| 2001 |
Crystal structure of the C-terminal PH domain of TAPP1 (PLEKHA1) at 1.4 Å resolution revealed the molecular basis for its specific binding to PtdIns(3,4)P2 but not PtdIns(3,4,5)P3. A key alanine residue adjacent to the D-5 inositol-phosphate-binding site (versus glycine in the related DAPP1) both sterically excludes PtdIns(3,4,5)P3 and induces a conformational change in neighboring residues. Mutagenesis confirmed this: the DAPP1 G→A mutation converted it to a TAPP1-like domain that only binds PtdIns(3,4)P2, while the TAPP1 A→G mutation permitted binding to PtdIns(3,4,5)P3. |
X-ray crystallography (1.4 Å) combined with site-directed mutagenesis and lipid-binding assays |
The Biochemical journal |
High |
11513726
|
| 2002 |
TAPP1 (PLEKHA1) translocates from cytoplasm to plasma membrane upon agonist-stimulated PtdIns(3,4)P2 production in Swiss 3T3 and 293 cells. Translocation requires a functional PtdIns(3,4)P2-binding C-terminal PH domain and is blocked by the PI3K inhibitor wortmannin. Endogenously expressed TAPP1 co-immunoprecipitates with endogenous MUPP1 (a multi-PDZ-domain protein), and TAPP1/TAPP2 interact with the 10th and 13th PDZ domains of MUPP1 via their C-terminal amino acids, suggesting TAPP1 recruits MUPP1 to the plasma membrane in response to PtdIns(3,4)P2 elevation. |
Live-cell imaging, co-immunoprecipitation of endogenous proteins, PH-domain mutant analysis, wortmannin inhibition |
The Biochemical journal |
High |
11802782
|
| 2002 |
TAPP1 and TAPP2 are recruited to the plasma membrane of human B-lymphoma cells (BJAB) upon B-cell antigen receptor (BCR) activation, with kinetics that are slow and sustained. The C-terminal PH domain alone is necessary and sufficient for BCR-induced membrane recruitment. Recruitment is abolished by PI3K blockade and constitutively driven by active PI3K. Membrane accumulation correlates with PtdIns(3,4)P2 (not PtdIns(3,4,5)P3) production. TAPP1 and TAPP2 preferentially accumulate in F-actin-rich membrane ruffles, implicating them in PI3K-driven cytoskeletal reorganization. |
Live-cell imaging, PI3K inhibitor/activator treatment, C-terminal PH domain truncation mutants, lipid production kinetics analysis |
Molecular and cellular biology |
High |
12101241
|
| 2003 |
Endogenously expressed TAPP1 is constitutively associated with the protein-tyrosine phosphatase PTPL1 (FAP-1). PTPL1 binds TAPP1 and TAPP2 principally through its first PDZ domain, enabling PTPL1 to associate with PtdIns(3,4)P2 in vitro. The TAPP1–PTPL1 interaction maintains PTPL1 in the cytoplasm; upon hydrogen-peroxide-stimulated PtdIns(3,4)P2 production, the TAPP1–PTPL1 complex translocates to the plasma membrane. TAPP1 binding does not alter PTPL1 phosphatase activity itself. RNAi-mediated knockdown of TAPP1 in HEK-293 cells enhanced IGF1-stimulated Akt activation and phosphorylation, consistent with a negative-regulatory role. |
Co-immunoprecipitation of endogenous proteins, in vitro lipid-binding assay, cellular localization imaging, siRNA knockdown with Akt phosphorylation readout |
The Biochemical journal |
High |
14516276
|
| 2004 |
Using GST-TAPP1-PH domain as a specific probe in on-section immunoelectron microscopy, PtdIns(3,4)P2 was detected not only at the plasma membrane but also on intracellular organelles including the endoplasmic reticulum and multivesicular endosomes after PDGF or hydrogen peroxide stimulation. Intracellular and plasma-membrane pools of PtdIns(3,4)P2 showed differential sensitivity to PTEN phosphatase, revealing compartmentally distinct signaling pools. |
Immunoelectron microscopy using GST-TAPP1-PH domain as a lipid probe, PTEN re-expression in PTEN-null cells |
The Biochemical journal |
Medium |
14604433
|
| 2004 |
TAPP1 interacts with the PDZ domains of gamma1-, alpha1-, and beta2-syntrophin via its C-terminal amino acids; this interaction is required for correct subcellular localization of TAPP1. Both TAPP1 and syntrophins co-localize to PDGF-induced dorsal circular membrane ruffles in NIH-3T3 cells. Ectopic overexpression of TAPP1 blocks PDGF-induced dorsal circular ruffle formation, but co-expression of alpha1- or gamma1-syntrophin rescues this blockade, indicating that syntrophins regulate TAPP1-mediated actin cytoskeletal remodeling downstream of PI3K/PtdIns(3,4)P2 signaling. |
