From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease

Among all enzymes in the HOIP pathway, IPMK is the only one whose deletion leads to embryonic lethality in mice.

“Notably, among all enzymes in the HOIP pathway, IPMK stands out as the only one whose deletion leads to embryonic lethality in mice, underscoring its critical role in mammalian development [25].”

• cites [25] Frederick, 2005, An Essential Role for an Inositol Polyphosphate Multikinase, Ipk2, in Mouse Embryogenesis and Second Messenger Production, Proc. Natl. Acad. Sci. USA sourceDisputed

  The Discussion (page not supplied) confirms that Ipk2/IPMK deletion is embryonically lethal, but explicitly reports a similar lethal phenotype for Ipk1-null mice. Thus the paper contradicts the claim that IPMK is the only enzyme in this pathway whose deletion causes embryonic lethality. (LLM, conf=0.93)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

InsP6 can undergo further phosphorylation to form InsP7/8 by InsP6 kinases 1/2/3.

“InsP6 can undergo further phosphorylation to form InsP7/8 by InsP6 kinases 1/2/3 [10].”

• cites [10] Chakraborty, 2011, Inositol Pyrophosphates as Mammalian Cell Signals, Sci. Signal. sourcePartly supported

  The Introduction (page not provided) says the three mammalian IP6 kinases generate 5-IP7 from IP6. It says a different enzyme, PP-IP5K, is primarily responsible for IP8 formation in mammals, so attributing both products to IP6 kinases 1/2/3 overstates the source. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

ITPK1 can utilize Glucose-6-phosphate-derived InsP3 to generate InsP4 (InsP 1,3,4,5).

“However, recent findings [38] suggest that ITPK1 can utilize Glucose-6-phosphate-derived InsP3 to generate InsP4 (InsP 1,3,4,5), and both isoforms of InsP4 are converted to InsP5 (InsP 1,3,4,5,6) exclusively by IPMK.”

• cites [38] Wilson, 2019, ITPK1 Mediates the Lipid-Independent Synthesis of Inositol Phosphates Controlled by Metabolism, Proc. Natl. Acad. Sci. USA sourcePartly supported

  The Results section, “ITPK1 Can Use I(3)P1 to Generate Higher IPs” (page unavailable), reports that ITPK1 can use a glucose-6-phosphate-derived substrate to make higher inositol phosphates. But it identifies that substrate as I(3)P1, not InsP3, and does not establish that the product is specifically InsP(1,3,4,5)P4. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

In mammalian cells, InsP5 and InsP6 are produced in significantly higher concentrations compared to other inositol phosphates.

“In mammalian cells, InsP5 and InsP6 are produced in significantly higher concentrations compared to other inositol phosphates [39,40], representing the highest products in the HOIP pathway.”

• cites [39] Letcher, 2008, Do Mammals Make All Their Own Inositol Hexakisphosphate?, Biochem. J. sourcePartly supported

  The Results (Table 1; page not provided) quantify InsP6 in rat tissues and HeLa cells, and the Introduction describes InsP5 as an intermediate in InsP6 synthesis. The paper does not establish that either compound is present at significantly higher concentrations than other inositol phosphates; its Discussion says the assay was not designed to quantify lower inositol phosphates. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [40] Stuart, 1994, The Intracellular Distribution of Inositol Polyphosphates in HL60 Promyeloid Cells, Biochem. J. sourceNot checked — no full text of the source

The N-lobe and C-lobe interface form a groove-like cavity that harbors the catalytic site, facilitating transfer of phosphates from ATP to inositol head groups of PIP2 and InsP3, InsP4.

“The N-lobe and the C-lobe interface form a groove-like cavity that harbors the catalytic site, which facilitates the transfer of phosphates from ATP to inositol head groups of PIP2 and InsP3, InsP4.”

• cites [41] Seacrist, C.D., and Blind, R.D. (2018). Crystallographic and Kinetic Analyses of Human IPMK Reveal Disordered Domains Modulate ATP Binding and Kinase Activity. Sci. Rep., 8. sourcePartly supported

  The Results section (‘Crystallography shows ΔIPMK maintains the ATP-grasp fold’; page unavailable) describes N- and C-terminal domains, and the Methods (‘IPMK Kinase Assays’; page unavailable) document transfer of radiolabeled phosphate from ATP to PIP2. Our copy does not establish that their interface forms the claimed groove-like catalytic cavity or specifically identify InsP3 and InsP4 as substrates in that cavity. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [42] Wang, 2017, Structural Features of Human Inositol Phosphate Multikinase Rationalize Its Inositol Phosphate Kinase and Phosphoinositide 3-Kinase Activities, J. Biol. Chem. sourceSupported

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].”

• cites [13] Fu, 2018, Inositol Polyphosphate Multikinase Inhibits Angiogenesis via Inositol Pentakisphosphate-Induced HIF-1α Degradation, Circ. Res. sourcePartly supported

  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
• cites [14] Guha, 2019, IPMK Mediates Activation of ULK Signaling and Transcriptional Regulation of Autophagy Linked to Liver Inflammation and Regeneration, Cell Rep. sourcePartly supported

  The Introduction (page unavailable) says IPMK generates IP4 and IP5, and describes their pathway toward IP6, IP7, and IP8. The Results section on autophagy (page unavailable) reports inositol profiling to verify kinase activity, but our copy does not state that loss of IPMK significantly reduces production of all five compounds or that IPMK is rate-limiting. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Deletion of IPMK results in severe developmental defects across various model organisms.

“The physiological significance of IPMK is highlighted by studies across various model organisms, where its deletion results in severe developmental defects [24,25].”

• cites [24] Seeds, 2015, Inositol Phosphate Kinase 2 Is Required for Imaginal Disc Development in Drosophila, Proc. Natl. Acad. Sci. USA sourceNot checked — no full text of the source
• cites [25] Frederick, 2005, An Essential Role for an Inositol Polyphosphate Multikinase, Ipk2, in Mouse Embryogenesis and Second Messenger Production, Proc. Natl. Acad. Sci. USA sourcePartly supported

  The Results report that Ipk2-null mouse embryos have severe developmental abnormalities and are embryonically lethal. The paper does not establish that deletion of IPMK causes developmental defects across various model organisms; its mention of zebrafish abnormalities concerns a different kinase, Ipk1. No page number is available in our copy. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

IPMK's lipid kinase enzymatic (PI3-kinase) activity is essential for activating AKT.

“Notably, research suggests that IPMK’s lipid kinase enzymatic (PI3-kinase) activity is essential for activating AKT [15], also known as PKB (protein kinase B), a crucial kinase involved in cell survival and proliferation.”

• cites [15] Maag, 2011, Inositol Polyphosphate Multikinase Is a Physiologic PI3-Kinase That Activates Akt/PKB, Proc. Natl. Acad. Sci. USA sourcePartly supported

  The Results and Discussion report that IPMK’s PI3-kinase activity is predominantly responsible for its contribution to Akt signaling: wild-type IPMK rescued Akt activation in IPMK-deleted cells, whereas a form lacking PI3-kinase activity did not. But deletion reduced activation by 40–50%, rather than eliminating it, so the paper does not establish that IPMK’s activity is essential for all Akt activation. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Studies across various organisms demonstrated a significant decrease in both InsP5 and InsP6 production in IPMK-null or kinase-dead cells.

