Affinage

DEPDC1B

DEP domain-containing protein 1B · UniProt Q8WUY9

Length
529 aa
Mass
61.8 kDa
Annotated
2026-06-09
33 papers in source corpus 23 papers cited in narrative 23 extracted findings
Cross-family judge faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DEPDC1B is a DEP- and RhoGAP-domain protein that couples cytoskeletal remodeling to cell-cycle progression and acts as a broadly oncogenic effector across multiple carcinomas (PMID:25458010, PMID:25091805). Its founding role is to coordinate de-adhesion with mitotic entry: it accumulates in G2 and inhibits a RhoA-based signaling complex by competing with RhoA for binding to the focal-adhesion protein PTPRF, thereby promoting focal-adhesion dismantling ahead of mitosis (PMID:25458010). DEPDC1B regulates Rho-family GTPase output, both binding and activating Rac1 to drive its membrane translocation and engage the Rac1–PAK1–LIMK1–cofilin1 axis that promotes migration, invasion, and EMT (PMID:25091805, PMID:33135357, PMID:32110046); its GAP domain conversely binds nucleotide-bound RAC1 and can suppress RAC1 activation and TRIO-induced actin polymerization, indicating context-dependent control of Rac1 (PMID:25704760). Beyond cytoskeletal signaling, DEPDC1B stabilizes pro-tumorigenic proteins by sequestering ubiquitin-pathway components—competing with the ubiquitin ligase CDC16 to protect SCUBE3 from proteasomal degradation and promote melanoma angiogenesis and metastasis (PMID:35088579)—and promotes Wnt/β-catenin signaling, in part through a DEPDC1B–USP5–β-catenin complex that deubiquitinates β-catenin to enhance breast cancer invasion (PMID:24971537, PMID:37642235). Its expression is set by transcription factors that activate (SOX10) or repress (Pitx2 via HDAC1 recruitment) the gene (PMID:25704760, PMID:35088579). DEPDC1B also drives myoblast proliferation and restrains premature myogenic differentiation, acting in parallel to RHOA and independently of canonical Wnt/β-catenin in that setting (PMID:31825138).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2014 High

    Established the founding mechanism: how a cell links focal-adhesion disassembly to mitotic timing, answered by showing DEPDC1B competes with RhoA at PTPRF to dismantle adhesions during G2/M.

    Evidence Reciprocal Co-IP, competition binding, siRNA with mitotic phenotype, live imaging, and zebrafish in vivo model

    PMID:25458010

    Open questions at the time
    • Does not define the structural basis of PTPRF competition
    • Does not address how G2 accumulation of DEPDC1B is regulated
  2. 2014 Medium

    Connected DEPDC1B to oncogenic transcriptional output by showing Wnt/β-catenin (TCF4/LEF1) is required for its migration/invasion effects in NSCLC.

    Evidence Ectopic expression/knockdown with TCF4/LEF1 epistasis, migration/invasion assays

    PMID:24971537

    Open questions at the time
    • No direct demonstration of β-catenin binding or the biochemical activation mechanism
  3. 2014 Medium

    Defined DEPDC1B as a positive regulator of Rac1, identifying GEF activity, Rac1 membrane translocation, and a downstream ERK1/2 axis driving migration.

    Evidence GEF activity assay, Rac1 membrane fractionation, knockdown with migration readout, pERK1/2 western

    PMID:25091805

    Open questions at the time
    • GEF activity not reconciled with later GAP-domain RAC1 suppression data
    • Single lab
  4. 2015 Medium

    Revealed the opposite, GAP-side activity—the DEPDC1B GAP domain binds nucleotide-bound RAC1 and suppresses RAC1 activation—and identified Pitx2/HDAC1 transcriptional repression, framing DEPDC1B as a context-dependent Rac1 regulator under transcriptional control.

    Evidence In vitro GAP-RAC1 binding, RAC1 activation and actin polymerization assays, ChIP and luciferase reporter, Pitx2 RNAi

    PMID:25704760

    Open questions at the time
    • Does not resolve when DEPDC1B acts as activator versus suppressor of RAC1
    • Additional partners (U2af2, Erh, Salm) lack functional follow-up
  5. 2019 Medium

    Extended DEPDC1B beyond cancer, showing it drives myoblast proliferation and blocks premature differentiation in parallel to RHOA and independently of canonical Wnt.

