Abstract
Neurotrophins signal through Trk tyrosine kinase receptors and the low-affinity neurotrophin receptor p75(NTR). We have shown previously that activation of Trk A tyrosine kinase activity can inhibit p75(NTR)-dependent sphingomyelin hydrolysis, that caveolae are a localized site for p75(NTR) signaling, and that caveolin can directly interact with p75(NTR). The ability of caveolin to also interact with tyrosine kinase receptors and inhibit their activity led us to hypothesize that caveolin expression may modulate interactions between neurotrophin signaling pathways. PC12 cells were transfected with caveolin that was expressed efficiently and targeted to the appropriate membrane domains. Upon exposure to nerve growth factor (NGF), caveolin-PC12 cells were unable to develop extensive neuritic processes. Caveolin expression in PC12 cells was found to diminish the magnitude and duration of Trk A activation in vivo. This inhibition may be due to a direct interaction of caveolin with Trk A, because Trk A co-immunoprecipitated with caveolin from Cav-Trk A-PC12 cells, and a glutathione S-transferase-caveolin fusion protein bound to Trk A and inhibited NGF-induced autophosphorylation in vitro. Furthermore, the in vivo kinetics of the inhibition of Trk A tyrosine kinase activity by caveolin expression correlated with an increased ability of NGF to induce sphingomyelin hydrolysis through p75(NTR). In summary, our results suggest that the interaction of caveolin with neurotrophin receptors may have functional consequences in regulating signaling through p75(NTR) and Trk A in neuronal and glial cell populations.
Highlights
Neurotrophins are a family of growth factors that mediate the survival, development, and death of specific populations of neurons and glial cells [1]
Significant amounts of caveolin were observed in the Cav-PC12 cells, and it had the same apparent molecular mass as caveolin from a human endothelial cell lysate prepared as a caveolin standard (Fig. 1B)
Trk A co-immunoprecipitated with caveolin in Trk A-PC12 cells that were transfected with caveolin
Summary
Dylinositol signaling pathways [30, 31]. most if not all cells contain caveolae-related membrane domains (CRDs). The interaction of these proteins with caveolin has functional consequences on signaling because caveolin can inhibit the activity of nitric oxide synthase [36, 39], protein kinase C isoforms [34], and tyrosine kinases [37]. We hypothesized that the interaction of caveolin with Trk may have functional consequences on regulating cross-talk between the Trk A and p75NTR signaling pathways. Similar to pharmacologic inhibition of Trk A [16], caveolin inhibition of Trk A signaling enables NGF to induce SM hydrolysis through p75NTR. These data raise the possibility that caveolin or caveolin-related proteins may regulate signaling through Trk and p75NTR receptors in specific neuronal populations
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