“Studies across various organisms, from yeast to mammalian cells, have demonstrated a significant decrease in both InsP5 and InsP6 production in IPMK-null or kinase-dead cells [12,14].”

• cites [12] Saiardi, 1999, Synthesis of Diphosphoinositol Pentakisphosphate by a Newly Identified Family of Higher Inositol Polyphosphate Kinases, Curr. Biol. sourcePartly supported

  The Results and discussion (page unavailable) show that yeast ArgRIII/IPMK phosphorylates InsP3 and InsP4 and produces higher inositol polyphosphates, including a product consistent with InsP6. They do not report decreased InsP5 or InsP6 production in IPMK-null or kinase-dead cells, whether in yeast or mammalian cells; the HEK293 experiments used transfected enzyme. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [14] Guha, 2019, IPMK Mediates Activation of ULK Signaling and Transcriptional Regulation of Autophagy Linked to Liver Inflammation and Regeneration, Cell Rep. sourcePartly supported

  The Introduction (page unavailable) says IPMK generates IP5 and describes a pathway leading to IP6. The Results section ‘IPMK Is Essential for Autophagy’ (page unavailable) identifies a kinase-dead IPMK mutant and reports inositol profiling, but the available text does not report a significant decrease in both InsP5 and InsP6 production in IPMK-null or kinase-dead cells across organisms. (LLM, conf=0.79)

  Experimental — accuracy not yet measured

Human IPMK is a 416 amino acid-long protein comprising two pseudo-domains, an N-lobe and a C-lobe, joined by a hinge.

“The human IPMK protein is a 416 amino acid-long protein comprising two pseudo-domains—an N-lobe and a C-lobe—joined by a hinge (Figure 2A).”

• cites [41] Seacrist, C.D., and Blind, R.D. (2018). Crystallographic and Kinetic Analyses of Human IPMK Reveal Disordered Domains Modulate ATP Binding and Kinase Activity. Sci. Rep., 8. sourcePartly supported

  The Methods (Protein Expression and Purification; page unavailable) identify residue 416 as the end of human IPMK, and the Results (Crystallography shows ΔIPMK maintains the ATP-grasp fold; page unavailable) describe N-terminal and C-terminal domains. Our copy does not describe those domains as joined by a hinge, so that part of the claim is not supported. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [42] Wang, 2017, Structural Features of Human Inositol Phosphate Multikinase Rationalize Its Inositol Phosphate Kinase and Phosphoinositide 3-Kinase Activities, J. Biol. Chem. sourceSupported

IPMK has dual inositol and lipid kinase activities.

“With dual inositol and lipid kinase activities, IPMK generates pivotal signaling molecules such as InsP4 (inositol tetraphosphate), InsP5 (inositol pentaphosphate), and PIP3 (phosphoinositide 3,4,5-trisphosphate), positioning it as a critical regulator of cellular mechanisms.”

• cites [11] Kim, 2016, IPMK: A Versatile Regulator of Nuclear Signaling Events, Adv. Biol. Regul. sourceNot checked — no full text of the source
• cites [12] Saiardi, 1999, Synthesis of Diphosphoinositol Pentakisphosphate by a Newly Identified Family of Higher Inositol Polyphosphate Kinases, Curr. Biol. sourcePartly supported

  The Results and discussion section describes IPMK as a multifunctional kinase that phosphorylates InsP3 and InsP4, supporting its inositol kinase activity. Our copy does not report lipid kinase activity or PIP3 production, so it does not establish the claimed dual activity. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

The reduction in InsP5 and InsP6 upon IPMK deletion is primarily attributed to the decrease in InsP5 levels, which serves as the major precursor of InsP6.

“This reduction is primarily attributed to the decrease in InsP5 levels, which serves as the major precursor of InsP6 upon IPMK deletion, underscoring the critical role of IPMK in regulating HOIPs levels.”

• cites [12] Saiardi, 1999, Synthesis of Diphosphoinositol Pentakisphosphate by a Newly Identified Family of Higher Inositol Polyphosphate Kinases, Curr. Biol. sourcePartly supported

  The Results and discussion section identifies InsP5 as a substrate for conversion to InsP6 and says IPMK can presumably convert InsP3 to InsP6. It does not report IPMK-deletion experiments, reduced InsP5 or InsP6 levels after deletion, or evidence that a fall in InsP5 is the primary cause of a fall in InsP6. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [14] Guha, 2019, IPMK Mediates Activation of ULK Signaling and Transcriptional Regulation of Autophagy Linked to Liver Inflammation and Regeneration, Cell Rep. sourcePartly supported

  The Introduction says IPMK generates IP5 and describes successive phosphorylation leading to IP6. The Results mention inositol profiling, but the passages in our copy do not state that IPMK deletion reduces both levels or that the IP6 reduction is primarily caused by a fall in IP5. Page numbers are unavailable in our copy. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

In the HOIP pathway, IPMK along with ITPK1 plays a crucial role in generating inositol polyphosphates from InsP3.

“In the HOIP pathway (Figure 1B), IPMK, along with Inositol-trisphosphate 3-kinase 1 (ITPK1), plays a crucial role in generating inositol polyphosphates (InsPs) from Inositol 1,4,5-trisphosphate (InsP3) [10,16].”

• cites [10] Chakraborty, 2011, Inositol Pyrophosphates as Mammalian Cell Signals, Sci. Signal. sourcePartly supported

  The Inositol Pyrophosphate Metabolism section (page unavailable) says IPMK sequentially converts IP3 to IP5 and IP3K converts IP3 to IP4. It does not identify IP3K as ITPK1 or describe a HOIP pathway, so those parts of the attributed claim are not supported by our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [16] Kim, 2024, The Inositol Phosphate Signalling Network in Physiology and Disease, Trends Biochem. Sci. sourcePartly supported

  In “Synthesis and turnover of InsP6” (page unavailable), the paper says IPMK helps convert Ins(1,4,5)P3 into higher inositol phosphates, but names IP3K—not ITPK1—as the other kinase in that route. It places ITPK1 in a separate pathway that begins with Ins3P, so the claim does not supportably pair ITPK1 with IPMK as acting from Ins(1,4,5)P3. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Crystal structures of human IPMK have been deposited in the PDB in free form, bound to substrates (ADP, InsP3), or inhibitors.

“Currently, different groups have deposited crystal structures of human IPMK in the PDB database in its free form (pdb id: 5w2g, 6e7f) [41,42] bound to substrates (ADP, InsP3) [42] or inhibitors [43].”

• cites [41] Seacrist, C.D., and Blind, R.D. (2018). Crystallographic and Kinetic Analyses of Human IPMK Reveal Disordered Domains Modulate ATP Binding and Kinase Activity. Sci. Rep., 8. sourcePartly supported

  The Methods and Results identify this paper’s human IPMK structure as the apo (free) form deposited as PDB 6E7F. The Results also discuss a previously reported human IPMK structure bound to ADP, but the InsP3-bound structures described are of other kinases, not human IPMK. The inhibitors clause is cited to a different source and is not judged here. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [42] Wang, 2017, Structural Features of Human Inositol Phosphate Multikinase Rationalize Its Inositol Phosphate Kinase and Phosphoinositide 3-Kinase Activities, J. Biol. Chem. sourceSupported
• cites [43] Gu, 2019, Inhibition of Inositol Polyphosphate Kinases by Quercetin and Related Flavonoids: A Structure-Activity Analysis, J. Med. Chem. sourceSupported

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].”

