NME7

NME7 is a nucleoside diphosphate kinase family member that functions in centrosome-based microtubule organization and ciliogenesis (PMID:24807905, PMID:39824631). It is a functional component of the γ-tubulin ring complex (γTuRC), binding through both of its kinase domains—domain A retains autophosphorylating activity while the catalytically inactive domain B contributes binding via Arg-322—and it promotes γTuRC-dependent microtubule nucleation in a kinase-dependent manner without affecting γTuRC assembly or localization (PMID:24807905). NME7 localizes to centrosomes, spindle poles, and basal bodies (with a small ciliary fraction) and is required for primary cilium assembly, ciliary microtubule stability, and Smoothened ciliary trafficking that supports Hedgehog signaling, with these roles depending on its NDK activity and γTuRC association (PMID:39824631). Consistent with a ciliary function, loss of Nme7 in mice and rats produces primary ciliary dyskinesia phenotypes including situs inversus, hydrocephalus, and sterility (PMID:20080492, PMID:33916973), and a homozygous in-frame deletion in the γTuRC-interacting NDK domain causes situs inversus totalis in humans (PMID:27060491). Independently, NME7 kinase activity phosphorylates GSK3β at Ser9 to activate Wnt/β-catenin signaling and drive MTHFD2-dependent one-carbon metabolism in a hepatocellular carcinoma model (PMID:34764205).

1. 2010 Medium

   Whether NME7 has an in vivo physiological role was unknown; loss-of-function in mice first tied it to motile cilia function through a defined multi-organ phenotype.

   Evidence Nme7 knockout mouse with gross and histological phenotyping

   PMID:20080492

   Open questions at the time

   • Does not identify the molecular activity underlying the ciliary defect
   • No cellular or biochemical mechanism established
2. 2012 Medium

   Beyond cilia, the question of whether NME7 contributes to cell identity was opened by showing it is required for embryonic stem cell self-renewal.

   Evidence shRNA knockdown and overexpression rescue with pluripotency marker, embryoid body, and teratoma assays in mouse ESCs

   PMID:22899353

   Open questions at the time

   • Mechanism linking NME7 to pluripotency factor expression not defined
   • Relationship to its ciliary/centrosomal role unclear
3. 2014 High

   The molecular basis of NME7 function was established by showing it is a γTuRC component whose kinase activity and Arg-322 in domain B are required to promote microtubule nucleation.

   Evidence Co-IP, site-directed mutagenesis, shRNA knockdown, and in vitro microtubule nucleation assays

   PMID:24807905

   Open questions at the time

   • Catalytic substrate of domain A within the γTuRC context not identified
   • Structural basis of γTuRC docking not resolved
4. 2016 Medium

   Whether the γTuRC-binding domain matters for human physiology was answered by linking an in-frame deletion in the second NDK domain to situs inversus totalis.

   Evidence Whole-exome sequencing and segregation analysis in a consanguineous family

   PMID:27060491

   Open questions at the time

   • Single family
   • Functional consequence of the deletion on γTuRC binding not directly assayed in patient cells
5. 2019 Low

   An extracellular NME7AB isoform was reported to drive primed-to-naïve pluripotency regression with mitochondrial reactivation, raising the possibility of a non-centrosomal mode of action.

   Evidence iPSC culture with NME7AB in bFGF-depleted medium, mitochondrial respiration and ATP assays

   PMID:31467990

   Open questions at the time

   • No mechanistic dissection of how NME7AB acts; single lab, single assay set
   • Relationship between secreted NME7AB activity and intracellular γTuRC function unestablished
6. 2021 Medium

   Independent replication in a second species confirmed NME7 as essential for ciliogenesis in vivo via a primary ciliary dyskinesia phenotype.

   Evidence CRISPR/Cas9 knockout rat with histology and transcriptomic profiling

   PMID:33916973

   Open questions at the time

   • Does not distinguish motile versus primary cilia contributions at the molecular level
7. 2021 Medium

   A signaling role distinct from centrosomes was defined by showing NME7 phosphorylates GSK3β-Ser9 to activate Wnt/β-catenin and MTHFD2-driven one-carbon metabolism in cancer.

   Evidence Kinase assay, Co-IP, knockdown/overexpression, mouse tumorigenesis model, organoid and β-catenin luciferase reporter assays

   PMID:34764205

   Open questions at the time

   • Single lab
   • How NME7 kinase specificity toward GSK3β is achieved not defined
   • Connection to its γTuRC/ciliary role unexplored
8. 2025 Medium

   The cellular pathway downstream of NME7's centrosomal localization was resolved by linking it to primary cilium assembly, ciliary microtubule stability, and Hedgehog signaling via Smoothened trafficking.

   Evidence siRNA/CRISPR knockout, immunofluorescence, nocodazole sensitivity, Hedgehog reporter, and Smo ciliary trafficking assays

   PMID:39824631

   Open questions at the time

   • Full mutagenesis demonstrating kinase-activity dependence not detailed
   • Single lab
   • Mechanism of how NME7 promotes Smo accumulation in cilia not defined

• How NME7's NDK/kinase activity is mechanistically coupled to both γTuRC-based microtubule nucleation and to substrate phosphorylation (e.g., GSK3β) remains unresolved, as does whether these functions operate through a common biochemical activity.
• No structure of NME7 within γTuRC
• Physiological substrate(s) of the active domain A not catalogued
• Relationship between intracellular and secreted-isoform functions unknown