Differential effects of spermine on phosphatidylinositol 3-kinase and phosphatidylinositol phosphate 5-kinase.
The metabolism of phosphoinositides plays an important role in the signal transduction pathways. We report here that naturally occurring polyamines affect the activities of phosphatidylinositol (PI) 3-kinase and PI 4-phosphate (PIP) 5-kinase differently. While polyamines inhibited the PI 3-kinase activity, they stimulated the activity of PIP 5-kinase in the order of spermine > spermidine > putrescine. Spermine inhibited the PI 3-kinase activity in a concentration-dependent manner with an IC50 of 100 microM. On the other hand, spermine (5 mM) stimulated the activity of PIP 5-kinase 2-3 fold. Kinetic studies of spermine-mediated inhibition of PI 3-kinase revealed that it was noncompetitive with respect to ATP. The effect of Mg2+ and PIP2 concentration on kinase activity was sigmoidal, with spermine inhibiting PI 3-kinase activity at all PIP2 concentrations. While 1 mM calcium stimulated PI 3-kinase activity at submaximal concentrations of Mg2+ (1.25 mM), inhibition was observed at optimal concentration of Mg2+ (2 mM). We propose that spermine may modulate the cellular signal by virtue of its differential effects on phosphoinositide kinases.
Singh
S S
SS
NYS Institute for Basic Research in Developmental Disabilities, Staten Island, N.Y. 10314, USA.
Chauhan
A
A
Brockerhoff
H
H
Chauhan
V P
VP
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D004789:Enzyme Activation; D008099:Liver / Q000201:enzymology; D015636:Magnesium Chloride / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D013096:Spermine / Q000494:pharmacology*; D013379:Substrate Specificity
D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D015636:Magnesium Chloride; D013096:Spermine; D000255:Adenosine Triphosphate; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase; D002118:Calcium