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Phosphoinositide 3‐kinase regulates crosstalk between Trk A tyrosine kinase and p75 NTR ‐dependent sphingolipid signaling pathways
Author(s) -
Bilderback Tim R.,
Gazula ValeswaraRao,
Dobrowsky Rick T.
Publication year - 2001
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2001.00171.x
Subject(s) - trk receptor , microbiology and biotechnology , sphingosine kinase , tropomyosin receptor kinase a , sphingolipid , sphingomyelin , biology , sphingosine , ceramide , signal transduction , ly294002 , tyrosine kinase , chemistry , neurotrophin , biochemistry , pi3k/akt/mtor pathway , sphingosine 1 phosphate , receptor , apoptosis , membrane
The mechanism of crosstalk between signaling pathways coupled to the Trk A and p75 NTR neurotrophin receptors in PC12 cells was examined. In response to nerve growth factor (NGF), Trk A activation inhibited p75 NTR ‐dependent sphingomyelin (SM) hydrolysis. The phosphoinositide 3‐kinase (PI 3‐kinase) inhibitor, LY294002, reversed this inhibition suggesting that Trk A activation of PI 3‐kinase is necessary to inhibit sphingolipid signaling by p75 NTR . In contrast, SM hydrolysis induced by neurotrophin‐3 (NT‐3), which did not activate PI‐3 kinase, was uneffected by LY294002. However, transient expression of a constituitively active PI 3‐kinase inhibited p75 NTR ‐dependent SM hydrolysis by both NGF and NT‐3. Intriguingly, NGF induced an association of activated PI 3‐kinase with acid sphingomyelinase (SMase). This interaction localized to caveolae‐related domains and correlated with a 50% decrease in immunoprecipitated acid SMase activity. NGF‐stimulated PI 3‐kinase activity was necessary for inhibition of acid SMase but was not required for ligand–induced association of the p85 subunit of PI 3‐kinase with the phospholipase. Finally, this interaction was specific for NGF since EGF did not induce an association of PI 3‐kinase with acid SMase. In summary, our data suggest that PI 3‐kinase regulates the inhibitory crosstalk between Trk A tyrosine kinase and p75 NTR ‐dependent sphingolipid signaling pathways and that this interaction localizes to caveolae‐related domains.