• cites [13] Fu, 2018, Inositol Polyphosphate Multikinase Inhibits Angiogenesis via Inositol Pentakisphosphate-Induced HIF-1α Degradation, Circ. Res. sourcePartly supported

  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
• cites [14] Guha, 2019, IPMK Mediates Activation of ULK Signaling and Transcriptional Regulation of Autophagy Linked to Liver Inflammation and Regeneration, Cell Rep. sourcePartly supported

  The Introduction (page unavailable) says IPMK generates IP4 and IP5 and describes a pathway leading to IP6, IP7, and IP8. It does not identify IPMK as rate-limiting or report that its loss significantly reduces production of all those downstream compounds. The Results’ inositol-profiling passage (page unavailable) describes a method, not that claimed effect. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

IPMK can use either InsP3 or InsP4 to generate InsP5.

“Hence, IPMK can use either InsP3 or InsP4 to generate InsP5 (Ins 1,3,4,5,6).”

• cites [10] Chakraborty, 2011, Inositol Pyrophosphates as Mammalian Cell Signals, Sci. Signal. sourceSupported
• cites [38] Wilson, 2019, ITPK1 Mediates the Lipid-Independent Synthesis of Inositol Phosphates Controlled by Metabolism, Proc. Natl. Acad. Sci. USA sourcePartly supported

  The Discussion section (“ITPK1 Is Essential for IPs Synthesis in Mammals”; page unavailable) proposes that IPMK phosphorylates a substrate to produce I(1,3,4,5,6)P5. It does not identify both InsP3 and InsP4 as substrates IPMK can use, so the claim’s either-or specificity is unsupported. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

IPMK is essential for mammalian embryonic development.

“Initially identified in yeast and later recognized as essential for mammalian embryonic development, IPMK has transitioned from a niche interest to a focal point in studies of nutrient sensing, growth factor signaling, mRNA transport, and transcription regulation.”

• cites [25] Frederick, 2005, An Essential Role for an Inositol Polyphosphate Multikinase, Ipk2, in Mouse Embryogenesis and Second Messenger Production, Proc. Natl. Acad. Sci. USA sourceSupported

Both yeast and mammalian IPMK exhibit lipid kinase properties.

“Both yeast and mammalian IPMK exhibit lipid kinase properties [15,26].”

• cites [15] Maag, 2011, Inositol Polyphosphate Multikinase Is a Physiologic PI3-Kinase That Activates Akt/PKB, Proc. Natl. Acad. Sci. USA sourcePartly supported

  The Results and Discussion report PI3K lipid-kinase activity for mouse IPMK, including reduced PIP3 generation in IPMK-deleted mouse embryonic fibroblasts. The passages found do not establish lipid-kinase activity for yeast IPMK, so the yeast half of the claim is unsupported by this paper. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [26] Resnick, 2005, Inositol Polyphosphate Multikinase Is a Nuclear PI3-Kinase with Transcriptional Regulatory Activity, Proc. Natl. Acad. Sci. USA sourceNot checked — no full text of the source

IPMK generates InsP4, InsP5, and PIP3.

“With dual inositol and lipid kinase activities, IPMK generates pivotal signaling molecules such as InsP4 (inositol tetraphosphate), InsP5 (inositol pentaphosphate), and PIP3 (phosphoinositide 3,4,5-trisphosphate), positioning it as a critical regulator of cellular mechanisms.”

• cites [11] Kim, 2016, IPMK: A Versatile Regulator of Nuclear Signaling Events, Adv. Biol. Regul. sourceNot checked — no full text of the source
• cites [12] Saiardi, 1999, Synthesis of Diphosphoinositol Pentakisphosphate by a Newly Identified Family of Higher Inositol Polyphosphate Kinases, Curr. Biol. sourcePartly supported

  The Results and discussion section (page unavailable) identifies IPMK as a kinase that phosphorylates InsP3 and InsP4, supporting its production of InsP4 and InsP5. Our copy does not establish lipid kinase activity or PIP3 production, so those parts of the citing sentence are unsupported. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Both isoforms of InsP4 are converted to InsP5 exclusively by IPMK.

“However, recent findings [38] suggest that ITPK1 can utilize Glucose-6-phosphate-derived InsP3 to generate InsP4 (InsP 1,3,4,5), and both isoforms of InsP4 are converted to InsP5 (InsP 1,3,4,5,6) exclusively by IPMK.”

• cites [38] Wilson, 2019, ITPK1 Mediates the Lipid-Independent Synthesis of Inositol Phosphates Controlled by Metabolism, Proc. Natl. Acad. Sci. USA sourcePartly supported

  The Discussion (page unavailable) proposes that IPMK phosphorylates a downstream substrate to produce I(1,3,4,5,6)P5. It does not identify both InsP4 isoforms as substrates or establish that IPMK does so exclusively; the Results also show that ITPK1 can produce an IP5, although its isomer was not identified. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

IPMK uniquely serves as a lipid kinase using PIP2 as a substrate to generate PIP3.

“IPMK uniquely serves as a lipid kinase (Figure 1A), utilizing Phosphatidylinositol 4,5-bisphosphate [PI (4,5) P2] (PIP2) as a substrate to generate [PI (3,4,5) P3] (PIP3).”

• cites [15] Maag, 2011, Inositol Polyphosphate Multikinase Is a Physiologic PI3-Kinase That Activates Akt/PKB, Proc. Natl. Acad. Sci. USA sourceSupported
• cites [26] Resnick, 2005, Inositol Polyphosphate Multikinase Is a Nuclear PI3-Kinase with Transcriptional Regulatory Activity, Proc. Natl. Acad. Sci. USA sourceNot checked — no full text of the source

The first β-strand of IPMK is not always visible in all crystal structures owing to the disordered nature of the first roughly 60 amino acids.

“The first β-strand (β0 in Figure 2B) is not always visible in all crystal structures owing to the disordered nature of the first roughly 60 amino acids [41,42], which has implications for interaction with other proteins (Table 1) as well as catalytic activity.”

• cites [41] Seacrist, C.D., and Blind, R.D. (2018). Crystallographic and Kinetic Analyses of Human IPMK Reveal Disordered Domains Modulate ATP Binding and Kinase Activity. Sci. Rep., 8. sourcePartly supported

  The Introduction says some IPMK regions are not resolved in all crystal structures, and the Discussion says the N-terminal I65–P69 sequence is disordered in most structures. The paper does not identify a β0 strand as the missing feature or establish that disorder of the first roughly 60 amino acids causes its absence. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [42] Wang, 2017, Structural Features of Human Inositol Phosphate Multikinase Rationalize Its Inositol Phosphate Kinase and Phosphoinositide 3-Kinase Activities, J. Biol. Chem. sourcePartly supported

  The “Structure of human IPMK” section identifies residues 66–69 as the β0 strand and says it was not observed in the yeast or plant IPMK structures. It does not attribute that absence to disorder in the first roughly 60 amino acids. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Certain IPMK SNPs, previously associated with decreased longevity, are protective factors for Late Onset Alzheimer's Disease.