    Evidence Single and combinatorial siRNA knockdown, RT-qPCR, immunolabelling, cell-cycle regulator profiling

    PMID:31825138

    Open questions at the time
    • Mechanism distinguishing RHOA-parallel action from the PTPRF/RhoA axis not defined
  6. 2020 Medium

    Consolidated the Rac1 effector model across prostate and pancreatic cancers, showing DEPDC1B binds Rac1 and activates the PAK1–LIMK1–cofilin1 cascade to drive EMT, migration, and metastasis.

    Evidence Co-IP, Rac1 activation assays, pathway westerns, Rac1 inhibitor/knockdown rescue, in vivo xenograft and liver-metastasis models

    PMID:32110046 PMID:33135357

    Open questions at the time
    • Does not address GEF-versus-GAP duality observed in earlier work
    • Direct effect on Rac1 nucleotide state not measured in these systems
  7. 2022 High

    Identified a non-GTPase mechanism: DEPDC1B competes with the ubiquitin ligase CDC16 to stabilize secreted SCUBE3, linking it to angiogenesis and metastasis downstream of SOX10.

    Evidence Reciprocal Co-IP, ubiquitination and protein-stability assays, in vivo angiogenesis/metastasis models

    PMID:35088579

    Open questions at the time
    • Generality of the ligase-sequestration mechanism to other substrates not established
  8. 2023 Medium

    Demonstrated DEPDC1B promotes β-catenin stability through a DEPDC1B–USP5–β-catenin complex that deubiquitinates β-catenin, providing a biochemical basis for its Wnt activation.

    Evidence Mass spectrometry, Co-IP, ubiquitination assay, siRNA knockdown, in vivo metastasis model

    PMID:37642235

    Open questions at the time
    • Whether USP5 recruitment is direct or requires bridging factors unresolved
    • Single lab
  9. 2023 Low

    Mapped DEPDC1B onto PI3K/AKT and ERK signaling, with the N-terminus binding the p85 PI3K subunit and modulating ligand-stimulated pAKT1 and pERK.

    Evidence Co-IP of DEPDC1B N-terminus with p85, pAKT1/pERK westerns on ligand stimulation, knockdown

    PMID:37191806

    Open questions at the time
    • No reconstitution or mutagenesis defining the p85-binding interface
    • Directionality of AKT regulation appears inconsistent across cancer contexts
  10. 2024 Low

    Defined transcriptional control of DEPDC1B, with the ZNF146/TFDP1 axis activating it and EBF1 (silenced by promoter hypermethylation) repressing it, linking its dysregulation to G2/M progression and EMT in tumors.

    Evidence Combinatorial knockdown, reporter/methylation studies, DEPDC1B rescue, cell-cycle flow cytometry, in vivo models

    PMID:38614125 PMID:41402613

    Open questions at the time
    • Direct promoter-binding assays not detailed in these reports
    • Single lab per axis

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DEPDC1B switches between Rac1-activating (GEF-like) and Rac1-suppressing (GAP) modes, and whether its RhoA/PTPRF de-adhesion role, ubiquitin-pathway sequestration, and PI3K/AKT cross-regulation operate through unified or distinct domains, remains unresolved.
  • No structural model reconciling GEF and GAP activities
  • Domain requirements for the many reported partners not systematically mapped
  • Most downstream-target studies rely on epistasis without direct biochemistry

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1640170 Cell Cycle 1
Partners
CDC16CTNNB1PIK3R1PTPRFRAC1UBE2TUSP5

