Multitasking in signal transduction by a promiscuous human Ins(3,4,5,6)P4 1-kinase/Ins(1,3,4)P3 5/6-kinase

We describe a human cDNA encoding 1-kinase activity that inactivates Ins(3,4,5,6)P₄, an inhibitor of chloride-channel conductance that regulates epithelial salt and fluid secretion, as well as membrane excitability. Unexpectedly, we further discovered that this enzyme has alternative positional specificity (5/6-kinase activity) towards a different substrate, namely Ins(1,3,4)P₃. Kinetic data from a recombinant enzyme indicate that Ins(1,3,4)P₃ (K_m = 0.3µM; V_max = 320 pmol/min per µg) and Ins(3,4,5,6)P₄ (K_m = 0.1µM; V_max = 780pmol/min per µg) actively compete for phosphorylation in vivo. This competition empowers the kinase with multitasking capability in several key aspects of inositol phosphate signalling.