“Another study investigating the relationship between Late Onset Alzheimer’s Disease (LOAD) and longevity found that certain IPMK SNPs, previously associated with decreased longevity, were protective factors for LOAD [91].”

• cites [91] Dato, 2021, IP6K3 and IPMK Variations in LOAD and Longevity: Evidence for a Multifaceted Signaling Network at the Crossroad between Neurodegeneration and Survival, Mech. Ageing Dev. sourceSupported

PIP3 plays a crucial role in cell proliferation by activating AKT.

“PIP3 plays a crucial role in cell proliferation by activating AKT, a key regulator of cellular growth [70].”

• cites [70] Hoxhaj, 2020, The PI3K-AKT Network at the Interface of Oncogenic Signalling and Cancer Metabolism, Nat. Rev. Cancer sourceSupported

IPMK's PI3K activity is crucial for activating SF-1-mediated transcription.

“IPMK’s PI3K activity is crucial for activating Steroidogenic factor 1 (SF-1)-mediated transcription [21].”

• cites [21] Blind, 2012, Direct Modification and Activation of a Nuclear Receptor-PIP2 Complex by the Inositol Lipid Kinase IPMK, Sci. Signal. sourceSupported

IPMK depletion impairs autophagy activation in both yeast and mammalian cells.

“IPMK depletion impairs autophagy activation in both yeast [64,65] and mammalian cells [14,82].”

• cites [64] Taylor, 2012, V KCS1 Deletion in Saccharomyces Cerevisiae Leads to a Defect in Translocation of Autophagic Proteins and Reduces Autophagosome Formation, Autophagy sourceSupported
• cites [65] Kanki, 2009, A Genomic Screen for Yeast Mutants Defective in Selective Mitochondria Autophagy, Mol. Biol. Cell sourcePartly supported

  The citation is attached to the yeast portion of the sentence. In the Results (page unavailable), the arg82 deletion strain is among mutants identified as defective in mitophagy, supporting an effect on selective mitochondrial autophagy. The paper also reports that these mutants had essentially normal nonspecific macroautophagy, so it does not establish impaired autophagy activation generally. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [14] Guha, 2019, IPMK Mediates Activation of ULK Signaling and Transcriptional Regulation of Autophagy Linked to Liver Inflammation and Regeneration, Cell Rep. sourceSupported
• cites [82] Guha, 2019, Noncatalytic Functions of IPMK Are Essential for Activation of Autophagy and Liver Regeneration, Autophagy sourceSupported

IPMK can modulate cellular signaling independently of its kinase activity through protein-protein interaction.

“This enzyme can modulate cellular signaling through multiple mechanisms: by generating highly phosphorylated inositol phosphates (HOIPs) [10,12,14], producing phosphatidylinositol 3,4,5-trisphosphate (PIP3) [10,12,14], or even functioning independently of its kinase activity through protein–protein interaction [10,11,12,14].”

• cites [10] Chakraborty, 2011, Inositol Pyrophosphates as Mammalian Cell Signals, Sci. Signal. sourceSupported
• cites [11] Kim, 2016, IPMK: A Versatile Regulator of Nuclear Signaling Events, Adv. Biol. Regul. sourceNot checked — no full text of the source
• cites [12] Saiardi, 1999, Synthesis of Diphosphoinositol Pentakisphosphate by a Newly Identified Family of Higher Inositol Polyphosphate Kinases, Curr. Biol. sourceCould not verify

  The Results and discussion section identifies ArgRIII as IPMK and demonstrates its inositol-phosphate kinase activity. Searches for kinase-independent signaling and protein–protein interactions found no passage in our copy addressing that mechanism. The cited paper therefore does not verify this part of the sentence. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [14] Guha, 2019, IPMK Mediates Activation of ULK Signaling and Transcriptional Regulation of Autophagy Linked to Liver Inflammation and Regeneration, Cell Rep. sourceSupported

IPMK can modulate cellular signaling by producing phosphatidylinositol 3,4,5-trisphosphate (PIP3).

“This enzyme can modulate cellular signaling through multiple mechanisms: by generating highly phosphorylated inositol phosphates (HOIPs) [10,12,14], producing phosphatidylinositol 3,4,5-trisphosphate (PIP3) [10,12,14], or even functioning independently of its kinase activity through protein–protein interaction [10,11,12,14].”

• cites [10] Chakraborty, 2011, Inositol Pyrophosphates as Mammalian Cell Signals, Sci. Signal. sourceSupported
• cites [12] Saiardi, 1999, Synthesis of Diphosphoinositol Pentakisphosphate by a Newly Identified Family of Higher Inositol Polyphosphate Kinases, Curr. Biol. sourceCould not verify

  The Results and discussion section says IPMK phosphorylates InsP3 and InsP4, but does not say it produces the lipid PIP3 or modulates signaling through PIP3 production. Searches for phosphatidylinositol 3,4,5-trisphosphate and PIP3 found no passage addressing that mechanism; page numbers were not available in our copy. (LLM, conf=0.74)

  Experimental — accuracy not yet measured
• cites [14] Guha, 2019, IPMK Mediates Activation of ULK Signaling and Transcriptional Regulation of Autophagy Linked to Liver Inflammation and Regeneration, Cell Rep. sourceSupported

IPMK physically interacts with the mammalian SWI/SNF complex by directly binding to SMARCB1, BRG1, and SMARCC1.

“Recent research by Beon et al. [20] expanded on these findings, showing that IPMK physically interacts with the mammalian SWI/SNF complex by directly binding to SWI/SNF complex components SMARCB1, BRG1, and SMARCC1.”

• cites [20] Beon, 2022, Inositol Polyphosphate Multikinase Physically Binds to the SWI/SNF Complex and Modulates BRG1 Occupancy in Mouse Embryonic Stem Cells, Elife sourceSupported

IPMK is an important regulator of necroptosis.

“Through a blind genome-scale knockout screening, Dovey et al. [50] identified IPMK as an important regulator of necroptosis.”

• cites [50] Dovey, 2018, MLKL Requires the Inositol Phosphate Code to Execute Necroptosis, Mol. Cell sourceSupported

InsP4 and/or InsP5 generated by IPK2 are crucial for modulating SWI/SNF and INO80 complexes' ability to induce transcription of phosphate-responsive genes.

“Mutational analysis revealed that InsP4 and/or InsP5, generated by IPK2, are crucial for modulating SWI/SNF and INO80 complexes’ ability to induce transcription of phosphate-responsive genes [19].”

• cites [19] Steger, 2003, Regulation of Chromatin Remodeling by Inositol Polyphosphates, Science sourcePartly supported

  The Abstract reports that ARG82/IPK2 mutants have impaired PHO5 transcription and reduced recruitment of SWI/SNF and INO80 to phosphate-responsive promoters. It concludes that IP4 and/or IP5 production may modulate these complexes’ ability to induce some phosphate-responsive genes, but presents that link as a suggestion rather than establishing that the molecules are crucial for phosphate-responsive genes generally. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

HsIPMK crystal structures bound to InsP4 or InsP5 were not successful.

