Affinage

SAPCD2

Suppressor APC domain-containing protein 2 · UniProt Q86UD0

Length
394 aa
Mass
42.6 kDa
Annotated
2026-06-10
32 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SAPCD2 (p42.3/C9orf140) is a cell cycle-regulated, cytoplasmic protein that controls mitotic spindle orientation by acting as a microtubule-associated protein (PMID:42151476, PMID:17525738). It directly binds LGN and negatively regulates LGN accumulation at the cell cortex, competing with NuMA to limit cortical LGN and thereby restraining planar spindle orientation during epithelial morphogenesis and asymmetric division of retinal progenitors (PMID:26766442). CDK1-mediated phosphorylation at S157, together with phosphorylation at S276, generates a mitosis-specific isoform that destabilizes astral microtubules; disruption of both sites prevents rescue of the spindle misorientation caused by SAPCD2 loss (PMID:42151476). Independently, SAPCD2 acts as a negative-feedback regulator of Wnt/β-catenin signaling by binding Axin1 and outcompeting PP2A, shifting β-catenin toward phosphorylation, while Wnt signaling itself induces SAPCD2 expression (PMID:29531269). In cancer contexts SAPCD2 drives proliferation and tumorigenicity, with expression peaking at M phase and depletion causing G2/M arrest (PMID:17525738); it directly binds cytoplasmic E2F7 to restrict its nuclear accumulation (PMID:35197448) and operates upstream of YAP1 to regulate Hippo-pathway-dependent growth (PMID:33384953). Its expression is post-transcriptionally repressed by miR-29a binding the 3′UTR (PMID:21998710).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2007 Medium

    Established SAPCD2 (p42.3) as a cell cycle-dependent, proliferation-promoting protein, defining its first functional context before any molecular mechanism was known.

    Evidence Cell cycle synchronization with RT-PCR/Western, siRNA knockdown, colony formation and xenograft assays in gastric cancer cells

    PMID:17525738

    Open questions at the time
    • No molecular partner or biochemical activity identified
    • Mechanism linking SAPCD2 to cyclin B1/Chk2 changes unresolved
  2. 2011 Medium

    Identified an upstream regulatory input by showing miR-29a directly represses SAPCD2 via its 3′UTR, placing SAPCD2 within a defined post-transcriptional control axis.

    Evidence 3′UTR luciferase reporter, miR-29a mimic, Western/qRT-PCR and cell cycle analysis in gastric cancer cells

    PMID:21998710

    Open questions at the time
    • Does not address downstream effector function of SAPCD2
    • Only one regulatory miRNA tested
  3. 2012 Medium

    Demonstrated SAPCD2 is oncogenic gain-of-function, accelerating mitotic progression and altering chromosome segregation, reinforcing a mitotic role.

    Evidence Stable overexpression in NIH3T3 cells with cell cycle protein Western blots and mitotic progression assays

    PMID:23192843

    Open questions at the time
    • No direct molecular target of SAPCD2 identified
    • Mechanism of altered segregation not defined
  4. 2016 High

    Provided the first direct molecular mechanism: SAPCD2 binds LGN and competes with NuMA to limit cortical LGN, controlling spindle orientation and asymmetric division in vivo.

    Evidence Co-IP/pulldown, NuMA competition assays, siRNA in epithelial cysts and mouse retinal progenitors

    PMID:26766442

    Open questions at the time
    • Structural basis of LGN binding not resolved
    • Did not establish how SAPCD2 itself is recruited to the cortex
  5. 2018 High

    Revealed a distinct signaling function as a negative-feedback regulator of Wnt/β-catenin through Axin1 binding and PP2A competition.

    Evidence TAP-MS, Co-IP, PP2A competition, β-catenin phosphorylation assays, zebrafish epistasis

    PMID:29531269

    Open questions at the time
    • Relationship between Wnt-regulatory and spindle-orientation functions unclear
    • No structural detail of the Axin1 interaction
  6. 2022 Medium

    Showed SAPCD2 directly binds cytoplasmic E2F7 and restricts its nuclear accumulation, linking SAPCD2 to transcriptional control of cell cycle and chromosome stability genes.

