Nm23 genes have been implicated in the control of tumor metastasis. For many types of tumors there is an inverse relationship between the level of nm23 expression and metastatic potential. Transfection of nm23 into highly metastatic cell lines reduces their metastatic potential. Nm23 genes are also thought to be involved in cellular proliferation and differentiation. Nm23 genes encode nucleoside diphosphate kinases (NDP kinases). These enzymes catalyze the phosphorylation of nucleoside diphosphates to triphosphates and are responsible for maintaining nucleoside triphosphate pools. However, the synthesis of nucleoside triphosphates does not appear to explain the role of nm23 in suppressing metastasis. We have found that nm23 protiens have protein kinase or phosphotransferase activities. We have previously reported that rat NDP kinase can phosphorylate ATP-citrate lyase. This phosphorylation results from a direct transfer of a phosphate from a histidine on NDP kinase to a histidine on ATP-citrate lyase. We subsequently found that NDP kinase can phosphorylate a histidine on succinyl thiokinase. The physiological significance of the phosphorylation of ATP-citrate lyase and succinyl thiokinase by NDP kinase is unclear as they are phosphorylated much more rapidly by ATP than by NDP kinase. We have recently partially purified a 43 kDa protein from bovine brain membranes that is phosphorylated by rat liver NDP kinase and by recombinant human nm23-H1. This protein is not phosphorylated when incubated with either ATP or GTP in the absence of added NDP kinase. Our results indicate that the phosphate is transferred from the catalytic histidines of these NDP kinases to an aspartate or glutamate residue on the 43 kDa protein. The phosphorylation of aspartate or glutamate residues by NDP kinase is analogous to phosphorylation reactions carried out by two-component histidine kinases. Two-component histidine kinases are involved in a number of cell signaling pathways in both prokaryotes and eukaryotes. These kinases autophosphorylate on a histidine and then transfer the phosphate to an aspartate on the same or different protein. This """"""""two-component"""""""" protein kinase like activity of nm23-H1 appears to correlate with its ability to inhibit the motility of human breast carcinoma cells. We are in the processes of identifying the 43 kDa protein phosphorylated by nm23 and characterizing the mechanism of this phosphate transfer reaction.