“HsIPMK crystal structures bound to InsP4 or InsP5 were not successful, so the authors of that study [41] modeled in an InsP4 (in silico) into the active site to suggest that”

• cites [41] Seacrist, C.D., and Blind, R.D. (2018). Crystallographic and Kinetic Analyses of Human IPMK Reveal Disordered Domains Modulate ATP Binding and Kinase Activity. Sci. Rep., 8. sourcePartly supported

  The Results section (“Crystallography shows ΔIPMK maintains the ATP-grasp fold”; page unavailable) says crystals grown with an IP4 substrate yielded an apo structure because the ligands were not detectable in the electron-density maps. That supports the lack of an IP4-bound structure, but our copy does not report an unsuccessful InsP5-bound structure; its Discussion describes modeling ADP and PIP2, not InsP4, into the structure. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

PIP3 serves as a crucial second messenger in cell migration.

“PIP3 serves as a crucial second messenger in cellular processes, particularly in cell migration [53].”

• cites [53] Loovers, 2006, Distinct Roles of PI(3,4,5)P3 during Chemoattractant Signaling in Dictyostelium: A Quantitative in Vivo Analysis by Inhibition of PI3-Kinase, Mol. Biol. Cell sourcePartly supported

  The section “The Function of PI(3,4,5)P3 in Cell Polarity and Chemotaxis” describes PI3K signaling as crucial to Dictyostelium chemotactic movement, particularly cell speed and polarity. But the Introduction says that severe reduction of PIP3 has no strong effect on chemotaxis once cells elongate. The source therefore supports a role for PIP3 in migration-related processes, not the unqualified claim that PIP3 itself is crucial for cell migration generally. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

PIP3 recognizes a specific sequence in RAD51 transcripts, facilitating their nuclear export through the ALY factor.

“PIP3 recognizes a specific sequence in RAD51 transcripts, facilitating their nuclear export through the ALY factor.”

• cites [61] Choi, 2019, A Nuclear Phosphoinositide Kinase Complex Regulates P53, Nat. Cell Biol. sourceCould not verify

  The Results section on p53 association with PI4,5P2 describes lipid binding to p53, not recognition of a sequence in RAD51 transcripts. Searches for RAD51, ALY, and transcript export found no passage in our copy addressing the claimed mechanism. (LLM, conf=0.75)

  Experimental — accuracy not yet measured

IPMK's lipid kinase activity promotes cell migration in immortalized mouse embryonic fibroblast cells.

“Studies by Sekine et al. [54] and Reilly et al. [34] have highlighted the significant role of IPMK’s lipid kinase activity in promoting cell migration in immortalized mouse embryonic fibroblast cells (MEFs).”

• cites [54] Padhi, 2019, Inositol Polyphosphate Multikinase Is a Metformin Target That Regulates Cell Migration, FASEB J. sourcePartly supported

  The Results (page unavailable) report that IPMK-deficient MEFs migrated more slowly than wild-type cells and that active IPMK, but not kinase-dead IPMK, accelerated wound closure. These experiments support a role for IPMK’s catalytic activity in MEF migration, but they do not isolate its lipid kinase activity from its other catalytic activity or establish that the MEFs were immortalized. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [34] Reilly, 2023, Loss of PI3k Activity of Inositol Polyphosphate Multikinase Impairs PDK1-Mediated AKT Activation, Cell Migration, and Intestinal Homeostasis, iScience sourceSupported

Nuclear-derived PIP3 is implicated in DNA repair.

“This nuclear-derived PIP3 is implicated in critical cellular processes such as DNA repair.”

• cites [59] Wang, 2017, DNA Damage Causes Rapid Accumulation of Phosphoinositides for ATR Signaling, Nat. Commun. sourceSupported
• cites [60] Lamm, 2020, Nuclear F-Actin Counteracts Nuclear Deformation and Promotes Fork Repair during Replication Stress, Nat. Cell Biol. sourcePartly supported

  The Main Text reports that an ATR–IPMK–mTOR pathway promotes replication fork repair through nuclear F-actin. It does not identify nuclear-derived PIP3 or establish a role for PIP3 in that repair; searches for “PIP3” and “phosphatidylinositol” found no such passage. Page numbers are unavailable in our copy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

H338 can contribute to charge balance in the catalytic cavity to facilitate γ-phosphate transfer from ATP to InsP3.

“Additionally, H338 can also contribute to charge balance in the catalytic cavity to facilitate γ-phosphate transfer from ATP to InsP3 [41] because of its proximity to the β-phosphate of ATP, one of the magnesium ions, and the 4-phosphate of IP3.”

• cites [41] Seacrist, C.D., and Blind, R.D. (2018). Crystallographic and Kinetic Analyses of Human IPMK Reveal Disordered Domains Modulate ATP Binding and Kinase Activity. Sci. Rep., 8. sourceCould not verify

  The Results section on ATP binding discusses I65–P69 as a possible ATP clamp, not H338. Searches for H338 and for charge balance near the ATP and InsP3 phosphates found no passage in our copy addressing the proposed role of H338 in phosphate transfer; page numbers were unavailable. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

IPMK is essential for the generation and maintenance of RORγt+ Treg cells and their regulatory functions.

“Researchers developed Treg-specific IPMK knockout mice and demonstrated that IPMK is essential for the generation and maintenance of RORγt+ Treg cells and their regulatory functions.”

• cites [100] Min, 2022, Differentiation and Homeostasis of Effector Treg Cells Are Regulated by Inositol Polyphosphates Modulating Ca2+ Influx, Proc. Natl. Acad. Sci. USA sourceSupported

IPMK plays a crucial role in autophagy.

“It plays a crucial role in cell proliferation [34], metabolism [58], autophagy [14,64], and migration [34,53,54].”

• cites [14] Guha, 2019, IPMK Mediates Activation of ULK Signaling and Transcriptional Regulation of Autophagy Linked to Liver Inflammation and Regeneration, Cell Rep. sourceSupported
• cites [64] Taylor, 2012, V KCS1 Deletion in Saccharomyces Cerevisiae Leads to a Defect in Translocation of Autophagic Proteins and Reduces Autophagosome Formation, Autophagy sourcePartly supported

  The paper identifies IPK2 as an inositol polyphosphate multikinase and reports that its deletion impairs autophagy in yeast, though less than KCS1 deletion. Its findings concern autophagy induced by nitrogen deprivation in yeast, so they do not establish the unqualified claim that IPMK plays a crucial role in autophagy generally (Results and Discussion; page unavailable in our copy). (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Unlike in yeast, the effect of IPMK on chromatin remodeling in mammalian cells is kinase-independent.

“Importantly, Beon et al. [20] found that, unlike in yeast, where inositol phosphate is required for chromatin remodeling, the effect of IPMK on chromatin remodeling in mammalian cells is kinase-independent.”

