to NGF-related substances in cholinergic basal forebrain and non-cholinergic systems. These findings suggest that pharmacological use of ligands for trkA could have beneficial effects on the multiple neuronal systems that are affected in such disorders as Alzheimer's disease. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe classic research of Levi-Montalcini and coworkers (for review, see Levi-Montalcini and Angeletti 1968;Thoenen and Barde, 1980) first demonstrated that nerve growth factor (NGF) was an important trophic substance for the development and maintenance of noradrenergic peripheral sympathetic neurons. A potential role for NFG within the central nervous system (CNS) was first identified in the adult rat brain following injection of radiolabeled NGF into the cortex and hippocampus. These investigations did not reveal retrogradely labeled perikarya within the noradrenergic locus coeruleus as expected, but instead exclusively labeled neurons within the septal/diagonal band complex and the nucleus basalis magnocellularis (Schwab et al., 1979; Seiler and Schwab, 1984). These transpor...

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K-252a and staurosporine selectively block autophosphorylation of neurotrophin receptors and neurotrophin-mediated responses.

Cited by 145 publications

References 45 publications

K252a inhibits the oncogenic properties of Met, the HGF receptor

K252a inhibits the oncogenic properties of Met, the HGF receptor

p53 associates with trk tyrosine kinase

TrkA‐immunoreactive profiles in the central nervous system: Colocalization with neurons containing p75 nerve growth factor receptor, choline acetyltransferase, and serotonin

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