| 2015 |
Crystal structure of the catalytic domain of zebrafish PIP5K1A resolved at 3.3 Å reveals a side-to-side dimer. Mutagenesis identified two adjacent interfaces for dimerization and interaction with the DIX domain of Dishevelled. Binding at these interfaces (either through dimerization or DIX interaction) stimulates PIP5K1A catalytic activity; DIX binding additionally enhances substrate binding. |
X-ray crystallography, site-directed mutagenesis, in vitro kinase activity assays |
Nature communications |
High |
26365782
|
| 2018 |
PIP5K1A is a KRAS-specific interactor (not shared with NRAS or HRAS), binding to a unique region in KRAS. PIP5K1A depletion specifically reduces oncogenic KRAS signaling and proliferation, and sensitizes pancreatic cancer cell lines to MAPK inhibitors. |
BirA proximity-dependent biotin identification (BioID) interactome, CRISPR-Cas9 loss-of-function screen, co-immunoprecipitation mapping of binding region, cell proliferation assays |
Nature communications |
High |
30194290
|
| 2017 |
Upon HGF stimulation, PIP5K1A is recruited to c-Met in an Arf6 activity-dependent manner, where it generates PIP2 and subsequently PIP3 to activate Akt and drive hepatocyte proliferation. In vivo, Pip5k1a knockout mice show suppressed hepatocyte proliferation and liver regeneration after partial hepatectomy. |
siRNA knockdown in HepG2 cells, co-immunoprecipitation/recruitment assay to c-Met, PI3P/PIP2/PIP3 measurement, Pip5k1a knockout mouse hepatectomy model |
Scientific reports |
High |
28842595
|
| 2021 |
CLIC1 recruits PIP5K1A and PIP5K1C from the cytoplasm to the leading edge of the plasma membrane in response to migration stimuli, where PIP5K1A generates a PIP2-rich microdomain that induces integrin-mediated cell-matrix adhesion formation and cytoskeletal extension signaling. |
Comparative proteomics, co-immunoprecipitation, subcellular fractionation/live imaging of protein recruitment, siRNA knockdown with adhesion and metastasis readouts, mouse lung metastasis model |
The Journal of clinical investigation |
High |
33079727
|
| 2019 |
Multiscale molecular dynamics simulations show that monomeric PIP5K1A binds specifically to PI4P-containing membranes (not zwitterionic or anionic membranes lacking PIPs), with initial encounter followed by reorientation to a productive binding pose; dimeric PIP5K1A cannot bind via both active sites simultaneously, suggesting conformational change or bilayer distortion is needed. |
Coarse-grained and atomistic molecular dynamics simulations |
Structure |
Low |
31204251
|
| 2023 |
PIP5K1A interacts with nuclear export protein XPO5 in the nucleus to regulate mature let-7 miRNA levels by blocking XPO5 binding to pre-let-7, thereby reducing nuclear export of pre-miRNA; this role is kinase-independent. The ortholog PPK-1 in C. elegans functions in the lin-28/let-7 heterochronic pathway. |
Co-immunoprecipitation (PIP5K1A–XPO5 interaction), kinase-dead mutant analysis, C. elegans genetic pathway analysis, quantitative miRNA level measurement in human cells |
Nucleic acids research |
Medium |
37655623
|
| 2025 |
PIP5K1A competitively binds the Kelch domain of KEAP1 in a kinase-independent manner, preventing NRF2 ubiquitination and degradation, thereby promoting NRF2-dependent transcription and suppressing ferroptosis in hepatocellular carcinoma cells. |
Co-immunoprecipitation (PIP5K1A–KEAP1 interaction), ubiquitination assays, kinase-dead mutant analysis, siRNA knockdown with lipid peroxidation and ferroptosis readouts, pharmacological inhibition (ISA-2011B) |
Advanced science |
Medium |
40405713
|
| 2024 |
PIP5K1A functions upstream of the Akt/GSK-3β pathway to regulate CDK2 and cyclin D1 expression and cell cycle progression in colorectal cancer; rupatadine inhibits PIP5K1A kinase activity (confirmed by kinase activity assay and bio-layer interferometry) and suppresses CRC proliferation in vitro and in vivo. |
Kinase activity assay, bio-layer interferometry, western blot, cell proliferation assays, in vivo xenograft |
Biomedicine & pharmacotherapy |
Medium |
38838507
|
| 2026 |
DCLK1 interacts with PIP5K1A and inhibits its threonine phosphorylation, thereby facilitating PIP5K1A membrane localization and downstream PI3K-AKT signaling activation in pancreatic cancer under high matrix stiffness conditions. |
Co-immunoprecipitation, phosphorylation analysis, subcellular fractionation of PIP5K1A localization, in vitro and in vivo tumor models with DCLK1 knockdown/overexpression |
Experimental hematology & oncology |
Medium |
41692802
|
| 2026 |
In porcine embryos, PIP5K1A residue Q169 mediates interaction with RhoA; the PIPB motif anchors PIP5K1A to the plasma membrane; the activation loop drives catalytic activity and is required for proper RhoA membrane localization. PIP5K1A-enriched membrane clusters serve as hubs for RhoA recruitment during cytokinesis. PIP5K1A also sustains PLC-IP3-Ca2+ signaling for vesicle fusion and cytoskeletal remodeling. |
Structure-function mutagenesis (Q169, PIPB motif, activation loop), live imaging of membrane localization, maternal depletion and overexpression in porcine embryos, co-localization with RhoA |
International journal of biological sciences |
Medium |
42212321
|
| 2025 |
PIP5K1A (referred to as PIP5KA in the paper) produces a dedicated PI(4,5)P2 pool at the plasma membrane in collaboration with the scaffolding protein EFR3A, which is required for sorting AT1R angiotensin II receptors into an AP2-positive compartment for rapid GPCR re-sensitization without receptor internalization. |
Genetic perturbation of PIP5K1A and EFR3A, PI(4,5)P2 reporter assays, GPCR re-sensitization assays, AP2 co-localization imaging |
bioRxiv (preprint)preprint |
Medium |
bio_10.1101_2025.03.28.645988
|