"IP6K3 (inositol hexakisphosphate kinase 3; EC 2.7.4.21)** is a human inositol phosphate kinase that catalyzes pyrophosphate formation on highly phosphorylated inositols, most prominently converting **InsP6 (IP6) to 5-InsP7 (5-IP7)** and participating in downstream generation of **InsP8**. Beyond catalysis, evidence indicates IP6K3 also has **noncatalytic scaffolding roles** (e.g., linking spectrin and adducin in neurons) and can enable **protein pyrophosphorylation-based signaling** (e.g., dynein intermediate chain Ser51), connecting inositol pyrophosphate metabolism to cytoskeletal organization, neuronal development, and metabolic physiology. "

"IP6K3 is reported to be **non-ubiquitous** and **enriched** in specific tissues compared with IP6K1/2. A review of IP6Ks notes that IP6K3 is expressed at higher levels in **skeletal muscle**, **cardiac muscle**, and the **thyroid**, whereas IP6K1/2 are described as more ubiquitous. "

"IP6K3 co-immunoprecipitates with **α/β-adducin** and **α2/β2-spectrin**, and these interactions were reported as **specific to IP6K3** (not observed similarly for IP6K1/2 in that study). Importantly, IP6K3's promotion of spectrin–adducin interaction was reported to be **independent of kinase activity**, consistent with a **noncatalytic scaffolding role** (kinase-dead mutant K217A still promotes binding). "

"A 2023 review summarizes evidence that IP6K3 binds **dynein intermediate chain 2 (DIC2)** and that IP7 produced by IP6K3 can **pyrophosphorylate DIC2 at Ser51**, enhancing interaction with **p150glued** and recruitment of the dynein/dynactin complex to the leading edge of migrating cells; this is integrated into a model linking IP6K-derived inositol pyrophosphates to focal adhesion and cytoskeletal control relevant to neuronal migration. "

"Reduced cerebellar molecular layer width** and **Purkinje dendritic defects** (withered dendritic trees), with reduced Purkinje cell size/volume and reduced spine density... **Large synaptic deficits** in the cerebellar molecular layer: electron microscopy quantification indicates both symmetric and asymmetric synapses decrease by **~40–50%**; immunostaining quantification shows synapse-type-specific reductions of approximately **~40% (GABAergic)**, **~40% (parallel fiber)**, and **~50% (climbing fiber)** synapses; GABA synapse unit area decreases by **~40%**. "

"Reported phenotypes in **Ip6k3−/− mice** include: **Lower blood glucose** and **reduced circulating insulin**, **Decreased fat mass** and **lower body weight**, **Increased plasma lactate**, **Enhanced glucose tolerance** and improved insulin tolerance, **Reduced skeletal muscle Pdk4 expression** under normal diet conditions, **Extended lifespan**, associated with reduced phosphorylation of cardiac **S6 ribosomal protein**. "

"We demonstrate that IP6K3 is highly concentrated in the brain in cerebellar Purkinje cells. IP6K3 physiologically binds to the cytoskeletal proteins adducin and spectrin, whose mutual interactions are perturbed in IP6K3-null mutants. Consequently, IP6K3 knock-out cerebella manifest abnormalities in Purkinje cell structure and synapse number, and the mutant mice display deficits in motor learning and coordination. "

"Thus, IP6K3 is a major determinant of cytoskeletal disposition and function of cerebellar Purkinje cells. "

"We detected high levels of both mouse and human IP6K3 mRNA in myotubes and muscle tissues... Ip6k3 was highly expressed in murine skeletal muscles (the soleus and gastrocnemius muscles) followed by the heart (Fig. 1a)... Similar results were obtained in human tissues (Fig. 1b), which also revealed the thyroid as an IP6K3-expressing site. Among the inositol kinases, IP6K3 showed the highest mRNA expression in human skeletal muscles (Fig. 1c). "

"Furthermore, when an AcGFP-human IP6K3 fusion protein construct was transfected into mouse C2C12 cells, the resultant AcGFP-IP6K3 was localized to both the cytoplasm and the nucleus (Fig. S3). "

"Ip6k3(-/-) mice demonstrated lower blood glucose, reduced circulating insulin, deceased fat mass, lower body weight, increased plasma lactate, enhanced glucose tolerance, lower glucose during an insulin tolerance test, and reduced muscle Pdk4 expression under normal diet conditions. Notably, Ip6k3 deletion extended animal lifespan with concomitant reduced phosphorylation of S6 ribosomal protein in the heart. "

"IP6K3 is highly expressed in the Purkinje cells and interneurons of the cerebellum as well as in the cortex, hippocampus, thalamus, and hypothalamus [134]. In IP6K3 KO mouse cerebella, the width of the molecular layer is decreased and the number of synapses is decreased by 50% [134]. GABAergic synapses as well as parallel and climbing fiber synapses were decreased in KO mouse cerebella [134]. Purkinje cells of KO mice display dendritic growth retardation, decreased cell size, as well as impaired migration into the Purkinje cell layer [16]. "

"In 2019, they expanded these discoveries to include IP6K3′s role in focal adhesion dynamics. They discovered that IP6K3 binds to directly to DIC2 [16]. IP7 generated by IP6K3 then pyrophosphorylates serine 51 on DIC2 [28], promoting its interaction with p150glued on dynactin, recruiting the complex to the leading edge of the cell membrane [16]. "

"IP6K1 and IP6K2 are expressed ubiquitously throughout the body, whereas IP6K3 is expressed in higher levels in skeletal muscle, cardiac muscle, and the thyroid [2,3]. "

"Finally, in humans, an exploratory study of single nucleotide polymorphisms (SNPs) of the IP6K3 gene revealed two SNPs in the promoter region that are associated with late onset Alzheimer's disease. One of these SNPs showed an increase in promoter activity and is associated with a decreased disease risk for Alzheimer's disease [135]. The other SNP did not affect promoter activity but was associated with an increased risk for Alzheimer's disease. "