    Evidence Co-IP (E2F7-specific, not E2F1), subcellular fractionation, siRNA with expression profiling in neuroblastoma

    PMID:35197448

    Open questions at the time
    • Mechanism of cytoplasmic sequestration not defined
    • Reciprocal validation of binding limited
  7. 2026 High

    Defined the mitotic switch mechanism: CDK1 phosphorylates SAPCD2 at S157 (with S276) to create a microtubule-destabilizing, mitosis-specific isoform required for correct spindle orientation.

    Evidence Live-cell imaging, phospho-site mutagenesis (S157A, S276A), in vitro CDK1 kinase identification, rescue experiments

    PMID:42151476

    Open questions at the time
    • Structural basis of microtubule binding unresolved
    • How phosphorylation alters microtubule association mechanistically not shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unclear how SAPCD2's distinct activities — astral microtubule destabilization, cortical LGN competition, Wnt/Axin1 feedback, and E2F7/YAP regulation — are integrated within a single cell or coordinated across cell-cycle stages.
  • No structural model of SAPCD2
  • No unified framework connecting its microtubule and signaling functions
  • Domain architecture mediating the multiple interactions undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005829 cytosol 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1640170 Cell Cycle 2 R-HSA-162582 Signal Transduction 1
Partners
AXIN1E2F7LGNNUMAPP2A

