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Cited by 28Angiogenesis and VEGF in CancerCancer, Hypoxia, and MetabolismProtein Kinase Regulation and GTPase Signaling

Inositol Polyphosphate Multikinase Inhibits Angiogenesis via Inositol Pentakisphosphate-Induced HIF-1α Degradation

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Fu, Chenglai, Tyagi, Richa, Chin, Alfred C., Rojas, Tomas, Li, Ruo-Jing, Guha, Prasun, Bernstein, Isaac A., Rao, Feng +6 more·2018·Circulation Research
DOI 10.1161/circresaha.117.311983PMC PMC5805644
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Abstract

Rationale: Inositol polyphosphate multikinase (IPMK) and its major product inositol pentakisphosphate (IP5) regulate a variety of cellular functions, but their role in vascular biology remains unexplored. Objective: We have investigated the role of IPMK in regulating angiogenesis. Methods and Results: Deletion of IPMK in fibroblasts induces angiogenesis in both in vitro and in vivo models. IPMK deletion elicits a substantial increase of VEGF (vascular endothelial growth factor), which mediates the regulation of angiogenesis by IPMK. The regulation of VEGF by IPMK requires its catalytic activity. IPMK is predominantly nuclear and regulates gene transcription. However, IPMK does not apparently serve as a transcription factor for VEGF. HIF (hypoxia-inducible factor)-1α is a major determinant of angiogenesis and induces VEGF transcription. IPMK deletion elicits a major enrichment of HIF-1α protein and thus VEGF. HIF-1α is constitutively ubiquitinated by pVHL (von Hippel–Lindau protein) followed by proteasomal degradation under normal conditions. However, HIF-1α is not recognized and ubiquitinated by pVHL in IPMK KO (knockout) cells. IP5 reinstates the interaction of HIF-1α and pVHL. HIF-1α prolyl hydroxylation, which is prerequisite for pVHL recognition, is interrupted in IPMK-deleted cells. IP5 promotes HIF-1α prolyl hydroxylation and thus pVHL-dependent degradation of HIF-1α. Deletion of IPMK in mouse brain increases HIF-1α/VEGF levels and vascularization. The increased VEGF in IPMK KO disrupts blood–brain barrier and enhances brain blood vessel permeability. Conclusions: IPMK, via its product IP5, negatively regulates angiogenesis by inhibiting VEGF expression. IP5 acts by enhancing HIF-1α hydroxylation and thus pVHL-dependent degradation of HIF-1α.

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Crossref · 10.1161/circresaha.117.311983

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  • IPMK acts as a rate-limiting enzyme in the HOIP pathway.

    “IPMK acts as a rate-limiting enzyme, with its loss of function significantly impacting the production of downstream HOIPs such as InsP4, InsP5, InsP6, InsP7, and InsP8 [13,14].”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [13]

    The Introduction identifies IPMK as the primary generator of IP5 and says it can also form IP4. The Results ('IP5 induces HIF-1α degradation'; page unavailable) report that IPMK deletion abolishes generation of IP5 and IP6. These passages support a central role in the pathway, but do not establish that IPMK is rate-limiting or show the claimed effects on IP7 and IP8. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Loss of IPMK function significantly impacts production of downstream HOIPs such as InsP4, InsP5, InsP6, InsP7, and InsP8.

    “IPMK acts as a rate-limiting enzyme, with its loss of function significantly impacting the production of downstream HOIPs such as InsP4, InsP5, InsP6, InsP7, and InsP8 [13,14].”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [13]

    The Results section (“IP5 induces HIF-1α degradation”; page not provided) states that IPMK deletion abolishes generation of InsP5 and InsP6. The Introduction says IPMK can form InsP4 and places InsP7 downstream of InsP6, but our copy does not establish that loss of IPMK significantly affects InsP4, InsP7, or InsP8 production, or describe IPMK as rate-limiting. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Authors
Fu, C., Tyagi, R., Chin, A. C., Rojas, T., Li, R.-J., Guha, P., Bernstein, I. A., Rao, F., Xu, R., Cha, J. Y., Xu, J., Snowman, A. M., Semenza, G. L., & Snyder, S. H.
Affiliations
  • From the Solomon H. Snyder Department of Neuroscience (C.F., R.T., A.C.C., T.R., P.G., I.A.B., F.R., R.X., J.Y.C., J.X., A.M.S., S.H.S.), Department of Pharmacology and Molecular Sciences (R.-J.L., S.H.S.), Institute for Cell Engineering (G.L.S.), McKusick-Nathans Institute of Genetic Medicine (G.L.S.), Department of Pediatrics (G.L.S.), Department of Medicine (G.L.S.), Department of Oncology (G.L.S.), Department of Radiation Oncology (G.L.S.), Department of Biological Chemistry (G.L.S.), and...
  • Johns Hopkins University (US)
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2018-02-02
Volume
122
Issue
3
Pages
457-472
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/circresaha.117.311983
PMC
PMC5805644
OpenAlex
W2780015747
Cited by
28
References
9
Citations by year
2026: 3 · 2025: 5 · 2024: 7 · 2023: 4 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 4
FWCI
0.67
Type
journal article
Language
en
Open access
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Johns Hopkins University
  • U.S. Public Health Service (MH‐18501)
  • National Institute of Mental Health (R01MH018501, R37MH018501)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
inositol polyphosphate multikinase, inositol pentakisphosphate, angiogenesis, HIF-1α degradation, vascular endothelial growth factor, von Hippel-Lindau protein, ubiquitination, prolyl hydroxylation, blood-brain barrier permeability, brain vascularization
MeSH terms
Animals, Blood-Brain Barrier, Cells, Cultured, Fibroblasts, Gene Expression Regulation, Humans, Inositol Phosphates, Male, Mice, Inbred C57BL, Specific Pathogen-Free Organisms, Culture Media, Conditioned, Phosphotransferases (Alcohol Group Acceptor), Neovascularization, Physiologic, Coculture Techniques, RNA, Small Interfering, Vascular Endothelial Growth Factor A, Mice, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit, Gene Knockout Techniques, HEK293 Cells, Proteolysis, Human Umbilical Vein Endothelial Cells

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