PI5P and PI(3,5)P&lt;sub&gt;2&lt;/sub&gt;: Minor, but Essential Phosphoinositides

Hasegawa, Junya; Strunk, Bethany S.; Weisman, Lois S.

doi:10.1247/csf.17003

Cited by 127 publications

(132 citation statements)

References 131 publications

(227 reference statements)

Supporting

Mentioning

126

Contrasting

Unclassified

Order By: Relevance

“…While the majority of PI-4,5-P2 is generated by phosphorylation of phosphatidylinositol 4phosphate (PI-4-P) on the 5-position by the Type I PI4P5K kinases, a PI5P4K-driven alternate route was discovered in 1997, hence the designation Type II (Rameh et al, 1997). The PI5P4Ks were traditionally thought to mainly be crucial direct regulators of PI-5-P levels Stijf-Bultsma & Sommer et al, 2015;Hasegawa, Strunk, & Weisman, 2017) however, PI5P4Kα was found to synthesize a pool of PI-4,5-P2 that is specifically important in mTORC2 regulation (Bulley et al, 2016) and to play a critical role in intracellular cholesterol transport by modulating PI-4,5-P2 homeostasis on peroxisome membranes (Hu et al, 2018). The low-activity isoform PI5P4Kγ was demonstrated to positively regulate Notch1 signaling by facilitating receptor recycling, suggesting that endosome-localized production of PI(4,5)P2 is involved Notch transport (Zheng & Conner, 2018).…”

Section: Introductionmentioning

confidence: 99%

Targeting the PI5P4K lipid kinase family in cancer using novel covalent inhibitors

Sivakumaren

Shim

Zhang

et al. 2019

Preprint

View full text Add to dashboard Cite

The PI5P4Ks have been demonstrated to be important for cancer cell proliferation and other diseases. However, the therapeutic potential of targeting these kinases is understudied due to a lack of potent, specific small molecules available. Here we present the discovery and characterization of a novel pan-PI5P4K inhibitor, THZ-P1-2, that covalently targets cysteines on a disordered loop in PI5P4K//. THZ-P1-2 demonstrates cellular on-target engagement with limited off-targets across the kinome. AML/ALL cell lines were sensitive to THZ-P1-2, consistent with PI5P4K's reported role in leukemogenesis. THZ-P1-2 causes autophagosome clearance defects and upregulation in TFEB nuclear localization and target genes, disrupting autophagy in a covalent-dependent manner and phenocopying the effects of PI5P4K genetic deletion. Our studies demonstrate that PI5P4Ks are tractable targets, with THZ-P1-2 as a useful tool to further interrogate the therapeutic potential of PI5P4K inhibition and inform drug discovery campaigns for these lipid kinases in cancer metabolism and other autophagy-dependent disorders.

show abstract

Section: Introductionmentioning

confidence: 99%

Targeting the PI5P4K lipid kinase family in cancer using novel covalent inhibitors

Sivakumaren

Shim

Zhang

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Each cDNA in the final plasmid was sequencevalidated in its entirety, and expression of the full-length fusion protein in HEK293 cells was mol % of one of six PIPs: PI(3)P, PI(4)P, PI(5)P, PI(3,4)P2, PI(4,5)P2, and PI (3,4,5)P3. The only PIP omitted in our assays was PI(3,5)P2 due to scarce evidence in the literature for its specific recognition by proteins (17) and the lack of a reliable positive control. Vesicles containing 5% phosphatidic acid (PA), a different type of signaling lipid than PIPs, were also included in our assays.…”

Section: Lipid-simpull Assay For Human Ph Domain Proteinsmentioning

confidence: 99%

Redefining the specificity of phosphoinositide-binding by human PH domain-containing proteins

Singh

Reyes-Ordoñez

Compagnone

et al. 2020

Preprint

View full text Add to dashboard Cite

Pleckstrin homology (PH) domains are presumed to bind phosphoinositides (PIPs), but specific interaction with and regulation by PIPs for most PH domain-containing proteins are unclear. Here we employed a single-molecule pulldown assay to study interactions of lipid vesicles with full-length proteins in mammalian whole cell lysates. We examined 67 human PH domain-containing proteins for interaction with PIPs, and found 51% of them to have affinity for PIPs with various specificity, the majority of which had not been reported before. Further investigation of ARHGEF3 revealed structural requirements and functional relevance of its newly discovered PI(4,5)P2 binding. Based on the assay data of the 67 proteins, we generated a recursive-learning algorithm, which identified amino acid determinants of PIP binding throughout the entire PH domain. This recursive functional classification predicted that 46% of 250 human PH domains bind PIPs with some specificity. Collectively, our findings reveal unexpected lipid-binding specificity of PH domain-containing proteins.

show abstract

“…The noncanonical PI(5)P-dependent pathway can compensate the absence of PI(3)P, e.g. due to defective Vps34, or overrule PI(3)P in particular circumstances, such as glucose starvation [82,83]. It also been reported that PI(3,5)P 2 is required for completion of basal autophagy, particularly in mouse models of neurodegeneration.…”

Section: Autophagic Cell Deathmentioning

confidence: 99%

Phosphoinositides: multipurpose cellular lipids with emerging roles in cell death

et al. 2019

View full text Add to dashboard Cite

Phosphorylated phosphatidylinositol lipids, or phosphoinositides, critically regulate diverse cellular processes, including signalling transduction, cytoskeletal reorganisation, membrane dynamics and cellular trafficking. However, phosphoinositides have been inadequately investigated in the context of cell death, where they are mainly regarded as signalling secondary messengers. However, recent studies have begun to highlight the importance of phosphoinositides in facilitating cell death execution. Here, we cover the latest phosphoinositide research with a particular focus on phosphoinositides in the mechanisms of cell death. This progress article also raises key questions regarding the poorly defined role of phosphoinositides, particularly during membrane-associated events in cell death such as apoptosis and secondary necrosis. The review then further discusses important future directions for the phosphoinositide field, including therapeutically targeting phosphoinositides to modulate cell death.• Do other lytic forms of cell death, including secondary necrosis, require phosphoinositides and what are the phosphoinositide-binding effectors?

show abstract

PI5P and PI(3,5)P<sub>2</sub>: Minor, but Essential Phosphoinositides

Cited by 127 publications

References 131 publications

Targeting the PI5P4K lipid kinase family in cancer using novel covalent inhibitors

Targeting the PI5P4K lipid kinase family in cancer using novel covalent inhibitors

Redefining the specificity of phosphoinositide-binding by human PH domain-containing proteins

Phosphoinositides: multipurpose cellular lipids with emerging roles in cell death

Contact Info

Product

Resources

About