Yeast two-hybrid screen, biochemical PDZ domain binding assays, co-localization imaging, overexpression and rescue experiments in NIH-3T3 cells |
The Journal of biological chemistry |
High |
15485858
|
| 2011 |
Knock-in mice homozygous for PtdIns(3,4)P2-binding-deficient mutations in both TAPP1 (R211L) and TAPP2 (R218L) are viable but display significantly enhanced Akt activation and improved whole-body insulin sensitivity with increased glucose disposal into muscle. Embryonic fibroblasts from double knock-in mice show enhanced IGF1-stimulated PtdIns(3,4,5)P3 production and Akt activity. This establishes that TAPP1/TAPP2 binding to PtdIns(3,4)P2 acts as a negative regulator of the PI3K–Akt–insulin signaling axis. |
Knock-in mouse genetics (R211L mutation), insulin clamp/glucose disposal assays, primary embryonic fibroblasts with PtdIns(3,4,5)P3 measurement and Akt phosphorylation |
The Biochemical journal |
High |
21204784
|
| 2015 |
TAPP1 (PLEKHA1) is selectively expressed in differentiating oligodendrocyte precursor cells (OPCs). Knockdown of TAPP1 promotes OPC differentiation and myelin gene expression, while overexpression suppresses differentiation. TAPP1 inhibition alters Erk1/2 (but not Akt) phosphorylation, placing TAPP1 as a negative regulator of OPC differentiation specifically through the Mek/Erk pathway rather than the canonical PI3K/Akt axis. |
siRNA knockdown and overexpression in primary OPC cultures, myelin gene expression assays, western blot for Erk1/2 and Akt phosphorylation |
Neuroscience bulletin |
Medium |
26242484
|
| 2024 |
EIF4G2 (a translation initiation factor) regulates PLEKHA1 protein expression via IRES-dependent translation in hepatocellular carcinoma (HCC). RNA immunoprecipitation showed EIF4G2 associates with PLEKHA1 mRNA, and dual-luciferase reporter assays confirmed IRES-dependent translational control. Polysome analysis and nascent protein synthesis assays validated EIF4G2 as the writer of this translational regulation. Combined depletion of EIF4G2 and PLEKHA1 synergistically inhibits HCC cell migration and invasion. |
RNA immunoprecipitation (RIP), dual-luciferase reporter assay, polysome profiling, nascent protein synthesis assay, siRNA knockdown |
Journal of proteome research |
Medium |
39213495
|
| 2025 |
A PLEKHA1-TACC2 chromosomal fusion gene produces a fusion protein that upregulates the EphA2/AKT/MMP2 signaling pathway and promotes vascular mimicry formation in esophageal squamous-cell carcinoma (ESCC) by reducing ubiquitylation of EphA2. In vivo, PLEKHA1-TACC2 fusion combined with Trp53 deletion significantly increases tumor incidence in a transgenic mouse model, suppressible by EphA2 inhibitors. |
RNA sequencing identification of fusion transcript, in vitro and in vivo functional assays, ubiquitylation assay for EphA2, transgenic mouse model, pharmacological inhibition with EphA2 inhibitors |
Cell death and differentiation |
Medium |
40615663
|
| 2025 |
Live imaging with a TAPP1 (PLEKHA1) 3xcPH domain probe in Xenopus laevis retinal ganglion cell filopodia showed that PtdIns(3,4)P2 accumulates specifically at filopodial tips. Quantitative cross-correlation and Granger causality analysis demonstrated that PI(3,4)P2 at filopodial tips both generates tip extension and responds to forward filopodial movement. Disruption of actin polymerization rapidly depleted tip PI(3,4)P2 prior to filopodial stalling, establishing a bidirectional relationship between PI(3,4)P2 and actin dynamics at filopodial tips. |
Live-cell TAPP1-3xcPH domain imaging, pharmacological PI3K perturbation, quantitative cross-correlation and Granger causality analysis, actin polymerization disruption |
bioRxivpreprint |
Medium |
bio_10.1101_2025.10.13.681625
|