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 DEPDC1B functions as an inhibitor of a RhoA-based signaling complex that assembles on the FA-associated protein PTPRF. By competing with RhoA for interaction with PTPRF, DEPDC1B promotes dismantling of focal adhesions, which is necessary for morphological changes preceding mitosis. DEPDC1B accumulates in G2 and coordinates de-adhesion events with cell-cycle progression at mitosis. Co-immunoprecipitation, competition binding assays, siRNA knockdown with mitotic phenotype readout, live imaging, zebrafish developmental model Developmental cell High 25458010
2014 DEPDC1B activates Wnt/β-catenin signaling to enhance migration and invasion of non-small cell lung cancer cells; depletion of TCF4 or LEF1 abrogated the biological effects of DEPDC1B on migration and invasion. Ectopic expression and siRNA knockdown, migration/invasion assays, epistasis via TCF4/LEF1 depletion Biochemical and biophysical research communications Medium 24971537
2014 DEPDC1B acts as a guanine nucleotide exchange factor (GEF), promotes Rac1 translocation to the cell membrane, regulates Rac1 activation, and drives cell migration and invasion via a DEPDC1B-Rac1-ERK1/2 signaling axis in oral cancer cells. GEF activity assay, Rac1 membrane fractionation/translocation assay, siRNA knockdown with migration/invasion readout, ERK1/2 phosphorylation western blot Journal of biomedical science Medium 25091805
2015 The GAP domain of DEPDC1B interacts with nucleotide-bound forms of RAC1 in vitro and suppresses RAC1 activation, interfering with actin polymerization induced by the GEF TRIO. DEPDC1B also interacts with signaling molecules U2af2, Erh, and Salm. Pitx2 transcriptionally represses DEPDC1B by recruiting HDAC1 to the first intron of the DEPDC1B gene. In vitro binding assay (GAP domain–RAC1), RAC1 activation assay, actin polymerization assay, chromatin immunoprecipitation (ChIP), luciferase reporter assay, RNAi depletion of Pitx2 Experimental cell research Medium 25704760
2020 DEPDC1B binds to Rac1 and activates the Rac1-PAK1 pathway to induce EMT and enhance proliferation of prostate cancer cells; this oncogenic effect is reversed by a Rac1-GTP inhibitor or Rac1 knockdown. Co-immunoprecipitation (DEPDC1B–Rac1), Rac1 activation assay, PAK1 phosphorylation western blot, Rac1 inhibitor rescue, siRNA knockdown, in vivo xenograft Clinical and translational medicine Medium 33135357
2020 DEPDC1B promotes migration and invasion in pancreatic cancer by interacting with Rac1 and activating the Rac1/PAK1-LIMK1-cofilin1 signaling pathway; Rac1 inhibition suppressed DEPDC1B-induced migration in vitro and liver metastasis in vivo. Co-immunoprecipitation (DEPDC1B–Rac1), western blotting for pathway components (PAK1, LIMK1, cofilin1 phosphorylation), wound healing/Transwell assay, Rac1 inhibitor rescue, in vivo liver metastasis model OncoTargets and therapy Medium 32110046
2020 DEPDC1B promotes bladder cancer cell growth through SHC1: knockdown of SHC1 in DEPDC1B-overexpressed cells abolished DEPDC1B-induced promotion effects, placing SHC1 downstream of DEPDC1B. siRNA knockdown, overexpression, epistasis rescue experiment (SHC1 KD in DEPDC1B-OE cells), in vivo xenograft Cell death & disease Low 33203836
