The trk family of receptors mediates nerve growth factor and neurotrophin-3 effects in melanocytes.

Yaar, Mina; Eller, Mark S.; DiBenedetto, P.; Reenstra, Wende R.; Zhai, Shengli; McQuaid, T. J.; Archambault, Michael; Gilchrest, Barbara A.

doi:10.1172/jci117496

Cited by 125 publications

(113 citation statements)

References 75 publications

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“…doses while melanocytes appear to be resistant to the same doses (Young, 1987). Melanocytes express NFG receptors (Yaar et al, 1994) and it has been shown that NGF, which is constitutively produced by keratinocytes and further induced by U.V.-irradiation, protects melanocytes from U.V.-induced apoptosis (Zhai et al, 1996). According to the data discussed above we predict that short term protection against U.V.-induced depletion of these minimally proliferating melanocytes is mediated by an Akt/PKB dependent pathway.…”

Section: Discussionmentioning

confidence: 94%

Specific TrkA survival signals interfere with different apoptotic pathways

Ulrich¹,

Düwel

Kauffmann‐Zeh³

et al. 1998

Oncogene

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Survival signalling by ligand-activated tyrosine kinase receptors plays a crucial role in maintaining the balance between cell viability and apoptosis in multicellular organisms. To identify receptor domains and pathways involved in survival signalling, the nerve growth factor receptor TrkA was expressed in Rat-1/MycER TM ®broblasts. We demonstrate that wt-TrkA receptor delays c-Myc-, U.V.-and Cycloheximide-induced apoptosis and activates targets such as the mitogen-activated protein kinase (MAPK) Erk2 and the serine/threonine kinase Akt/PKB, both of which have been implicated in survival signalling. TrkA mutated within its SHC binding site (Y490F) delays c-Myc-induced apoptosis without activating endogenous Akt/PKB. In contrast, the TrkA Y490F mutant receptor does not delay U.V.-induced apoptosis whilst TrkA mutated at its PLC-g binding site (Y785F) is capable of protecting from apoptosis induced by c-Myc or U.V. treatment. The double mutant TrkA YY490/785FF fails to block either of these two apoptotic stimuli. While PI3-kinase inhibitors LY294002 and Wortmannin competely block survival signalling following U.V. treatment, neither drug a ects the ability of TrkA to block c-Myc-induced apoptosis. We show that the Akt/PKB pathway is essential for NGF stimulated TrkA survival signalling in the case of U.V.-induced apoptosis, but that apoptosis induced by c-Myc is also blocked by a novel, Akt/PKB-independent, pathway. These observations suggest that TrkA can activate di erent survival signalling pathways, which can interfere with speci®c apoptotic pathways.

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Section: Discussionmentioning

confidence: 94%

Specific TrkA survival signals interfere with different apoptotic pathways

Ulrich¹,

Düwel

Kauffmann‐Zeh³

et al. 1998

Oncogene

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“…Proteins were extracted in radioimmunoprecipitation assay buffer, and then half of the preparation was resuspended in Laemmli buffer containing 2-mercaptoethanol and the other half in buffer containing no reducing agents. Samples were processed for Western blotting and reacted with anti-human p75 NTR antibodies as described (30). The same number of cells were incubated in suspension at 37°C with A␤ (20 M) or diluent for 30 min followed by DTSSP (2 mM) for 30 min at 4°C.…”

Section: Methodsmentioning

confidence: 99%

“…The same number of cells were incubated in suspension at 37°C with A␤ (20 M) or diluent for 30 min followed by DTSSP (2 mM) for 30 min at 4°C. Cells were lysed and processed for Western blotting and reacted with antihuman p75 NTR (3T3 cells) or anti-rat p75 NTR (neurons) antibodies as described (30).…”

Section: Methodsmentioning

confidence: 99%

“…Furthermore, disruption of the cross-linking led to increased intensity of the 75-kDa band and decreased intensity of the 220 -230-kDa band, with a redistribution of p75 NTR immunoreactivity quantitatively most consistent with disaggregation of trimers into monomers. Neither can we completely exclude the possibility that the higher molecular mass band represents receptor trimerization as a result of autocrine neurotrophic factors produced by the 3T3 cells (30,32) or paracrine neurotrophic factors produced by contaminating cells, other than neurons, in the fetal rat brain cultures (reviewed in Refs. 33 and 34).…”

Section: P75mentioning

confidence: 99%

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Amyloid β Binds Trimers as Well as Monomers of the 75-kDa Neurotrophin Receptor and Activates Receptor Signaling