• cites [20] Beon, 2022, Inositol Polyphosphate Multikinase Physically Binds to the SWI/SNF Complex and Modulates BRG1 Occupancy in Mouse Embryonic Stem Cells, Elife sourcePartly supported

  The Results section on BRG1 occupancy reports that catalytically dead IPMK increased BRG1 occupancy in IPMK-depleted mouse embryonic stem cells, supporting kinase independence for that effect. The paper does not establish kinase independence for chromatin remodeling generally across mammalian cells; its yeast discussion describes IP products promoting remodeling and impaired remodeling after mutation, rather than showing that inositol phosphate is universally required. Page numbers were not available in our copy. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

IPMK plays a crucial role in cell proliferation.

“It plays a crucial role in cell proliferation [34], metabolism [58], autophagy [14,64], and migration [34,53,54].”

• cites [34] Reilly, 2023, Loss of PI3k Activity of Inositol Polyphosphate Multikinase Impairs PDK1-Mediated AKT Activation, Cell Migration, and Intestinal Homeostasis, iScience sourceSupported

In Dictyostelium, cells with cPI3K genetically eliminated still migrate but are substantially retarded.

“However, studies conducted in the model organism Dictyostelium, where cPI3K was genetically eliminated, revealed that cells still migrate but are substantially retarded [53,54].”

• cites [53] Loovers, 2006, Distinct Roles of PI(3,4,5)P3 during Chemoattractant Signaling in Dictyostelium: A Quantitative in Vivo Analysis by Inhibition of PI3-Kinase, Mol. Biol. Cell sourcePartly supported

  The Effect of LY294002 on Chemotaxis section reports that pi3k1/2-null cells still migrate, but their speed without inhibitor is not very different from wild-type cells. The substantial slowing occurs after LY294002 treatment, not from genetic disruption alone; the paper also specifies that only two of six potential PI3-kinase genes were disrupted. Page numbers were not available in our copy. (LLM, conf=0.89)

  Experimental — accuracy not yet measured
• cites [54] Padhi, 2019, Inositol Polyphosphate Multikinase Is a Metformin Target That Regulates Cell Migration, FASEB J. sourceCould not verify

  The Results (page unavailable) report that mouse embryonic fibroblasts lacking IPMK still migrated, but more slowly than wild-type cells. Searches for Dictyostelium and genetically eliminated cPI3K found no passage addressing migration in those cells; the reported result concerns a different organism and gene. (LLM, conf=0.77)

  Experimental — accuracy not yet measured

IPMK plays a crucial role in migration.

“It plays a crucial role in cell proliferation [34], metabolism [58], autophagy [14,64], and migration [34,53,54].”

• cites [34] Reilly, 2023, Loss of PI3k Activity of Inositol Polyphosphate Multikinase Impairs PDK1-Mediated AKT Activation, Cell Migration, and Intestinal Homeostasis, iScience sourceSupported
• cites [53] Loovers, 2006, Distinct Roles of PI(3,4,5)P3 during Chemoattractant Signaling in Dictyostelium: A Quantitative in Vivo Analysis by Inhibition of PI3-Kinase, Mol. Biol. Cell sourceCould not verify

  The section ‘The Function of PI(3,4,5)P3 in Cell Polarity and Chemotaxis’ describes a crucial role for PI3K signaling in Dictyostelium chemotaxis, not for IPMK. Searches for IPMK and inositol polyphosphate multikinase found no passage in our copy addressing IPMK’s role in migration. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [54] Padhi, 2019, Inositol Polyphosphate Multikinase Is a Metformin Target That Regulates Cell Migration, FASEB J. sourceSupported

IPMK depletion impairs AMPK activation.

“IPMK depletion impairs AMPK activation [30], which is crucial for glucose sensing and metabolism.”

• cites [30] Bang, 2014, Convergence of IPMK and LKB1-AMPK Signaling Pathways on Metformin Action, Mol. Endocrinol. sourcePartly supported

  In “Deletion of IPMK impairs metformin-mediated activation of LKB1/AMPK,” IPMK-depleted cells show reduced AMPK activation after metformin or AICAR treatment. The same section reports that IPMK deletion does not affect AMPK phosphorylation induced by a calcium ionophore, so the unqualified claim is broader than the finding. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

IPMK-generated PIP3 in mammalian cells regulates nuclear export of RAD51 mRNA.

“A separate investigation by Wickramasinge et al. [61] discovered that IPMK-generated PIP3 in mammalian cells plays a crucial role in regulating the nuclear export of RAD51 mRNA, a key protein in DNA repair.”

• cites [61] Choi, 2019, A Nuclear Phosphoinositide Kinase Complex Regulates P53, Nat. Cell Biol. sourceCould not verify

  The Results section on PIPKIα and the Discussion describe PIPKIα-generated PI4,5P2 regulating nuclear p53 stability, not IPMK-generated PIP3 regulating mRNA export. Searches for RAD51 mRNA, IPMK, and Wickramasinghe found no passage in our copy addressing the attributed finding. Page numbers were not available. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

IPMK can modulate cellular signaling by generating highly phosphorylated inositol phosphates (HOIPs).

“This enzyme can modulate cellular signaling through multiple mechanisms: by generating highly phosphorylated inositol phosphates (HOIPs) [10,12,14], producing phosphatidylinositol 3,4,5-trisphosphate (PIP3) [10,12,14], or even functioning independently of its kinase activity through protein–protein interaction [10,11,12,14].”

• cites [10] Chakraborty, 2011, Inositol Pyrophosphates as Mammalian Cell Signals, Sci. Signal. sourceSupported
• cites [12] Saiardi, 1999, Synthesis of Diphosphoinositol Pentakisphosphate by a Newly Identified Family of Higher Inositol Polyphosphate Kinases, Curr. Biol. sourcePartly supported

  The Results and discussion (page not provided) show that the yeast enzyme ArgRIII, identified as IPMK, generates higher inositol polyphosphates from InsP3. The paper does not show that this production modulates cellular signaling, so it supports the proposed mechanism only in part. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [14] Guha, 2019, IPMK Mediates Activation of ULK Signaling and Transcriptional Regulation of Autophagy Linked to Liver Inflammation and Regeneration, Cell Rep. sourceSupported

IPMK is a potential alternative PI3-kinase that can generate PIP3 independently of cPI3K.

“Recent research has identified IPMK as a potential alternative PI3-kinase that can generate PIP3 independently of cPI3K [34].”

• cites [34] Reilly, 2023, Loss of PI3k Activity of Inositol Polyphosphate Multikinase Impairs PDK1-Mediated AKT Activation, Cell Migration, and Intestinal Homeostasis, iScience sourceSupported

Crystal structures of a different IP6K captured with IP3 and IP5 suggest an alternative less energetically costly 180° rotation about an axis at the center of the inositol ring.

“However, crystal structures of a different IP6K captured with IP3 and IP5 in its active site [51] suggest an alternative and less energetically costly alternative—a 180° rotation about an axis that is at the center of the inositol ring, such that each inositol carbon position is moved to a new position three numbers down, i.e., 1 to 4, 2 to 5, and so on, in order to position the 6 position in line”

• cites [51] Wang, 2014, IP6K Structure and the Molecular Determinants of Catalytic Specificity in an Inositol Phosphate Kinase Family, Nat. Commun. sourcePartly supported

  The Results section, “The Molecular determinants of Inositol Phosphate binding” (page unavailable), reports EhIP6KA crystal structures with InsP3 and InsP5 and models a 180° reorientation of bound InsP3. It describes a flip across the ring’s 1/4 axis, however, not the claimed rotation that moves carbon 1 to position 4, and it does not assess whether that rotation is less energetically costly. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Attempts to rescue cell migration in IPMK-deleted MEFs by overexpressing β1 integrin were unsuccessful.