2019 DEPDC1B drives myoblast proliferation and prevents premature myogenic differentiation independently of canonical WNT/β-catenin signaling; co-knockdown of DEPDC1B and RHOA had an additive effect on reducing proliferation and enhancing differentiation, suggesting they act in parallel rather than in the same pathway in myoblasts. siRNA knockdown (single and combinatorial), RT-qPCR, immunolabelling, cell cycle regulator expression analysis (cyclins, CDKs, CDKIs) Cell proliferation Medium 31825138
2022 DEPDC1B competitively associates with ubiquitin ligase CDC16 to prevent SCUBE3 from undergoing ubiquitin-proteasome-mediated degradation, thereby stabilizing secreted SCUBE3 and promoting melanoma angiogenesis and metastasis. This mechanism is downstream of the transcription factor SOX10, which directly activates DEPDC1B expression. Co-immunoprecipitation (DEPDC1B–CDC16), ubiquitination assay, SCUBE3 stability assay (proteasome inhibitor), siRNA/overexpression functional assays, tissue microarray, in vivo angiogenesis and metastasis models Advanced science High 35088579
2021 DEPDC1B interacts with CDK1 and its knockdown inhibits HCC progression; CDK1 overexpression rescues the inhibitory effects of DEPDC1B knockdown, placing CDK1 downstream of DEPDC1B in hepatocellular carcinoma. Co-immunoprecipitation, human GeneChip profiling to identify CDK1 as downstream target, CDK1 overexpression rescue experiment, in vivo xenograft Aging Medium 34032605
2021 DEPDC1B regulates chordoma progression through UBE2T-mediated ubiquitination of BIRC5 (Survivin): DEPDC1B interacts with UBE2T by Co-IP, and BIRC5 overexpression rescues the inhibitory effects of DEPDC1B knockdown. RNA sequencing, Co-immunoprecipitation (DEPDC1B–UBE2T), BIRC5 overexpression rescue, in vivo xenograft Cell death & disease Medium 34330893
2022 DEPDC1B promotes cholangiocarcinoma by enhancing the protein stability of CDK1 through the ubiquitin-proteasome system; DEPDC1B knockdown leads to decreased CDK1 protein stability, and CDK1 knockdown weakens DEPDC1B-overexpression-driven CCA promotion. Gene profiling, western blotting for CDK1 stability with proteasome inhibitor, epistasis via CDK1 knockdown in DEPDC1B-OE cells, in vivo xenograft Frontiers in oncology Medium 36568241
2023 DEPDC1B mediates deubiquitination of β-catenin via USP5 to activate Wnt/β-catenin signaling and promote breast cancer invasion and migration; DEPDC1B, USP5, and β-catenin form a protein complex identified by mass spectrometry and confirmed by Co-IP and ubiquitination assay. Mass spectrometry, Co-immunoprecipitation (DEPDC1B–USP5–β-catenin), ubiquitination assay, siRNA knockdown, in vivo metastasis model American journal of physiology. Cell physiology Medium 37642235
2023 DEPDC1B interacts with GABRD (GABA receptor delta subunit) in esophageal squamous cell carcinoma; GABRD knockdown partially reverses DEPDC1B-driven ESCC progression, and GABRD regulates ESCC progression through the PI3K/AKT/mTOR pathway. Co-immunoprecipitation (DEPDC1B–GABRD), shRNA knockdown epistasis, western blotting for PI3K/AKT/mTOR components Cancer cell international Low 35706026
2023 DEPDC1B promotes proliferation of epithelial ovarian cancer cells by enhancing AKT phosphorylation at Ser473; this effect is suppressed by AKT inhibitors MK2206 and LY294002. DEPDC1B overexpression, western blotting for pAKT-Ser473, pharmacological inhibition with MK2206 and LY294002, proliferation assay Journal of Cancer Low 37056386