Yaar

Zhai²,

Fine

et al. 2002

Journal of Biological Chemistry

149

132

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p75NTR , a nerve growth factor co-receptor that has been implicated in apoptosis of neurons, is structurally related to Fas and the receptors for tumor necrosis factor-␣ that display ligand independent assembly into trimers. Using embryonic day 17 fetal rat cortical neurons and p75 NTR -expressing NIH-3T3 cells, we now show that p75 NTR exists as a trimer as well as a monomer. Furthermore, we have reported and others have confirmed that amyloid ␤ binds p75 NTR , and that this binding leads to apoptotic cell death. We now report that amyloid ␤ binds to trimers of p75 NTR as well as to p75 NTR monomers but not to the p140 trkA , the nerve growth factor co-receptor that mediates neuronal survival. Furthermore, amyloid ␤ activates p75 NTR , strongly inducing the transcription of c-Jun mRNA and stimulating the stress-activated c-Jun NH 2 -terminal kinase, as measured by phosphorylation of its substrate (glutathione S-transferase-c-Jun-(1-79)). Our data suggest that p75 NTR may be present as a preformed trimer that binds amyloid ␤ to induce receptor activation, and support the hypothesis that p75 NTR activation by amyloid ␤ is causally related to Alzheimer's disease.

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“…Recently, sensitive in situ hybridization and RNase protection analyses have unveiled widespread expression of trkA in many non-neuronal tissues, including kidney, thymus, testes, stomach and muscle (Lomen-Hoerth and Shooter, 1995;Wheeler et al, 1998). It has also been shown that NGF-triggered trkA signaling is involved in many autocrine and paracrine circuits playing important roles in the growth, survival and/or di erentiation of di erent cell types, including mast cells and B memory cells (Tam et al, 1997;Torcia et al, 1996; skin melanocytes (Yaar et al, 1994); and cells from the ovary (Mayerhofer et al, 1996); prostate (Dalal et al, 1997); and pancreas (Miralles et al, 1998). Loss of trkA function is responsible for a human disease, congenital insensitivity to pain with anhidrosis (CIPA), characterized by lack of reaction to noxious stimuli (Indo et al, 1996).…”

mentioning

confidence: 99%

Molecular cloning and characterization of the 5′ region of the mouse trkA proto-oncogene

et al. 1999

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The trkA proto-oncogene encodes a high-a nity NGF receptor that is essential for the survival, di erentiation and maintenance of many neural and non-neural cell types. Altered expression of the trkA gene or trkA receptor malfunction have been implicated in neurodegeneration, tumor progression and oncogenesis. We have cloned and characterized the 5' region of the mouse trkA gene and have identi®ed its promoter. trkA promoter sequences are GC-rich, lack genuine TATA or CAAT boxes, and are contained within a CpG island which extends over the entire ®rst coding exon. The mouse trkA transcription start site is located 70/71 bp upstream to the AUG translation initiation codon. Sequence analysis showed that the gene encoding the insulin receptor-related receptor, IRR, is located just 1.6 kbp upstream to the trkA gene and is transcribed in the opposite direction. We have used trkA-CAT transcriptional fusions to study trkA promoter function in transient transfection experiments. RNase protection assays and CAT protein ELISA analyses showed that a 150 bp long DNA segment, immediately upstream to the start site, is su cient to direct accurate transcription in trkA-expressing cells. Dissection of this fragment allowed us to identify a 13 bp cis-regulatory element essential for both promoter activity and cell-type speci®c expression. Deletion of this 13 bp segment as well as modi®cation of its sequence by site-directed mutagenesis led to a dramatic decline in promoter activity. Gel mobility shift assays carried out with double-stranded oligonucleotides containing the 13 bp element revealed several speci®c DNA-protein complexes when nuclear extracts from trkA-expressing cells were used. Supershift experiments showed that the Sp1 transcription factor was a component of one of these complexes. Our results identify a minimal trkA gene promoter, located very close to the transcription start site, and de®ne a 13 bp enhancer within this promoter sequence.

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The trk family of receptors mediates nerve growth factor and neurotrophin-3 effects in melanocytes.

Cited by 125 publications

References 75 publications

Specific TrkA survival signals interfere with different apoptotic pathways

Specific TrkA survival signals interfere with different apoptotic pathways

Amyloid β Binds Trimers as Well as Monomers of the 75-kDa Neurotrophin Receptor and Activates Receptor Signaling

Molecular cloning and characterization of the 5′ region of the mouse trkA proto-oncogene

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