“However, attempts to rescue cell migration in IPMK-deleted MEFs by overexpressing β1 integrin were unsuccessful [54], suggesting that integrin-independent pathways likely play a role in IPMK-mediated cell migration.”

• cites [54] Padhi, 2019, Inositol Polyphosphate Multikinase Is a Metformin Target That Regulates Cell Migration, FASEB J. sourceSupported

IPMK loss significantly impairs p53-mediated transcription in cell lines.

“Xu et al. [48] demonstrated that IPMK loss significantly impairs p53-mediated transcription in cell lines.”

• cites [48] Xu, 2013, Inositol Polyphosphate Multikinase Is a Coactivator of P53-Mediated Transcription and Cell Death, Sci. Signal. sourceSupported

When IPMK is deleted, InsP5 and InsP6 concentrations within cells show a notable reduction.

“When IPMK is deleted, InsP5 and InsP6 concentrations within cells show a notable reduction, highlighting its importance in maintaining these HOIPs [14].”

• cites [14] Guha, 2019, IPMK Mediates Activation of ULK Signaling and Transcriptional Regulation of Autophagy Linked to Liver Inflammation and Regeneration, Cell Rep. sourcePartly supported

  The Introduction (page unavailable) says IPMK physiologically generates IP5 and describes the pathway leading to IP6. The Results mention inositol profiling (page unavailable), but our copy does not report a notable reduction in cellular IP5 or IP6 concentrations after IPMK deletion. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

The disordered region of ≈60 amino acids influences ATP binding such that its absence manifests in higher catalytic activity.

“Starting with the N-lobe, the disordered region of the ≈60 amino acids influences ATP binding such that its absence manifests in higher catalytic activity.”

• cites [42] Wang, 2017, Structural Features of Human Inositol Phosphate Multikinase Rationalize Its Inositol Phosphate Kinase and Phosphoinositide 3-Kinase Activities, J. Biol. Chem. sourceCould not verify

  The ‘Description of the nucleotide-binding region of HsIPMK’ describes ATP binding between the N- and C-lobes, but does not link it to a disordered ≈60-amino-acid region. The ‘Structure of human IPMK’ describes a crystallization construct with deletions, but reports no increase in catalytic activity from removing that region. Searches for the proposed region, its effect on ATP binding, and increased activity did not establish the claim. (LLM, conf=0.74)

  Experimental — accuracy not yet measured

IPMK knockdown or mutations affecting PIP2 binding to SF-1 disrupt SF-1-mediated transcription.

“IPKM knockdown or mutations affecting PIP2 binding to SF-1 disrupt this process.”

• cites [21] Blind, 2012, Direct Modification and Activation of a Nuclear Receptor-PIP2 Complex by the Inositol Lipid Kinase IPMK, Sci. Signal. sourceSupported

IPMK is a key regulator of DNA methylation.

“A recent study revealed that IPMK is a key regulator of DNA methylation [87], as its depletion in cells led to changes in over 22,000 differentially methylated regions (DMRs).”

• cites [87] Sin, Z., Kinnear, E., Doshi, R., Chatterjee, S., Derbel, H., Guha, P., and Liu, Q. (2025). IPMK Depletion Influences Genome-Wide DNA Methylation. Biochem. Biophys. Res. Commun., 766. sourceSupported

IPMK's role in regulating chromatin remodeling and transcription was first discovered by Steger et al. in yeast.

“The pivotal role of IPMK in regulating chromatin remodeling and transcription was first discovered by Steger et al. in yeast [19].”

• cites [19] Steger, 2003, Regulation of Chromatin Remodeling by Inositol Polyphosphates, Science sourceSupported

IPMK is an essential PI3-kinase-generating PIP3 critical for AKT activation.

“Studies by Resnick et al. [26], Maag et al. [15], and Reilly et al. [34] indicated that IPMK is an essential PI3-kinase-generating PIP3, which is critical for AKT activation.”

• cites [26] Resnick, 2005, Inositol Polyphosphate Multikinase Is a Nuclear PI3-Kinase with Transcriptional Regulatory Activity, Proc. Natl. Acad. Sci. USA sourceNot checked — no full text of the source
• cites [15] Maag, 2011, Inositol Polyphosphate Multikinase Is a Physiologic PI3-Kinase That Activates Akt/PKB, Proc. Natl. Acad. Sci. USA sourceSupported
• cites [34] Reilly, 2023, Loss of PI3k Activity of Inositol Polyphosphate Multikinase Impairs PDK1-Mediated AKT Activation, Cell Migration, and Intestinal Homeostasis, iScience sourceSupported

Deletion of IPMK or inhibition of its kinase activity results in impaired cell migration.

“Deletion of IPMK or inhibition of its kinase activity resulted in impaired cell migration, indicating its essential function in this process.”

• cites [54] Padhi, 2019, Inositol Polyphosphate Multikinase Is a Metformin Target That Regulates Cell Migration, FASEB J. sourceSupported
• cites [34] Reilly, 2023, Loss of PI3k Activity of Inositol Polyphosphate Multikinase Impairs PDK1-Mediated AKT Activation, Cell Migration, and Intestinal Homeostasis, iScience sourceSupported

Depletion of IPMK (IPK2/Arg82) hinders recruitment of SWI/SNF and INO80 chromatin remodeling complexes to promoters of phosphate-responsive genes PHO5 and PHO8.

“In their study, depletion of IPMK, also known as IPK2 or Arg82, hindered the recruitment of SWI/SNF and INO80 chromatin remodeling complexes to the promoters of phosphate-responsive genes such as PHO5 and PHO8 (Figure 3C).”

• cites [19] Steger, 2003, Regulation of Chromatin Remodeling by Inositol Polyphosphates, Science sourcePartly supported

  The passage on ChIP experiments (section labeled Abstract; page unavailable) reports that deleting ARG82 reduced Ino80 recruitment to PHO5 and PHO84, and Snf2 (SWI/SNF) recruitment to PHO84. The paper names PHO84, not PHO8, and says it could not detect substantial Snf2 recruitment to PHO5; it therefore does not support reduced recruitment of both complexes to both promoters named in the claim. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

IPMK is a critical regulator of cellular mechanisms.

“With dual inositol and lipid kinase activities, IPMK generates pivotal signaling molecules such as InsP4 (inositol tetraphosphate), InsP5 (inositol pentaphosphate), and PIP3 (phosphoinositide 3,4,5-trisphosphate), positioning it as a critical regulator of cellular mechanisms.”

IPMK has potential as a therapeutic target in human health and disease.

“This review charts IPMK’s journey from obscurity to prominence, examining its structure–function relationships, cellular roles, and emerging physiological impacts, while highlighting its potential as a therapeutic target in human health and disease.”

IPMK influences various cellular functions through kinase-independent mechanisms, primarily via protein-protein interaction.

“IPMK, despite its PI3-kinase and inositol kinase activities, influences various cellular functions through kinase-independent mechanisms, primarily via protein–protein interaction.”

