Nerve growth factor induced stimulation of Ras requires Trk interaction with Shc but does not involve phosphoinositide 3-OH kinase

Hållberg, Bengt; Ashcroft, Margaret; Loeb, David M.; Kaplan, David R.; Downward, Julian

doi:10.1038/sj.onc.1201980

Cited by 48 publications

(52 citation statements)

References 23 publications

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“…Both of these proteins mediate signaling through the well characterized Ras-ERK pathway and ultimately affect changes in gene expression (9,10). SHC is also critical for the activation of phosphotidylinositide 3-OH kinase (11), which, along with its substrate Akt, participates in the prevention of apoptosis in PC12 cells following NGF withdrawal (12,13).…”

Section: Ngfmentioning

confidence: 99%

A Novel Apoptotic Pathway Induced by Nerve Growth Factor-mediated TrkA Activation in Medulloblastoma

Chou

Trojanowski

Lee

2000

Journal of Biological Chemistry

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Nerve growth factor (NGF) induces apoptosis in a human medulloblastoma cell line (MED283) engineered to express TrkA (MED283-TrkA) (Muragaki, Y., Chou, T. T., Kaplan, D. R., Trojanowski, J. Q., and Lee, V. M. (1997) J. Neurosci. 17, 530 -542). To dissect the molecular signaling pathway that mediates this novel effect, specific receptor mutations in Trk have been employed. We showed that phosphorylation of tyrosine 490 is required for activation of phosphoinositide 3-OH kinase, whereas phosphorylation of tyrosine 785 is required for activation of phospholipase C-␥. TrkA-mediated apoptosis was abolished when either the ATP-binding site or both tyrosines 490 and 785 were mutated. Because tyrosines 490 and 785 mediate redundant signaling through the Rasextracellular signal-regulated kinase (Ras-ERK) pathway, we examined the role of Ras-ERK signaling in NGFinduced apoptosis. We found that MED283-TrkA cells expressing a dominant negative Ras inhibitor (N17Ras) failed to undergo ERK activation and apoptosis following NGF treatment, whereas the ERK kinase (mitogenactivated protein kinase kinase) inhibitors PD98059 and U0126 eliminated ERK activation but had no effect on apoptosis. We infer from these data that NGF-induced apoptosis is mediated by a novel Ras and/or Raf signaling pathway.

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Section: Ngfmentioning

confidence: 99%

A Novel Apoptotic Pathway Induced by Nerve Growth Factor-mediated TrkA Activation in Medulloblastoma

Chou

Trojanowski

Lee

2000

Journal of Biological Chemistry

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“…However, recent analyses have proposed that shc might play a dual role. There are data suggesting that PI-3K does not bind directly to trk A, but probably through shc since mutation of Y490 a ects the level of PI-3K activation when cells are stimulated by NGF (Ashcroft et al, 1999;Hallberg et al, 1998). trk A can also bind to several proteins which include shp-1, shp-2 (Vambutas et al, 1995;Goldsmith and Koizumi, 1997), Chk (Yamashita et al, 1999), Aps and SH2-B (Qian et al, 1998), but the signi®cance of these associations needs to be de®ned.…”

mentioning

confidence: 99%

c-abl is involved in the association of p53 and trk A

et al. 2000

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The p53 tumour suppressor phosphoprotein associates with proteins involved in DNA replication, transcription, cell cycle machinery and regulation of its own expression. Recently it has been shown that p53 can also bind to trk A tyrosine kinase which is the receptor for nerve growth factor (NGF). This study demonstrates that p53 appears to associate with trk A via c-abl. Endogenous cabl was detected when the trk A and p53 complex was immunoprecipitated from lysates of NGF stimulated NIH3T3 cells expressing trk A or NIH3T3 cells expressing trk A and a temperature sensitive p53 (val 135). Endogenous c-abl and trk A association was observed in NGF stimulated p53 negative ®broblasts transfected with trk A alone; suggesting that c-abl can independently bind to trk A in the absence of p53. Interestingly, association between endogenous p53 and trk A was not detected in NGF stimulated abl negative ®broblasts transfected with trk A or when these cells were exposed to gamma radiation. This result suggests that p53 preferentially binds to trk A in the presence of c-abl and that p53 and trk A do not appear to associate directly even if p53 is activated and its levels increased by gamma radiation. Overall, these data suggest that cabl is possibly acting as an adaptor or bridge between p53 and trk A. Oncogene (2000) 19, 3032 ± 3040.

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“…Nerve growth factor (NGF), 1 a representative of the neurotrophin family of growth factors, plays a critical role in the differentiation, proliferation, survival, and cell death of neurons and neural tumors (2)(3)(4)(5). Neurotrophins act on two types of cell surface receptors: high affinity tyrosine kinase Trk receptors (including TrkA, TrkB, and TrkC) and the low affinity neurotrophin receptor p75 NTR .…”

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confidence: 99%

ShcB and ShcC Activation by the Trk Family of Receptor Tyrosine Kinases

Liu¹,

Meakin²

2002

Journal of Biological Chemistry

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(TrkB), they are tyrosine-phosphorylated in response to neurotrophin stimulation, and they enhance the activation of mitogen-activated protein kinase in Trk-expressing cells. Moreover, neurotrophin treatment of primary cortical neurons stimulates ShcB/ShcC-Trk interaction and the tyrosine phosphorylation of ShcB/ShcC, indicating that they are bona fide targets of the Trk receptors in vivo. Interestingly, two proteins (pp60 and pp75) coimmunoprecipitate with ShcB and ShcC in response to neurotrophin stimulation in primary cortical neurons, suggesting a potential role of these unknown targets in neurotrophin signaling. Collectively, these results demonstrate that ShcB and ShcC, and their co-immunoprecipitating proteins, are activated by the Trk receptors in primary neurons.

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Nerve growth factor induced stimulation of Ras requires Trk interaction with Shc but does not involve phosphoinositide 3-OH kinase

Cited by 48 publications

References 23 publications

A Novel Apoptotic Pathway Induced by Nerve Growth Factor-mediated TrkA Activation in Medulloblastoma

A Novel Apoptotic Pathway Induced by Nerve Growth Factor-mediated TrkA Activation in Medulloblastoma

c-abl is involved in the association of p53 and trk A

ShcB and ShcC Activation by the Trk Family of Receptor Tyrosine Kinases

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