2023 DEPDC1B interacts with NUP37 (nucleoporin 37) and activates PI3K/AKT signaling in colorectal cancer; NUP37 overexpression rescues the inhibitory effects of DEPDC1B silencing, placing NUP37 downstream of DEPDC1B. Co-immunoprecipitation (DEPDC1B–NUP37), western blotting for PI3K/AKT pathway, NUP37 overexpression rescue, in vivo xenograft Molecular medicine reports Low 37203403
2022 DEPDC1B interacts with KIF23 in hepatocellular carcinoma; KIF23 overexpression reverses the inhibitory effects of DEPDC1B knockdown and suppresses p53 signaling pathway activation, placing KIF23 downstream of DEPDC1B to mediate its effects via p53. Co-immunoprecipitation (DEPDC1B–KIF23), KIF23 overexpression rescue, western blotting for p53 pathway proteins Bioengineered Low 34983303
2023 DEPDC1B N-terminus binds to the p85 subunit of PI3K, and DEPDC1B overexpression results in decreased ligand-stimulated tyrosine phosphorylation of p85 and downregulation of pAKT1. DEPDC1B knockdown is associated with downregulation of ligand-stimulated pERK expression, identifying DEPDC1B as a cross-regulator of AKT1 and ERK pathways. Co-immunoprecipitation (DEPDC1B N-terminus–p85 PI3K), western blotting for pAKT1 and pERK upon ligand stimulation, siRNA knockdown Methods in molecular biology Low 37191806
2020 DEPDC1B activates the Akt/GSK3β/Snail signaling pathway to induce EMT and promote migration and invasion in pancreatic ductal adenocarcinoma; DEPDC1B overexpression induced EMT markers detectable by western blotting and immunofluorescence. Overexpression and siRNA knockdown, western blotting and immunofluorescence for EMT markers and pAkt/pGSK3β/Snail, migration/invasion assays Oncology letters Low 32934714
2023 DEPDC1B promotes multiple myeloma progression by upregulating CCNB1 (Cyclin B1) and inhibiting p53 signaling; CCNB1 knockdown partially phenocopies DEPDC1B depletion, and CCNB1 is identified as a putative downstream target co-expressed with DEPDC1B. siRNA knockdown, overexpression, flow cytometry for cell cycle/apoptosis, western blotting for p53 pathway, in vivo xenograft, co-expression analysis Tissue & cell Low 37979396
2023 XTP1 (DEPDC1B) activates CDK6 in gastric cancer: XTP1 knockdown inhibits CDK6 expression and CDK6 knockdown abates the proliferative promotion induced by XTP1 overexpression, placing CDK6 downstream of XTP1. Lentiviral overexpression and knockdown, human GeneChip assay, RT-qPCR, western blotting, CDK6 knockdown rescue experiment, cell cycle and apoptosis assays Annals of translational medicine Low 36819538
2024 TFDP1 transcriptionally activates DEPDC1B expression; ZNF146 knockdown reduces TFDP1 transcription, decreasing DEPDC1B levels and causing G2/M arrest in ovarian cancer cells. Ectopic DEPDC1B expression rescues tumor progression inhibited by ZNF146 knockdown, placing DEPDC1B downstream of the ZNF146/TFDP1 transcriptional axis. ChIP or transcriptional reporter for TFDP1 binding to DEPDC1B promoter (implied), siRNA combinatorial knockdown, DEPDC1B overexpression rescue, flow cytometry for cell cycle, in vivo xenograft Reproduction Low 38614125
2025 EBF1 transcriptionally represses DEPDC1B in colon adenocarcinoma; EBF1 loss (due to promoter hypermethylation) leads to DEPDC1B transcriptional activation, driving cell cycle progression and EMT. EBF1 overexpression reduces DEPDC1B expression, and DEPDC1B restoration negates EBF1's tumor-suppressive effects. siRNA knockdown and overexpression epistasis, 5-azacytidine treatment restoring EBF1, RT-qPCR and western blotting, isograft tumor models Biochemical genetics Low 41402613

