Faculty Bibliography

The p75 receptor is the founding member of the TNF receptor superfamily. Members in this receptor family share a common cysteine motif repeated two to six times that serves as the ligand binding domain. In addition, several members contain a cytoplasmic region designated the death domain. The neurotrophins NGF, BDNF, NT-3, and NT-4 each bind to the p75 receptor and also more selectively to members of the Trk family of receptor tyrosine kinases. Although the biological functions of p75 have been elusive, recent experimental evidence supports an involvement of this receptor in apoptosis. This presents a counter-intuitive function for neurotrophins, which are normally required for the survival of neurons during development. The life-and-death decisions by neurotrophins appear to be governed by the level of expression and signaling activities of the p75 and Trk tyrosine kinase receptors and their downstream effector molecules. The generation of the correct number of cells in the nervous system is a highly controlled and coordinated process that is the consequence of cell proliferation and cell death decisions. The appropriate number of neuronal and glial cells formed during development guarantees the establishment of proper innervation and functional synaptic connections. One common mechanism to account for the number of viable cells is the ability to form ligand-receptor complexes that promote cell survival under conditions of limiting concentrations of trophic factors. Another diametrically opposed mechanism is to produce ligand-receptor interactions that can activate programmed cell death directly

Treatment with NGF causes long-term cultures of oligodendrocytes to die via a yet undefined mechanism mediated by the p75 neurotrophin receptor. The p75 receptor belongs to the TNF receptor superfamily of molecules, which includes Fas and p55 TNF receptors. The Fas and TNF receptors use adaptor molecules to recruit and activate caspase-8 to the receptor. Using a combination of immunohistochemical and Western blotting assays, we have examined caspase activity during NGF-induced apoptosis. Interestingly, although caspase-1 [interleukin-1beta-converting enzyme (ICE)], caspase-2, caspase-3, and caspase-8 were expressed in oligodendrocytes, only caspase-1, -2, and -3 were activated after NGF treatment, whereas caspase-8 was not. These data suggest that the mechanism of apoptosis by NGF through the p75 receptor is different from TNF and Fas-mediated killing. gamma Radiation of oligodendrocytes also activated a similar subset of caspases as NGF, indicating that NGF-induced oligodendrocyte apoptosis uses a similar cell death execution mechanism as injury models. This consolidates a potential role of the p75 neurotrophin receptor during stress and inflammatory conditions

Neurotrophins are target-derived soluble factors required for neuronal survival. Nerve growth factor (NGF) the founding member of the neurotrophin family, binds to two types of receptors: Trk tyrosine kinase and the p75 neurotrophin receptor, which belongs to the Fas-tumor necrosis factor (TNF) receptor superfamily. Binding of neurotrophins to Trk receptor tyrosine kinases initiate signaling cascades that promote cell survival sand differentiation. In contrast, p75 NGFR has been shown to modulate the susceptibility to death of selective cellular populations--including differentiated rat oligodendrocytes--in specific conditions. Notably, NGF effect on viability was only observed in fully differentiated oligodendrocytes and not in oligodendrocyte progenitor cells. The effect of p75 activation on oligodendrocyte survival correlates with increased activity of the stress related kinase JNK-1 and cleavage of specific caspases. Indeed, activation of additional stress pathways or impairment of survival signals may be required for p75 mediated activation of cell death execution programs. Interestingly, co-expression of the TrkA receptor in the same cell type abolishes the JNK-1 mediated death signal and induces MAP kinase activity, resulting in cell survival. This suggests that glial cell survival results from a balance between positive and negative regulators modulated by selective signalling pathways by tyrosine kinases and cytokine receptors

The p75 neurotrophic receptor (p75) shares structural features with the Fas receptor (FasR). Both receptors contain extracellular cysteine-rich repeats, a single transmembrane domain, and intracellular death domains. However, it has not been clearly established whether their death domains are equivalent in their ability to mediate apoptosis. To understand better the role of p75 during apoptosis, we constructed chimeric receptors that contained the extracellular portion of the FasR and the intracellular portion of p75. These chimeric receptors, one containing the p75 transmembrane domain and the other containing the FasR transmembrane portion, as well as wild-type p75 and Fas receptors, were transiently transfected into human U373 glioma cells and human embryonic kidney 293 cells (293 cells), which are both responsive to Fas-mediated apoptosis. Whereas expression of FasR was sufficient to induce apoptosis in U373 and 293 cells, expression of p75 and the chimeric receptors induced only minimal levels of cell death compared to FasR. The results indicate that the magnitudes of FasR- and p75-induced killing are different and suggest that the death domain of p75 does not function in the same manner as the FasR death domain

Phosphatidylinositol-5-phosphate 4-kinase (PIP4K) is required for the production of phosphoinositol-4,5-hisphosphate (PIP2), which has been closely associated with growth factor signalling. Here we have tested the possibility that phosphoinositide kinases may be take part in signal transduction through interactions with the epidermal growth factor (EGF) receptor and the ErbB family of tyrosine kinase receptors. Interactions of the Type IIbeta isoform of PIP4K were observed with the EGF receptor family members in a number of diverse cell lines, including A431, PC12 and MCF7 cells but not with the N6F TrkA receptor. Co-immunoprecipitation experiments indicate that PIP4K interacts with not only the EGF receptor, but also selectively with members of the ErbB tyrosine kinase family. These results demonstrate another enzyme substrate for EGF receptors that facilitates the production of phosphoinositides at the cell membrane