| NM23A, also termed NME1 or NM23‑H1, is a founding member of the NME/nucleoside diphosphate kinase family and functions as a multifunctional enzyme and signaling regulator with roles in nucleotide homeostasis, cytoskeletal dynamics, transcriptional control, and metastasis suppression. The protein forms a homo‑ or hetero‑hexamer with related NME isoforms, and its active site histidine participates in a classical ping‑pong phosphotransfer mechanism that transfers the terminal phosphate from nucleoside triphosphates, predominantly ATP, to a broad spectrum of nucleoside diphosphates, thereby supporting balanced synthesis of GTP, CTP, UTP, and other NTPs for DNA/RNA synthesis and GTP‑dependent signaling. It also exhibits catalytic activities, including histidine protein kinase and 3′–5′ exonuclease functions, and can associate with DNA and protein substrates in the nucleus and cytoplasm, placing it at the intersection of nucleotide metabolism and signaling and DNA processing. NM23‑H1 negatively regulates multiple pro‑invasive signaling routes such as Rac1, MAPK/SAPK, and PI3K–Akt by modulating the activity or availability of upstream regulators and small GTPases, and it influences actin cytoskeleton organization and endocytic trafficking, which are both central to migration and matrix invasion. Nuclear NM23‑H1 interacts with transcriptional regulators and chromatin components and contributes to transcriptional repression of pro‑metastatic genes and to DNA damage responses through its exonuclease activity and cooperation with nucleases such as TREX1, where it introduces nicks that facilitate further processing of damaged DNA strands. The protein is widely expressed, with notable levels in liver, brain, endocrine tissues, and hematopoietic and epithelial compartments, and participates in developmental and differentiation programs as part of NME hexamers that support proliferation and specialized functions. Clinically, NME1 was originally identified by reduced expression in highly metastatic tumor cells, and low NM23‑H1 levels or cytoplasmic‑restricted localization correlate with increased metastatic potential and unfavorable prognosis in several cancers, including breast carcinoma and neuroblastoma, whereas preserved or nuclear NM23‑H1 associates with more indolent behavior. NM23‑H1 suppresses multiple steps of metastasis, including local invasion and colonization at distant sites, by jointly constraining pro‑migratory signaling pathways and modulating transcriptional programs, and its expression can be influenced by upstream regulators such as cAMP–PKA–CREB signaling, which links extracellular cues to NME1‑dependent control of metastatic capacity. |
