Recruitment of Actin Modifiers to TrkA Endosomes Governs Retrograde NGF Signaling and Survival

The Solomon H. Snyder Department of Neuroscience and Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Cell (Impact Factor: 32.24). 08/2011; 146(3):421-34. DOI: 10.1016/j.cell.2011.07.008
Source: PubMed


The neurotrophins NGF and NT3 collaborate to support development of sympathetic neurons. Although both promote axonal extension via the TrkA receptor, only NGF activates retrograde transport of TrkA endosomes to support neuronal survival. Here, we report that actin depolymerization is essential for initiation of NGF/TrkA endosome trafficking and that a Rac1-cofilin signaling module associated with TrkA early endosomes supports their maturation to retrograde transport-competent endosomes. These actin-regulatory endosomal components are absent from NT3/TrkA endosomes, explaining the failure of NT3 to support retrograde TrkA transport and survival. The inability of NT3 to activate Rac1-GTP-cofilin signaling is likely due to the labile nature of NT3/TrkA complexes within the acidic environment of TrkA early endosomes. Thus, TrkA endosomes associate with actin-modulatory proteins to promote F-actin disassembly, enabling their maturation into transport-competent signaling endosomes. Differential control of this process explains how NGF but not NT3 supports retrograde survival of sympathetic neurons.

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    • "For example, NGF induced the differentiation of PC12 cells into functional dopaminergic neurons [9]. Mechanistic studies revealed that NGF induced neurite outgrowth and neuronal differentiation through sustained activation of extracellular signal-regulated kinase 1/2 (ERK1/2) by interacting with its specific receptor tyrosine kinase (TrkA) in PC12 cells [10, 11]. "
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    • "Biochemical analysis of the actions of NGF upon primary peripheral neurons has often been hampered by the lack of a variety of neuronal cell models responsive to NGF, but do not require it for survival and also because it is difficult to obtain large numbers of sympathetic neurons for in vitro studies [39]. Furthermore, in a primary neuron model the development of sympathetic neurons might be critically regulated by two neurotrophins NT3 and NGF, acting through a common receptor TrkA, as reported earlier [41]. For these reasons, whether the results of the present study using PC12 cells can be extrapolated to primary neurons remains to be investigated. "
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    • "These results raise the interesting possibility that endosomal pH influences Akt phosphorylation in addition to TrkA trafficking. Phosphoinositide 3-ki- nase (PI3K)–Akt signaling occurs in endosomes in various cell types (Garcia-Regalado et al., 2008; Schenck et al., 2008; Tsutsumi et al., 2009; Walz et al., 2010; Fujioka et al., 2011; Nazarewicz et al., 2011), including NGF-treated PC12 cells (Lin et al., 2006; Varsano et al., 2006), and endosomal Akt signaling contributes to persistent NGF- TrkA signaling after the ligand–receptor complex is endocytosed (Harrington et al., 2011). Recruitment of not only class II and class III PI3Ks, whose association with endosomes is well recognized, but also class I PI3K to endosomes and their possible activation therein has been suggested (Vanhaesebroeck et al., 2010). "
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