HUMAN PRONGF: BIOLOGICAL EFFECTS AND BINDING PROFILES AT TRKA, P75NTRAND SORTILIN
| Autor: | Oliver Clewes, Shelley J Allen, Caterina Catania, Heon Seok, Judy J. Watson, David Dawbarn, SJ Tyler, Kwangwook Cho, Mark S. Fahey |
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| Rok vydání: | 2008 |
| Předmět: |
medicine.medical_specialty
Time Factors animal structures Neurite Cell Survival Nerve Tissue Proteins Receptors Nerve Growth Factor Tropomyosin receptor kinase A Biochemistry Receptor tyrosine kinase Radioligand Assay Cellular and Molecular Neuroscience Internal medicine Nerve Growth Factor Neurites medicine Animals Humans Low-affinity nerve growth factor receptor Receptors Growth Factor Phosphorylation Protein Precursors Receptor trkA Receptor Cells Cultured Cerebral Cortex Neurons Mitogen-Activated Protein Kinase 3 biology Caspase 3 Chemistry Recombinant Proteins Rats Cell biology Adaptor Proteins Vesicular Transport Nerve growth factor Endocrinology Animals Newborn nervous system Mutation biology.protein Protein Binding Signal Transduction Neurotrophin |
| Zdroj: | Journal of Neurochemistry. |
| ISSN: | 1471-4159 0022-3042 |
| DOI: | 10.1111/j.1471-4159.2008.05698.x |
| Popis: | Nerve growth factor (NGF) promotes cell survival via binding to the tyrosine kinase receptor A (TrkA). Its precursor, proNGF, binds to p75(NTR) and sortilin receptors to initiate apoptosis. Current disagreement exists over whether proNGF acts neurotrophically following binding to TrkA. As in Alzheimer's disease the levels of proNGF increase and TrkA decrease, it is important to clarify the properties of proNGF. Here, wild-type and cleavage-resistant mutated forms (M) of proNGF were engineered and their binding characteristics determined. M-proNGF and NGF bound to p75(NTR) with similar affinities, whilst M-proNGF had a lower affinity than NGF for TrkA. M-proNGF behaved neurotrophically, albeit less effectively than NGF. M-proNGF addition resulted in phosphorylation of TrkA and ERK1/2, and in PC12 cells elicited neurite outgrowth and supported cell survival. Conversely, M-proNGF addition to cultured cortical neurons initiated caspase 3 cleavage. Importantly, these biological effects were shown to be mediated by unprocessed M-proNGF. Surprisingly, binding of the pro region alone to TrkA, at a site other than that of NGF, caused TrkA and ERK1/2 phosphorylation. Our data show that M-proNGF stimulates TrkA to a lesser degree than NGF, suggesting that in Alzheimer brain the increased proNGF : NGF and p75(NTR) : TrkA ratios may permit apoptotic effects to predominate over neurotrophic effects. |
| Databáze: | OpenAIRE |
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