Source papers

Stage 0 corpus · 33 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 DEPDC1B coordinates de-adhesion events and cell-cycle progression at mitosis. Developmental cell 78 25458010
2014 DEPDC1B enhances migration and invasion of non-small cell lung cancer cells via activating Wnt/β-catenin signaling. Biochemical and biophysical research communications 60 24971537
2020 The metastatic promoter DEPDC1B induces epithelial-mesenchymal transition and promotes prostate cancer cell proliferation via Rac1-PAK1 signaling. Clinical and translational medicine 49 33135357
2014 A putative novel protein, DEPDC1B, is overexpressed in oral cancer patients, and enhanced anchorage-independent growth in oral cancer cells that is mediated by Rac1 and ERK. Journal of biomedical science 47 25091805
2020 DEPDC1B is a tumor promotor in development of bladder cancer through targeting SHC1. Cell death & disease 31 33203836
2017 High levels of DEPDC1B predict shorter biochemical recurrence-free survival of patients with prostate cancer. Oncology letters 30 29163701
2020 DEP Domain-Containing Protein 1B (DEPDC1B) Promotes Migration and Invasion in Pancreatic Cancer Through the Rac1/PAK1-LIMK1-Cofilin1 Signaling Pathway. OncoTargets and therapy 29 32110046
2019 DEPDC1B knockdown inhibits the development of malignant melanoma through suppressing cell proliferation and inducing cell apoptosis. Experimental cell research 29 30880030
2021 Overexpressed DEPDC1B contributes to the progression of hepatocellular carcinoma by CDK1. Aging 24 34032605
2022 DEPDC1B Promotes Melanoma Angiogenesis and Metastasis through Sequestration of Ubiquitin Ligase CDC16 to Stabilize Secreted SCUBE3. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 19 35088579
2021 DEPDC1B regulates the progression of human chordoma through UBE2T-mediated ubiquitination of BIRC5. Cell death & disease 15 34330893
2019 DEPDC1B is a key regulator of myoblast proliferation in mouse and man. Cell proliferation 15 31825138
2023 DEPDC1B-mediated USP5 deubiquitination of β-catenin promotes breast cancer metastasis by activating the wnt/β-catenin pathway. American journal of physiology. Cell physiology 14 37642235
2020 DEPDC1B promotes migration and invasion in pancreatic ductal adenocarcinoma by activating the Akt/GSK3β/Snail pathway. Oncology letters 14 32934714
2015 Identification of the GTPase-activating protein DEP domain containing 1B (DEPDC1B) as a transcriptional target of Pitx2. Experimental cell research 12 25704760
2022 DEPDC1B collaborates with GABRD to regulate ESCC progression. Cancer cell international 10 35706026
2016 In Silico Approach for SAR Analysis of the Predicted Model of DEPDC1B: A Novel Target for Oral Cancer. Advances in bioinformatics 10 27034663
2023 DEPDC1B is involved in the proliferation, metastasis, cell cycle arrest and apoptosis of colon cancer cells by regulating NUP37. Molecular medicine reports 9 37203403
2022 DEPDC1B promotes colorectal cancer via facilitating cell proliferation and migration while inhibiting apoptosis. Cell cycle (Georgetown, Tex.) 9 36016512
2020 Knockdown of DEPDC1B inhibits the development of glioblastoma. Cancer cell international 9 32684847
2024 ZNF146 regulates cell cycle progression via TFDP1 and DEPDC1B in ovarian cancer cells. Reproduction (Cambridge, England) 8 38614125
2022 DEP domain containing 1B (DEPDC1B) exerts the tumor promoter in hepatocellular carcinoma through activating p53 signaling pathway via kinesin family member 23 (KIF23). Bioengineered 7 34983303
2014 Arrested detachment: a DEPDC1B-mediated de-adhesion mitotic checkpoint. Developmental cell 7 25458006
2023 Platycodin D inhibits glioblastoma cell proliferation, migration, and invasion by regulating DEPDC1B-mediated epithelial-to-mesenchymal transition. European journal of pharmacology 5 37742812
2023 Circ_0005276 Promotes Prostate Cancer Progression Through the Crosstalk of miR-128-3p/DEPDC1B Axis. Biochemical genetics 3 36913076
2023 Role of DEP domain-containing protein 1B (DEPDC1B) in epithelial ovarian cancer. Journal of Cancer 3 37056386
2025 DEPDC1B, CDCA2, APOBEC3B, and TYMS are potential hub genes and therapeutic targets for diagnosing dialysis patients with heart failure. Frontiers in cardiovascular medicine 2 39844908
2020 Establishment of rat anti-canine DEP domain containing 1B (DEPDC1B) monoclonal antibodies. The Journal of veterinary medical science 2 32147621
2023 XTP1 facilitates the growth and development of gastric cancer by activating CDK6. Annals of translational medicine 1 36819538
2023 Illuminating DEPDC1B in Multi-pronged Regulation of Tumor Progression. Methods in molecular biology (Clifton, N.J.) 1 37191806
2023 DEPDC1B enhances malignant phenotypes of multiple myeloma through upregulating CCNB1 and inhibiting p53 signaling pathway. Tissue & cell 1 37979396
2022 DEPDC1B promotes development of cholangiocarcinoma through enhancing the stability of CDK1 and regulating malignant phenotypes. Frontiers in oncology 1 36568241
2025 Transcription Activation of DEPDC1B Upon EBF1 Loss Contributes to Cell Cycle Progression and Epithelial-Mesenchymal Transition in Colon Adenocarcinoma. Biochemical genetics 0 41402613

Missed literature

Know a paper Affinage missed for DEPDC1B? Flag it for the maintainers and the community.

No submissions yet.