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 SAPCD2 (p42.3) physically interacts with LGN and negatively regulates LGN localization at the cell cortex, likely by competing with NuMA for LGN binding, thereby controlling mitotic spindle orientation in epithelial cells and mouse retinal progenitor cells in vivo. Co-IP/pulldown to identify LGN as binding partner; siRNA loss-of-function in epithelial cyst cultures and in vivo retinal progenitor assays; competition binding assays with NuMA Developmental cell High 26766442
2026 SAPCD2 functions as a microtubule-associated protein that promotes microtubule stability; CDK1-mediated phosphorylation at S157, together with phosphorylation at S276, generates a mitosis-specific isoform that destabilizes astral microtubules to control spindle orientation. Disruption of phosphorylation at both S157 and S276 fails to rescue spindle misorientation caused by SAPCD2 depletion. Live-cell imaging; siRNA depletion; phospho-site mutagenesis (S157A, S276A); microtubule stability assays; identification of CDK1 as the kinase for S157 Communications biology High 42151476
2018 C9orf140 (SAPCD2) is a negative regulator of Wnt/β-catenin signaling that interacts with Axin1, outcompetes PP2A for Axin1 binding, thereby shifting the balance toward phosphorylation of β-catenin and reducing Wnt3A-induced β-catenin accumulation. Wnt signaling in turn induces C9orf140 expression via β-catenin, forming a negative feedback loop. Tandem-affinity purification and mass spectrometry to identify Axin1 as binding partner; Co-IP; competition assay with PP2A; β-catenin phosphorylation assays in cultured cells; zebrafish embryo functional validation Oncogene High 29531269
2007 p42.3 (SAPCD2) expression is cell cycle-dependent in gastric cancer cell lines, with peak expression at M phase. RNAi-mediated depletion causes G2/M arrest, suppresses cell proliferation and tumorigenicity, and alters expression of cyclin B1 and Chk2. Cell cycle synchronization + RT-PCR/Western blot; siRNA knockdown; colony formation and xenograft tumorigenicity assays; flow cytometry Oncogene Medium 17525738
2012 p42.3 (SAPCD2) overexpression in NIH3T3 cells promotes malignant transformation with accelerated mitotic progression, altered chromosome segregation, upregulation of Cyclin B1, and downregulation of Cdc2-Tyr15 phosphorylation. Stable transfection of p42.3 into NIH3T3 cells; Western blot for cell cycle proteins; mitotic progression assays Molecular carcinogenesis Medium 23192843
2022 SAPCD2 directly binds cytoplasmic E2F7 (but not E2F1) and alters its subcellular distribution; SAPCD2 knockdown increases nuclear E2F7 accumulation, thereby affecting expression of genes involved in cell cycle regulation and chromosome instability in neuroblastoma cells. Co-IP to demonstrate direct SAPCD2–E2F7 (not E2F1) binding; subcellular fractionation; siRNA knockdown with gene expression profiling; in vitro and in vivo functional assays Cell death & disease Medium 35197448
2011 miR-29a directly binds the 3′UTR of p42.3 (SAPCD2) mRNA to repress p42.3 expression at both mRNA and protein levels, inducing cell cycle arrest and inhibiting proliferation in gastric cancer cells. 3′UTR luciferase reporter assay; Western blot and qRT-PCR; miR-29a mimic transfection; cell cycle analysis PloS one Medium 21998710
2020 Silencing SAPCD2 in fibrosarcoma cells activates the Hippo signaling pathway (reduces YAP1 activity); constitutively active YAP1-S127A rescues the inhibitory effects of SAPCD2 knockdown on colony formation, anchorage-independent growth, and apoptosis, placing SAPCD2 upstream of YAP1 in this pathway. siRNA knockdown; genetic epistasis with YAP1-S127A rescue construct; colony formation and anchorage-independent growth assays; apoptosis assay; in vivo lung metastasis model Frontiers in oncology Medium 33384953
2020 SAPCD2 knockdown in breast cancer cells reduces YAP/TAZ protein expression and inhibits proliferation, migration, and invasion; simultaneous YAP overexpression reverses these effects, placing SAPCD2 upstream of YAP/TAZ. siRNA knockdown; YAP overexpression rescue; Western blot for YAP/TAZ; CCK-8, transwell assays European review for medical and pharmacological sciences Low 32329855
2019 LncRNA PXN-AS1-L directly interacts with SAPCD2 mRNA 3′UTR to prevent miRNA-AGO silencing complex binding, thereby upregulating SAPCD2 mRNA and protein levels in nasopharyngeal carcinoma cells. RNA pull-down / RNA-RNA interaction assay; qRT-PCR and Western blot; SAPCD2 depletion rescue experiments in vitro and in vivo Cancer medicine Low 31173488
2026 SAPCD2 stabilizes TANK protein by preventing its ubiquitin-mediated degradation by SYVN1, activates MAPK signaling, and through CREB phosphorylation enhances PLAGL2 expression, which in turn amplifies SAPCD2 expression in a positive feedback loop driving bladder cancer progression. Co-IP; ubiquitination assays; CREB phosphorylation assays; siRNA/overexpression functional assays; in vivo tumor models Cancers Low 41682005
2014 STAT5 directly interacts with EZH2 and β-catenin to enhance C9orf140 (SAPCD2) gene transactivation, and C9orf140 promotes epithelial-mesenchymal transition and CRC cell invasion downstream of STAT5, EZH2, and β-catenin. siRNA knockdown and overexpression; Co-IP for STAT5-EZH2-β-catenin interaction; EMT marker analysis; in vivo metastasis model Carcinogenesis Low 24608043
2023 SAPCD2 protein is localized predominantly in the cytoplasm of CRC cells, as determined by immunofluorescence with SAPCD2-EGFP recombinant constructs. Immunofluorescence with SAPCD2-EGFP fusion constructs in HCT116 cells Cellular and molecular biology Low 38158695

