K-252a: a specific inhibitor of the action of nerve growth factor on PC 12 cells

Koizumi, Shinichi; Contreras, Margarita L.; Matsuda, Yuzuru; Hama, Tokiko; Lazarovici, Philip; Guroff, Gordon

doi:10.1523/jneurosci.08-02-00715.1988

Cited by 321 publications

(225 citation statements)

References 37 publications

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“…For example it reversibly and selectively inhibited the NGF-induced morphological transformations of proliferating PC12 cells, whereas similar effects of EGF and bFGF were not blocked (Matsuda and Fukuda, 1988;Koizumi et al, 1988). Furthermore, treatment with 100 nM K252a resulted in reversion of the phenotype of Trktransformed rodent fibroblasts (Tapley et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

K252a inhibits the oncogenic properties of Met, the HGF receptor

et al. 2002

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“…However, the degree of functional insulation between the two respective signaling pathways remains equivocal. The NGF-and cAMP-dependent pathways for differentiation have been shown to be readily pharmacologically dissociable (15,16), and NGF-induced differentiation of PC12 cells does not appear to require PKA (14). On the other hand, crosstalk between the NGF and cAMP differentiation pathways has been reported (17).…”

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confidence: 99%

Separate Cyclic AMP Sensors for Neuritogenesis, Growth Arrest, and Survival of Neuroendocrine Cells

Emery¹,

Eiden

2014

Journal of Biological Chemistry

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Background: Three cAMP sensors (PKA, Epac1/2, and NCS/Rapgef2) coexist in neuroendocrine cells. Their roles in differentiation require elucidation. Results: Epac2, PKA, and NCS/Rapgef2 independently gate signaling for growth arrest, cell survival, and neuritogenesis after GPCR-G s engagement in PC12 cells. Conclusion: Parallel, insulated pathways effect cAMP-dependent neuroendocrine cell differentiation. Significance: Assays for parcellated cAMP signaling in neuroendocrine cells have a broad application for CNS drug discovery.

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“…KT5926, however, seems distinct in site of action from such agents. For instance, our data show that KT5926 clearly contrasts with K-252a (Kntisel and Hefti, 1992), which blocks all actions of NGF (Koizumi et al, 1988) and appears to do so by selectively inhibiting the tyrosine kinase activity of the gp140pr010"k NGF receptor (Berg et al, 1992;Nye et al, 1992). KT5926 is also distinct from 5'-S-methyl adenosine, which blocks all NGF responses (Seeley et al, 1984).…”

Section: Mechanistic Considerationsmentioning

confidence: 85%

“…K-252a was initially defined in vitro as a selective protein kinase C inhibitor (Kase et al, 1986) but, as noted above, was subsequently shown to inhibit gp140pr010trk tyrosine kinase activity in intact cells (Berg et al, 1992;Nye et al, 1992). Finally, like K-252a (Koizumi et al, 1988) and a structurally similar compound, staurosporine (Hashimoto and Hagino, 1989) KT5926 does not exert an inhibitory effect on basic fibroblast growth factor-induced neurite outgrowth from PC1 2 or PC12-C4 1 cells. Taken together, our results suggest that KT5926 may suppress NGF-regulated neurite outgrowth via inhibition of a hitherto unidentified protein kinase.…”

Section: Mechanistic Considerationsmentioning

confidence: 93%

“…It has been reported that K-252a is a potent and specific inhibitor of NGF-stimulated gp 1 40pmt*rk tyrosine kinase activity (Berg et al, 1992;Nye et al, 1992) and consequently blocks all responses of PC12 cells to NGF (Koizumi et al, 1988). Since KT5926 is an n-propoxy derivative of K-252a (Nakanishi et al, 1990), it is conceivable that this compound may affect NGFdependent neurite outgrowth by a similar mechanism involving the tyrosine kinase activity of the receptor.…”

Section: Kt5926 Does Not Afeet the Overall Ngf Signaling Mechanismmentioning

confidence: 99%

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KT5926 selectively inhibits nerve growth factor-dependent neurite elongation

Teng

Greene

1994

J. Neurosci.

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We have examined the effects of the protein kinase inhibitor KT5926 on NGF-promoted responses in PC12 and PC12-C41 cells (a subclone of the parental cell line). Our findings reveal that this compound specifically and reversibly prevents the NGF-induced outgrowth and regeneration of neurites. In addition, neurites of NGF-pretreated cells cease further elongation upon exposure to KT5926. However, preexisting neurite networks in the cultures remain intact in the presence of the drug. The inhibition of neuritic growth appears to occur at least in part at the level of growth cones since KT5926 also causes these structures to collapse and inhibits NGF-promoted reactivation of NGF- deprived growth cones. Although KT5926 is an analogue of K-252a, which blocks all responses to NGF, it does not affect other NGF-elicited cellular responses examined, including NGF-dependent priming of cells, gp140prototrk autophosphorylation, immediate-early gene induction, and phosphorylation of several known cytoskeletal proteins (MAP 1.2/1B, chartin MAPs, and beta-tubulin). However, phosphate incorporation into a cytoskeletally localized 58 kDa phosphoprotein, designated pp58, is selectively reduced in KT5926-treated cultures (+/- NGF). Although KT5926 is an in vitro inhibitor of myosin light chain kinase and calmodulin-dependent protein kinase II, inhibition of these two kinase activities by ML-9 and KN-62, respectively, applied alone or together, does not mimic the effects of KT5926 on neurite growth and on pp58 phosphorylation. Taken together, our findings suggest that KT5926, via a previously unidentified protein kinase inhibitory activity, differentially interferes with NGF-promoted growth cone function and consequently affects neuritic outgrowth. This compound should therefore be a useful tool for dissecting the mechanism of NGF actions and affords a means to identify phosphoproteins that play specific roles in neurite growth/elongation.

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K-252a: a specific inhibitor of the action of nerve growth factor on PC 12 cells

Cited by 321 publications

References 37 publications

K252a inhibits the oncogenic properties of Met, the HGF receptor

K252a inhibits the oncogenic properties of Met, the HGF receptor

Separate Cyclic AMP Sensors for Neuritogenesis, Growth Arrest, and Survival of Neuroendocrine Cells

KT5926 selectively inhibits nerve growth factor-dependent neurite elongation

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