IP6K2 Human
Description
Biochemical Functions and Gene Characteristics
IP6K2 is a 58-kDa protein with kinase activity specific to inositol phosphates. Key features include:
IP6K2’s enzymatic products, such as InsP7, modulate cellular phosphate homeostasis and energy dynamics. Inositol pyrophosphates (IP7/PP-InsP4) generated by IP6K2 act as signaling molecules, inhibiting pro-growth pathways like PI3K/Akt/mTOR while promoting apoptosis in specific contexts .
Cellular Roles in Energy Metabolism and Neuroprotection
IP6K2 is essential for maintaining mitochondrial function and ATP production, particularly in neurons.
Energy Homeostasis in the Brain
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CK-B Interaction: IP6K2 physically binds CK-B, a key enzyme in phosphocreatine (PCr)/ATP shuttling. Deletion of IP6K2 in mice reduces CK-B expression, leading to:
| Parameter | IP6K2-WT | IP6K2-KO |
|---|---|---|
| ATP levels | Normal | ↓ 40–50% |
| PCr levels | Normal | ↓ 30–40% |
| ROS levels | Low | ↑ 2–3× |
| Cytochrome c1 (CIII) | Normal | ↓ 50% |
Data derived from PNAS studies .
Neuronal Morphogenesis
IP6K2-deficient neurons exhibit reduced dendritic branching, a phenotype reversible by ATP restoration. This underscores IP6K2’s role in neurodevelopment and synaptic plasticity .
Signaling Pathway Regulation
IP6K2 modulates key signaling cascades:
Hedgehog (Hh) Signaling
IP6K2 acts as a positive effector downstream of Smoothened (Smo) and upstream of Gli transcription factors. In zebrafish and mammalian models:
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IP6K2 depletion inhibits Hh target gene expression (e.g., ptch2, gli1) .
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Overexpression enhances Hh pathway activation, rescuing phenotypes caused by cyclopamine (a Smo inhibitor) .
Akt/GSK3 Pathway
IP6K2 binds GSK3, preventing its phosphorylation by Akt. This enhances GSK3 activity, suppressing pro-survival signals in cancer cells .
Clinical Relevance and Disease Associations
IP6K2’s dual roles in apoptosis and energy metabolism position it as a therapeutic target in cancer and neurodegeneration.
Cancer Prognosis
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Breast Cancer: High IP6K2 expression correlates with ER positivity and improved survival in systemically untreated patients. This may reflect its inhibition of PI3K/Akt/mTOR signaling .
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Ovarian Cancer: IP6K2 enhances interferon-β-induced apoptosis, suggesting a tumor-suppressive role .
| Cancer Type | IP6K2 Expression | Clinical Outcome |
|---|---|---|
| Breast | High | Favorable prognosis |
| Ovarian | Variable | Apoptosis induction |
Neurological Disorders
IP6K2-KO mice exhibit mitochondrial complex III deficiency, a phenotype linked to Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease .
Key Studies
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IP6K2 and CK-B Interaction:
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Hh Pathway Modulation:
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Phosphate Homeostasis:
Product Specs
Product Science Overview
IP6K2 is primarily responsible for the conversion of inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7/PP-InsP5) . This conversion is significant because InsP7 is involved in various cellular processes, including energy metabolism, apoptosis, and DNA repair . Additionally, IP6K2 can convert 1,3,4,5,6-pentakisphosphate (InsP5) to PP-InsP4 .
The activity of IP6K2 is linked to several critical cellular functions:
- Apoptosis: IP6K2 has been shown to affect the growth suppressive and apoptotic activities of interferon-beta in some ovarian cancers .
- Energy Metabolism: By regulating the levels of inositol phosphates, IP6K2 plays a role in cellular energy homeostasis .
- DNA Repair: InsP7, a product of IP6K2 activity, is involved in the DNA repair process, highlighting its importance in maintaining genomic stability .
Recombinant human IP6K2 is produced using various expression systems, such as Escherichia coli . The recombinant protein is often tagged with a His tag at the N-terminus to facilitate purification and detection . The recombinant form retains the functional properties of the native protein, making it useful for research and therapeutic applications .
Recombinant IP6K2 is widely used in biochemical and cellular studies to understand its role in inositol phosphate metabolism and its impact on cellular functions. It is also utilized in drug discovery and development, particularly in the context of cancer research, due to its involvement in apoptosis and growth suppression .