Source papers

Stage 0 corpus · 32 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 MiR-29a inhibits cell proliferation and induces cell cycle arrest through the downregulation of p42.3 in human gastric cancer. PloS one 89 21998710
2007 Identification and characterization of a novel p42.3 gene as tumor-specific and mitosis phase-dependent expression in gastric cancer. Oncogene 38 17525738
2016 SAPCD2 Controls Spindle Orientation and Asymmetric Divisions by Negatively Regulating the Gαi-LGN-NuMA Ternary Complex. Developmental cell 32 26766442
2019 Long noncoding RNA PXN-AS1-L promotes the malignancy of nasopharyngeal carcinoma cells via upregulation of SAPCD2. Cancer medicine 24 31173488
2021 YY1-inudced activation of lncRNA DUXAP8 promotes proliferation and suppresses apoptosis of triple negative breast cancer cells through upregulating SAPCD2. Cancer biology & therapy 23 33683171
2018 C9orf140, a novel Axin1-interacting protein, mediates the negative feedback loop of Wnt/β-catenin signaling. Oncogene 17 29531269
2012 Cell cycle-dependent expression of p42.3 promotes mitotic progression in malignant transformed cells. Molecular carcinogenesis 17 23192843
2022 SAPCD2 promotes neuroblastoma progression by altering the subcellular distribution of E2F7. Cell death & disease 14 35197448
2020 Overexpression of SAPCD2 correlates with proliferation and invasion of colorectal carcinoma cells. Cancer cell international 14 32055236
2013 Overexpression of p42.3 promotes cell growth and tumorigenicity in hepatocellular carcinoma. World journal of gastroenterology 14 23704824
2014 Role of C9orf140 in the promotion of colorectal cancer progression and mechanisms of its upregulation via activation of STAT5, β-catenin and EZH2. Carcinogenesis 13 24608043
2020 SAPCD2 promotes invasiveness and migration ability of breast cancer cells via YAP/TAZ. European review for medical and pharmacological sciences 12 32329855
2013 A DNA vaccine targeting p42.3 induces protective antitumor immunity via eliciting cytotoxic CD8+T lymphocytes in a murine melanoma model. Human vaccines & immunotherapeutics 12 24051432
2022 MiR-486-5p specifically suppresses SAPCD2 expression, which attenuates the aggressive phenotypes of lung adenocarcinoma cells. Histology and histopathology 11 35467005
2020 Silencing SAPCD2 Represses Proliferation and Lung Metastasis of Fibrosarcoma by Activating Hippo Signaling Pathway. Frontiers in oncology 10 33384953
2017 Depletion of p42.3 gene inhibits proliferation and invasion in melanoma cells. Journal of cancer research and clinical oncology 10 28093638
2014 Differential expression of p42.3 in low- and high-grade gliomas. World journal of surgical oncology 9 24927751
2016 Application of intelligent algorithm in the optimization of novel protein regulatory pathway: Mechanism of action of gastric carcinoma protein p42.3. Journal of cancer research and therapeutics 8 27461626
2015 Positive relationship between p42.3 gene and inflammation in chronic non-atrophic gastritis. Journal of digestive diseases 7 26316259
2014 p42.3 promotes cell proliferation and invasion in human Renal-Cell Carcinoma. International journal of clinical and experimental medicine 7 25663993
2017 Establishment of optimal regulatory network of colorectal cancer based on p42.3 protein. Saudi journal of biological sciences 6 29551923
2015 p42.3: An abductor of cell cycle. Anti-cancer agents in medicinal chemistry 6 25142318
2015 Optimization and Corroboration of the Regulatory Pathway of p42.3 Protein in the Pathogenesis of Gastric Carcinoma. Computational and mathematical methods in medicine 5 26106439
2020 Expression of p42.3 in non-small cell lung cancer. Annals of translational medicine 4 32793664
2016 Overexpression of p42.3 promotes cell proliferation, migration, and invasion in human gastric cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 4 27449033
2022 The Function and Regulation of SAPCD2 in Physiological and Oncogenic Processes. Journal of Cancer 3 35517423
2025 Comprehensive Bioinformatics Analyses and Experimental Validation of the Cell Cycle Related Protein SAPCD2 as a New Biomarker and Potential Therapeutic Target in Pancreatic Cancer. Journal of inflammation research 2 40034688
2023 The Generation and Application of Monoclonal Antibodies to Detect SAPCD2 Expression in Precancerous and Malignant Gastric Lesions. Iranian journal of immunology : IJI 2 37161922
2023 Homologous proteins SAPCD2X1 and SAPCD2 have significantly different carcinogenic capacities in human colorectal cancer cells based on structural prediction and functional verification. Cellular and molecular biology (Noisy-le-Grand, France) 1 38158695
2026 SAPCD2 Drives Bladder Cancer Progression by Stabilizing TANK and Engaging a CREB-PLAGL2 Feedback Loop to Sustain MAPK Signaling. Cancers 0 41682005
2026 SAPCD2 phosphorylation modulates astral microtubule stability to control spindle orientation. Communications biology 0 42151476
2016 Erratum: Application of intelligent algorithm in the optimization of novel protein regulatory pathway: Mechanism of action of gastric carcinoma protein p42.3. Journal of cancer research and therapeutics 0 28054541

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