NME4
Description
The NME4 (NME/NM23 nucleoside diphosphate kinase 4) is a protein-coding gene located on chromosome 16.
NME4, also known as Non-metastatic cells 4, is a protein encoded by the NME4 gene in humans. It is a member of the nucleoside diphosphate (NDP) kinase family, which catalyzes the transfer of gamma-phosphates between nucleoside and dioxynucleoside tri- and diphosphates. The first nm23 gene, nm23-H1 (NME1), was identified as a metastasis suppressor gene due to its reduced expression in highly metastatic melanoma cells. A second gene, nm23-H2 (NME2), was later discovered, and both genes are located on chromosome 17q21.3. These genes encode proteins known as the A and B subunits of NDP kinases, which form heterohexamers. The expression of NDP kinases is elevated in tumors compared to normal tissues. Lower expression of NME1 in some cell lines and solid tumors is linked to increased metastatic potential. Interestingly, when NME1 is introduced into aggressive cell lines like human breast carcinoma, it can decrease their metastatic potential.
NME4 plays a crucial role in synthesizing nucleoside triphosphates other than ATP. This occurs through a ping-pong mechanism involving the transfer of the gamma phosphate from ATP to the beta phosphate of NDP, utilizing a phosphorylated active site. This exchange of gamma phosphates between di- and triphosphonucleosides contributes to the regulation of intracellular nucleotide homeostasis. NME4 interacts with anionic phospholipids, specifically cardiolipin, which inhibits its phosphotransfer activity. NME4 acts as a mitochondria-specific nucleoside diphosphate kinase. Its association with the cardiolipin-containing mitochondrial inner membrane is linked to respiration, implying that ADP regenerated within the inner membrane space by its action is directly absorbed through ANT ADP/ATP translocase into the matrix space, stimulating respiratory ATP regeneration. NME4 is proposed to enhance GTP loading on the dynamin-related GTPase OPA1 within mitochondria. In vitro, NME4 can induce liposome cross-linking, suggesting its ability to cross-link inner and outer membranes to form contact sites and facilitate the intermembrane migration of anionic phospholipids. NME4 promotes the redistribution of cardiolipin between the mitochondrial inner and outer membranes, which is implicated in pro-apoptotic signaling.
NME4 is also known as NDPK-D, NM23H4, nm23-H4.
