| 2001 |
Yeast TIP41 (ortholog of TIPRL) interacts with TAP42 (ortholog of alpha4) and negatively regulates the TOR signaling pathway; deletion of TIP41 confers rapamycin resistance and prevents dissociation of SIT4 phosphatase from TAP42, blocking SIT4-dependent dephosphorylation of NPR1 and nuclear translocation of GLN3. TIP41 binding to TAP42 is stimulated by rapamycin treatment via SIT4-dependent dephosphorylation of TIP41, establishing a feedback loop that amplifies SIT4 phosphatase activity under TOR-inactivating conditions. |
Genetic epistasis (deletion/suppressor analysis), co-immunoprecipitation, phosphorylation assays, nuclear translocation assays |
Molecular cell |
High |
11741537
|
| 2007 |
TIPRL interacts with the C-terminal region (residues 210–309) of the catalytic subunits of PP2A, PP4, and PP6 via a region distinct from the alpha4-binding site; TIPRL and alpha4 can simultaneously bind PP2Ac, forming a stable ternary complex (alpha4:PP2Ac:TIPRL). TIPRL inhibits PP2Ac activity in vitro. Single amino acid substitutions D71L, I136T, M196V, and D198N on TIPRL disrupt its interaction with PP2Ac. The complex is rapamycin-insensitive in human cells. |
Yeast two-hybrid screen, pull-down assays with recombinant proteins, reverse two-hybrid mutagenesis, in vitro phosphatase activity assay, co-immunoprecipitation from human cells |
The FEBS journal |
High |
17944932
|
| 2013 |
Mammalian TIPRL positively regulates mTORC1 signaling (in contrast to yeast TIP41 which is inhibitory); overexpression of TIPRL suppressed dephosphorylation of mTORC1 substrates under amino acid withdrawal, while knockdown of TIPRL attenuated phosphorylation of mTORC1 substrates after amino acid refeeding. This action requires TIPRL association with the catalytic subunit of PP2A (PP2Ac). |
Overexpression and siRNA knockdown with phosphorylation readouts (immunoblot), co-immunoprecipitation |
FEBS letters |
Medium |
23892082
|
| 2015 |
TIPRL negatively regulates protein phosphatase 4 (PP4) activity; knockdown of TIPRL increases PP4 phosphatase activity and promotes formation of the active PP4-C/PP4R2 complex that dephosphorylates γ-H2AX. Overexpression of TIPRL promotes H2AX phosphorylation and increases γ-H2AX foci in response to DNA damage, while TIPRL knockdown inhibits γ-H2AX phosphorylation and protects cells from genotoxic stress. |
siRNA knockdown, overexpression, phosphatase activity assay, co-immunoprecipitation (PP4-C/PP4R2 complex), immunofluorescence (γ-H2AX foci), cell viability assays |
PloS one |
Medium |
26717153
|
| 2016 |
Crystal structure of human TIPRL solved at 2.15 Å resolution reveals a novel fold organized around a central core of antiparallel beta-sheet with an N-terminal α/β region and a conserved cleft. Mutagenesis, pulldown, and hydrogen/deuterium exchange mass spectrometry demonstrate that this conserved cleft binds the conserved C-terminal tail of PP2Ac (mimicked by the peptide DYFL). TIPRL preferentially binds the unmodified PP2A C-terminal tail peptide over its tyrosine-phosphorylated version. Docking modeling suggests TIPRL blocks the phosphatase's active site. |
X-ray crystallography (2.15 Å), mutagenesis, pulldown assays, hydrogen/deuterium exchange mass spectrometry, docking modeling |
Scientific reports |
High |
27489114
|
| 2014 |
TIPRL interacts with MKK7 (MAP kinase kinase 7) and this interaction contributes to resistance to TRAIL-induced apoptosis by inhibiting the MKK7-JNK pathway. Disruption of the MKK7-TIPRL interaction (by Tussilago farfara extract) restores MKK7/JNK phosphorylation and sensitizes cells to TRAIL-induced apoptosis. |
GST pull-down assay, ELISA-based interaction detection, co-treatment functional apoptosis assay (cell viability, caspase activation) |
Oncology reports |
Medium |
24969837
|
| 2017 |
TIPRL directly interacts with MKK7, and inhibition of this interaction by small molecule compounds leads to increased MKK7 and JNK phosphorylation and sensitizes hepatocellular carcinoma cells to TRAIL-induced apoptosis in vitro and in vivo. |
ELISA-based high-throughput screening of MKK7-TIPRL interaction, cell viability assay, immunoblot for MKK7/JNK phosphorylation, xenograft in vivo tumor regression assay |
Oncotarget |
Medium |
29348850
|
| 2019 |
TIPRL interacts with eIF2α and promotes eIF2α phosphorylation, activating the eIF2α-ATF4 pathway to induce autophagy in non-small cell lung cancer cells. TIPRL depletion reduces autophagic clearance and increases apoptosis. |
Co-immunoprecipitation (TIPRL-eIF2α interaction), immunoblot for eIF2α phosphorylation and ATF4 levels, autophagy assays (LC3-II/p62), siRNA knockdown, xenograft assay |
Cell death & disease |
Medium |
31862913
|
| 2024 |
TIPRL binds directly to CaMKK2 (calcium/calmodulin-dependent protein kinase kinase 2) in lung cancer stem cells, causing sustained activation of the CaMKK2 signaling pathway, which phosphorylates CaMK4, leading to phosphorylation of CREB at Ser129 and Ser133. Activated CREB then drives expression of Bcl2 and HMG20A and transcriptionally activates TIPRL itself, forming a positive feedback loop. TIPRL depletion sensitizes lung cancer stem cells to afatinib and reduces distal metastasis in vivo. |
Co-immunoprecipitation (TIPRL-CaMKK2), immunoblot for CaMK4 and CREB phosphorylation, CREB transcriptional reporter, gene expression analysis, siRNA/CRISPR knockdown, xenograft metastasis assay |
Advanced science |
Medium |
39076120
|
| 2023 |
ATM kinase phosphorylates TIPRL1 at Ser265 upon irradiation. A non-phosphorylatable Ser265Ala mutant cannot rescue the increased radiosensitivity of TIPRL1-depleted HNSCC cells, demonstrating that ATM-dependent phosphorylation of TIPRL1 at Ser265 is required for its role in radiotherapy resistance. TIPRL1 was also found to interact with DNA-PKcs, RAD51, and nucleosomal histones (novel interactors beyond PP2A-family phosphatases); histone binding is stimulated by RT but adversely affected by Ser265 phosphorylation. |
Mass spectrometry (phosphorylation site mapping and interactomics), CRISPR/Cas9 deletion, rescue with Ser265Ala mutant, immunoblot (DDR signaling), microscopy (micronuclei), flow cytometry (cell cycle) |
Cellular oncology |
Medium |
37971644
|
| 2005 |
Fission yeast (S. pombe) Tip41 ortholog regulates type 2A phosphatase activity: overexpression of tip41+ increases type 2A phosphatase activity, and in a ppa2 deletion strain with reduced PP2A activity, overexpression of tip41+ no longer blocks the cell cycle G1 shift upon nitrogen starvation, placing Tip41 upstream of PP2A in cellular responses to nitrogen nutrient conditions. |
Genetic epistasis (tip41 deletion and ppa2 deletion double mutant), overexpression, phosphatase activity assay, cell cycle analysis |
Biochimica et biophysica acta |
Medium |
16297994
|