Signal transduction for clinicians: Why should we care?

Pediatric Center for Neuroscience and Division of Child Neurology, Children's Hospital of Pittsburgh, and Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Pediatric Neurology (Impact Factor: 1.7). 12/2001; 25(5):361-7. DOI: 10.1016/S0887-8994(01)00320-4
Source: PubMed


Neurons must respond to a bewildering array of external and internal stimuli and must distinguish among them to generate an appropriate response or change in metabolic or electrical activity. Furthermore, the response of a cell to a given stimulus must depend on what else is happening inside and outside the cell at the time of arrival of that stimulus. The process of signal transduction is what gives the cell and organism the flexibility and "knowledge base" to carry out these functions. Conversely, aberrations of signal transduction underlie an increasing array of developmental, genetic, and acquired diseases and conditions of the nervous system. Pharmacological modulation of signal transduction pathways and their effectors holds great promise for the remediation of these neurologic disorders.

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    • "The protein kinase of each receptor monomer then phosphorylates a distinct set of tyrosine residues in the cytosolic portion of its dimer partner, which is the beginning of the signaling cascade that induces cellular proliferation, differentiation and survival. TrkA contains an extracellular portion, a single hydrophobic transmembrane a helix, and a cytosolic portion that includes a region with protein tyrosine kinase activity [32] [33] [34] [35] [36]. Of the five domains comprising the extracellular portion, the immunoglobulin-like domain (TrkA-d5 domain) provides the high-affinity binding site to NGF [33] [36] [42] [43]. "
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    ABSTRACT: Necdin is a protein known to interact with the neurotrophin receptors, neurotrophic tyrosine kinase receptor type 1 (TrkA) and 75 kD low-affinity neurotrophin receptor (p75NTR). TrkA and p75NTR play roles in development and disease of the nervous system and chemoresistance of nervous system tumors. Necdin deletion is associated with Prader-Willi syndrome. The present studies demonstrate that the effects of necdin on the susceptibility of neuroblastoma cells to oxidant stress are dependent on the ratio of p75NTR to TrkA in the cell. In low p75NTR:TrkA ratio cells, necdin down-regulation decreases sensitivity to oxidant stress and expression of and signaling through TrkA. In high p75NTR:TrkA cells, necdin down-regulation is without effect. The effects of necdin deletion on the developing nervous system may depend on the relative expression of p75NTR and TrkA in the cells of particular regions of the nervous system.
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