Nm23 proteins have been implicated in the regulation of tumor metastasis, cell motility, and cellular differentiation. Nm23 proteins are nucleoside diphosphate kinases and catalyze the phosphorylation of nucleoside 5'-diphosphates to triphosphates. However, this kinase activity does not account for the effects of Nm23 proteins on Drosophila development, tumor metastasis, or cell motility, and it has been suggested that Nm23 proteins might phosphorylate other kinds of substrates. Our current research concerns the identification and characterization of these substrates. The binding of ADP to Nm23 proteins is primarily through the sugar and pyrophosphate moieties; the base lies in a hydrophobic cleft and forms no specific polar interactions with the enzyme. This suggested to us that other pyrophosphates might also be substrates for Nm23 proteins. We have found that geranyl and farnesyl pyrophosphates are phosphorylated by Nm23 proteins to give the corresponding triphosphates. Wild type Nm23-H1 has higher geranyl and farnesyl pyrophosphate kinase activities than do mutants of Nm23-H1 that do not inhibit cell motility. The phosphorylation of farnesyl pyrophosphate by Nm23 proteins appears to occur in vivo ; cells with an elevated level of Nm23-H1 contain an elevated level of farnesyl triphosphate. To our knowledge, the presence of farnesyl triphosphate in cells has not been previously reported. We have found that cells with elevated levels of Nm23-H1 have an elevated level of farnesyl triphosphate and an altered pattern of protein farnesylation. We are currently investigating the biochemical activities of farnesyl triphosphate both in vitro and in vivo and trying to determine whether it has a role in metastasis suppression and/or motility inhibition.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC005265-18
Application #
6433007
Study Section
(LB)
Project Start
Project End
Budget Start
Budget End
Support Year
18
Fiscal Year
2000
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code