A novel phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase associates with the interleukin-3 receptor.
To gain insight into the intracellular signaling cascades that are activated by the binding of interleukin-3 (IL-3) to its target cells, we have embarked on the identification of proteins that are associated with the IL-3 receptor (IL-3R). In a previous study we reported that a 110-kDa serine/threonine protein kinase is constitutively associated with the IL-3R and activated following IL-3 stimulation. We now report that a phosphatidylinositol-3,4, 5-trisphosphate (PtdIns-3,4,5-P3) 5-phosphatase (5-ptase) is also constitutively associated with the IL-3R. This 5-ptase is magnesium-dependent and removes the 5-position phosphate from PtdIns-3,4,5-P3 but does not metabolize PtdIns-4,5-P2, inositol (Ins)-1,3,4,5-P4, or Ins-1,4,5-P3. This substrate specificity distinguishes it from any previously characterized 5-ptase. Interestingly, it may be bound indirectly via phosphatidylinositol 3-kinase (PI 3-kinase), another enzyme that is constitutively bound to the IL-3R. However, unlike PI 3-kinase which becomes activated following IL-3 stimulation, this receptor-associated 5-ptase activity does not increase following IL-3 stimulation, and its primary function may be to keep the principal in vivo product of PI 3-kinase, PtdIns-3,4,5-P3, at low levels in unstimulated cells, to terminate the PI 3-kinase signal following IL-3 stimulation or to metabolize PtdIns-3,4,5-P3 to a metabolically active second messenger, i.e. PtdIns-3,4-P2.
Liu
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Terry Fox Laboratory, British Columbia Cancer Agency, University of British Columbia, Vancouver, British Columbia, Canada V5Z 1L3.
Jefferson
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Zhang
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Norris
F A
FA
Majerus
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PW
Krystal
G
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D000818:Animals; D019556:COS Cells; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D016185:Receptors, Interleukin-3 / Q000378:metabolism*; D013379:Substrate Specificity
D016185:Receptors, Interleukin-3; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); C096024:phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase; D010744:Phosphoric Monoester Hydrolases