IPMK is a multifaceted enzyme with diverse functions spanning from the nucleus to the cytoplasm.

“Research over the past two decades has revealed IPMK as a multifaceted enzyme with diverse functions spanning from the nucleus to the cytoplasm.”

IPK2 enhances DNA binding of the ArgR-MCM1 complex independently of its kinase activity.

“This study revealed that IPK2 (yeast IPMK) enhances DNA binding of the ArgR-MCM1 complex independently of its kinase activity.”

• cites [73] Odom, 2000, A Role for Nuclear Inositol 1,4,5-Trisphosphate Kinase in Transcriptional Control, Science sourceNot checked — no full text of the source

IPMK is enriched in the nucleus.

“Over-expression studies indicate that IPMK is enriched in the nucleus [26], suggesting that PIP3 production also occurs within the nucleus.”

• Also stated in: § 7. Conclusions · plain

  “IPMK is a distinctive protein that serves both as an inositol kinase and a lipid kinase, and its enrichment in the nucleus highlights a novel area for exploring the roles of HOIP and PIP3 in nuclear function, a field that remains largely uncharted.”

• cites [26] Resnick, 2005, Inositol Polyphosphate Multikinase Is a Nuclear PI3-Kinase with Transcriptional Regulatory Activity, Proc. Natl. Acad. Sci. USA sourceNot checked — no full text of the source

The impacts of IPMK loss can be attributed to three distinct roles: lipid kinase, inositol kinase, or kinase-independent functions.

“These impacts can be attributed to three distinct roles: its function as a lipid kinase, its function as an inositol kinase, or functions that are independent of its kinase activity.”

Mammalian IPMK acts as a transcriptional co-activator of SRF, promoting gene transcription through physical interaction with SRF, independent of its kinase activity.

“Kim et al. [46] found that mammalian IPMK acts as a transcriptional co-activator of SRF, promoting gene transcription through physical interaction with SRF, independent of its kinase activity.”

• cites [46] Kim, 2013, Inositol Polyphosphate Multikinase Is a Coactivator for Serum Response Factor-Dependent Induction of Immediate Early Genes, Proc. Natl. Acad. Sci. USA sourceNot checked — no full text of the source

The interaction between RhoE and ROCK1 inhibits ROCK1's ability to phosphorylate MLC, preventing cell migration.

“At the molecular level, the interaction between RhoE and ROCK1 inhibits ROCK1’s ability to phosphorylate MLC, thereby preventing cell migration.”

• cites [55] Pinner, 2008, PDK1 Regulates Cancer Cell Motility by Antagonising Inhibition of ROCK1 by RhoE, Nat. Cell Biol. sourceNot checked — no full text of the source

Loss of AKT activation occurs in IPMK-deleted hepatocytes.

“Interestingly, a study by Jung et al. indicated the loss of AKT activation in IPMK-deleted hepatocytes [58].”

• cites [58] Jung, 2023, Inositol Polyphosphate Multikinase Modulates Free Fatty Acids-Induced Insulin Resistance in Primary Mouse Hepatocytes, J. Cell. Biochem. sourceNot checked — no full text of the source

IPMK plays a crucial role in metabolism.

“It plays a crucial role in cell proliferation [34], metabolism [58], autophagy [14,64], and migration [34,53,54].”

• cites [58] Jung, 2023, Inositol Polyphosphate Multikinase Modulates Free Fatty Acids-Induced Insulin Resistance in Primary Mouse Hepatocytes, J. Cell. Biochem. sourceNot checked — no full text of the source

InsP4 (Ins 1,4,5,6) is crucial for activating the ArgR-MCM1 transcription factor in yeast.

“The York group demonstrated that InsP4 (Ins 1, 4, 5, 6) is crucial for activating the ArgR-MCM1 transcription factor in yeast [73], which regulates genes involved in cell cycle, cell type specificity, and responses to pheromones and nutrients.”

• cites [73] Odom, 2000, A Role for Nuclear Inositol 1,4,5-Trisphosphate Kinase in Transcriptional Control, Science sourceNot checked — no full text of the source

Loss of IPMK function affects a wide range of cellular mechanisms.

“Research with IPMK mutant cell lines has demonstrated that the loss of IPMK function affects a wide range of cellular mechanisms.”

IPMK gene disruption in mouse models and human mutation analyses have highlighted IPMK's potential involvement in various diseases.

“Studies involving IPMK gene disruption in mouse models and human mutation analyses have highlighted its potential involvement in various diseases.”

The transcriptional function of ArgR-MCM1 is regulated by InsP4 and InsP5, which are products of IPK2's kinase activity.

“However, the transcriptional function of this complex is regulated by InsP4 and InsP5, which are products of IPK2’s kinase activity.”

• cites [73] Odom, 2000, A Role for Nuclear Inositol 1,4,5-Trisphosphate Kinase in Transcriptional Control, Science sourceNot checked — no full text of the source

Genes affecting longevity may also play a role in the development of age-related diseases like Alzheimer's disease.

“This finding underscores the complexity of genetic factors influencing disease risk and longevity, suggesting that genes affecting longevity may also play a role in the development of age-related diseases like AD.”

IPMK has a known C-terminal nuclear localization signal (NLS).

“Consistent with this, Meyer et al. [45] identified a nuclear export signal (NES, amino acid 170–179) in addition to IPMK’s known C-terminal nuclear localization signal (NLS), suggesting that IPMK may shuttle between these compartments.”

• cites [45] Meyer, 2012, Nucleocytoplasmic Shuttling of Human Inositol Phosphate Multikinase Is Influenced by CK2 Phosphorylation, Biol. Chem. sourceNot checked — no full text of the source

Meyer et al. identified a nuclear export signal (NES, amino acid 170-179) in IPMK.

“Consistent with this, Meyer et al. [45] identified a nuclear export signal (NES, amino acid 170–179) in addition to IPMK’s known C-terminal nuclear localization signal (NLS), suggesting that IPMK may shuttle between these compartments.”

• cites [45] Meyer, 2012, Nucleocytoplasmic Shuttling of Human Inositol Phosphate Multikinase Is Influenced by CK2 Phosphorylation, Biol. Chem. sourceNot checked — no full text of the source

Localization of PDK1 to the membrane is crucial for dissociation of the inhibitory RhoE/ROCK1 complex.

“The localization of PDK1 to the membrane is crucial for the dissociation of the inhibitory RhoE/ROCK1 complex [55].”

• cites [55] Pinner, 2008, PDK1 Regulates Cancer Cell Motility by Antagonising Inhibition of ROCK1 by RhoE, Nat. Cell Biol. sourceNot checked — no full text of the source

Meyer et al. were the first to investigate IPMK's intracellular distribution in-depth using immunofluorescence analysis of overexpressed N-terminal EYFP-IPMK fusion constructs.

“Meyer et al. [45] were the first to investigate this in-depth, using immunofluorescence analysis of overexpressed N-terminal EYFP-IPMK fusion constructs.”

• cites [45] Meyer, 2012, Nucleocytoplasmic Shuttling of Human Inositol Phosphate Multikinase Is Influenced by CK2 Phosphorylation, Biol. Chem. sourceNot checked — no full text of the source