p75(NTR) and hypoxia A breath of fresh air in neurotrophin receptor signaling

University of California, San Francisco
Cell cycle (Georgetown, Tex.) (Impact Factor: 4.57). 03/2012; 11(5):829-30. DOI: 10.4161/cc.11.5.19436
Source: PubMed


Comment on: Le Moan N, et al. Mol Cell 2011; 44:476-90.

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    ABSTRACT: Although identified almost 20 years ago, the precise physiological role of the p75 neurotrophin receptor (p75NTR) has remained elusive. Recent studies have revealed that p75NTR is a component of three distinct receptor platforms that bind different ligands and that, under differing circumstances, facilitate cell survival, cell death, or growth inhibition. These recent developments provide new insights into the functions of this enigmatic receptor.
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    ABSTRACT: Signaling by the p75 neurotrophin receptor (p75) has been implicated in diverse neuronal responses, including the control of neuronal survival versus death and axonal regeneration and growth cone collapse, involving p75 in different neuropathological conditions. There are different levels of complexity regulating p75-mediated signaling. First, p75 can interact with different ligands and co-receptors in the plasma membrane, forming tripartite complexes, whose activation result in different cellular outcomes. Moreover, it was recently described that trafficking capacities of p75 in neurons are regulating, in addition to p75 downstream interactions, also the sequential cleavage of p75. The proteolytical processing of p75 involves, first, a shedding event that releases a membrane-bound carboxiterminal fragment (p75-CTF), followed by a gamma-secretase mediated cleavage, generating a soluble intracellular domain (p75-ICD) with signaling capabilities. The first shedding event, generating a p75-CTF, is the key step to regulating the production of p75-ICD, and although the generation of p75-ICD is important for both p75-mediated control of neuronal survival and the control of neurite outgrowth, little is known how both cleavage events are regulated. In this review, we argue that both sheddases and gamma-secretase are key membrane components regulating p75-mediated signaling transduction; therefore, further attention should be paid to their roles as p75 signaling regulators.
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    ABSTRACT: The p75 neurotrophin receptor (p75(NTR)) is expressed on many cell types and can influence a variety of cellular functions. This receptor can mediate cell survival or cell death, can promote or inhibit axonal growth and can facilitate or attenuate proliferation, depending on the cell context. The emerging picture regarding p75(NTR) indicates that it can partner with different coreceptors to dictate specific responses. It then signals by recruiting intracellular binding proteins to activate different signaling pathways. The function of p75(NTR) has mainly been studied in neurons; however, it is also expressed in a variety of glial populations, especially during development and after injury, where its roles have been poorly defined. In this review, we will examine the potential roles for p75(NTR) in glial function.
    Trends in Neurosciences 03/2008; 31(2):99-104. DOI:10.1016/j.tins.2007.11.005 · 13.56 Impact Factor