K-252a inhibits nerve growth factor-induced trk proto-oncogene tyrosine phosphorylation and kinase activity.

Berg, Margaret M.; Sternberg, David; Parada, Luis F.; Chao, Moses V.

doi:10.1016/s0021-9258(18)48447-5

Cited by 337 publications

(19 citation statements)

References 26 publications

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“…A number of approaches were used to answer this question. First, we applied a low concentration (0.2 M) of k252a, which is known to specifically inhibit the tyrosine kinase activity of Trk receptors (Berg et al, 1992). k252a (pretreated for 30 min) reliably prevented TrkB tyrosine phosphorylation induced by BDNF (Fig.…”

Section: Resultsmentioning

confidence: 99%

Regulation of TrkB receptor tyrosine kinase and its internalization by neuronal activity and Ca2+ influx

Feng

Zaitsev

et al. 2003

The Journal of Cell Biology

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Internalization of the neurotrophin–Trk receptor complex is critical for many aspects of neurotrophin functions. The mechanisms governing the internalization process are unknown. Here, we report that neuronal activity facilitates the internalization of the receptor for brain-derived neurotrophic factor, TrkB, by potentiating its tyrosine kinase activity. Using three independent approaches, we show that electric stimulation of hippocampal neurons markedly enhances TrkB internalization. Electric stimulation also potentiates TrkB tyrosine kinase activity. The activity-dependent enhancement of TrkB internalization and its tyrosine kinase requires Ca2+ influx through N-methyl-d-aspartate receptors and Ca2+ channels. Inhibition of internalization had no effect on TrkB kinase, but inhibition of TrkB kinase prevents the modulation of TrkB internalization, suggesting a critical role of the tyrosine kinase in the activity-dependent receptor endocytosis. These results demonstrate an activity- and Ca2+-dependent modulation of TrkB tyrosine kinase and its internalization, and they provide new insights into the cell biology of tyrosine kinase receptors.

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Section: Resultsmentioning

confidence: 99%

Regulation of TrkB receptor tyrosine kinase and its internalization by neuronal activity and Ca2+ influx

Feng

Zaitsev

et al. 2003

The Journal of Cell Biology

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“…Because UVB irradiation strikingly affects NGF function and causes keratinocyte apoptosis, we asked whether endogenous NGF could protect keratinocytes from UVB-induced cell death. To this purpose, cultured keratinocytes were UVB irradiated with or without the addition of K252, a speci®c inhibitor of trk phosphorylation (Berg et al, 1992). As shown in Fig 2, percentage of apoptotic keratinocytes following UVB irradiation was signi®cantly higher in cell cultures pretreated with K252 than in those provided with diluent alone.…”

Section: K252 Enhances Uvb-induced Keratinocyte Apoptosismentioning

confidence: 98%

Nerve Growth Factor Protects Human Keratinocytes from Ultraviolet-B-Induced Apoptosis

Marconi

Vaschieri

Zanoli

et al. 1999

Journal of Investigative Dermatology

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Ultraviolet radiation is a potent inducer of apoptosis, whereas autocrine nerve growth factor protects human keratinocytes from programmed cell death. To evaluate the role of nerve growth factor in the mechanisms of ultraviolet B-induced apoptosis, cultured human keratinocytes were ultraviolet B irradiated following pretreatment with K252, a specific inhibitor of the tyrosine kinase high-affinity nerve growth factor receptor. Here we report that the addition of K252 significantly enhanced keratinocyte apoptosis. We then transfected normal human keratinocytes with pNUT-hNGF. Nerve growth factor overexpressing keratinocytes secreted the highest amounts of nerve growth factor in culture supernatants, were more viable, and had a higher rate of proliferation than mock-transfected cells. Whereas ultraviolet B radiation downregulated nerve growth factor mRNA and protein as well as the tyrosine kinase high-affinity nerve growth factor receptor in normal keratinocytes, it failed to do so in nerve growth factor-transfected cells. Moreover, nerve growth factor overexpressing keratinocytes were partially resistant to apoptosis induced by increasing doses of ultraviolet B at 24 and 48 h. These results indicate that downregulation of nerve growth factor function plays an important part in the mechanisms of ultraviolet B-induced apoptosis in human keratinocytes. In addition, ultraviolet B caused a decrease in BCL-2 and BCL-xL expression in mock-transfected keratinocytes, but not in nerve growth factor overexpressing cells. Finally, nerve growth factor prevented the cleavage of the enzyme poly(ADP-ribose) polymerase induced in human keratinocytes by ultraviolet B. These results are consistent with a model whereby the autocrine nerve growth factor protects human keratinocytes from ultraviolet B-induced apoptosis by maintaining constant levels of BCL-2 and BCL-xL, which in turn might block caspase activation.

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“…NGF treatment for 15 min resulted in maximum TrkA polyubiquitination (Figure 1A); although, polyubiquitination was sustained above basal levels in the presence of NGF. Pretreatment of the cells with K252a, an inhibitor of TrkA tyrosine kinase activity (Berg et al, 1992), reduced TrkA polyubiquitination by 60% (Figure 1B). Under stringent SDS-denaturing conditions, TRAF6 did not coprecipitate with TrkA, excluding the possibility that the polyubiquitin signal was a result of autoubiquitinated TRAF6 coprecipitating (not shown).…”

Section: Ngf Induces the Ubiquitination Of Trkamentioning

confidence: 99%

Lysine 63 Polyubiquitination of the Nerve Growth Factor Receptor TrkA Directs Internalization and Signaling

2005

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Nerve growth factor (NGF) binding to p75(NTR) influences TrkA signaling, yet the molecular mechanism is unknown. We observe that NGF stimulates TrkA polyubiquitination, which was attenuated in p75(-/-) mouse brain. TrkA is a substrate of tumor necrosis factor receptor-associated factor 6 (TRAF6), and expression of K63R mutant ubiquitin or an absence of TRAF6 abrogated TrkA polyubiquitination and internalization. NGF stimulated formation of a TrkA/p75(NTR) complex through the p62 scaffold, recruiting the E3/TRAF6 and E2/UbcH7. Peptide targeted to the TRAF6 binding site present in p62 blocked interaction with TRAF6 and inhibited ubiquitination of TrkA, signaling, internalization, and NGF-dependent neurite outgrowth. Mutation of K485 to R blocked TRAF6 and NGF-dependent polyubiquitination of TrkA, resulting in retention of the receptor on the membrane and an absence in activation of specific signaling pathways. These findings reveal that polyubiquitination serves as a common platform for the control of receptor internalization and signaling.

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K-252a inhibits nerve growth factor-induced trk proto-oncogene tyrosine phosphorylation and kinase activity.

Cited by 337 publications

References 26 publications

Regulation of TrkB receptor tyrosine kinase and its internalization by neuronal activity and Ca2+ influx

Regulation of TrkB receptor tyrosine kinase and its internalization by neuronal activity and Ca2+ influx

Nerve Growth Factor Protects Human Keratinocytes from Ultraviolet-B-Induced Apoptosis

Lysine 63 Polyubiquitination of the Nerve Growth Factor Receptor TrkA Directs Internalization and Signaling

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