Affinage

ANAPC2

Anaphase-promoting complex subunit 2 · UniProt Q9UJX6

Length
822 aa
Mass
93.8 kDa
Annotated
2026-06-09
25 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ANAPC2 is the cullin subunit of the anaphase-promoting complex/cyclosome (APC/C), a multi-subunit E3 ubiquitin ligase that controls cell-cycle progression and broader protein turnover (PMID:28968996). Together with the RING subunit ANAPC11, ANAPC2 forms the catalytic cullin-RING module that drives ubiquitin chain elongation in conjunction with the E2 enzyme UBE2C/UbcH10 (PMID:25161877). APC/C engages substrates through D-box recognition, as shown for Dishevelled, which it ubiquitylates on a conserved lysine to position ANAPC2/APC/C upstream of Dvl in the planar cell polarity pathway governing motile cilia orientation and directional fluid flow (PMID:19805045). Beyond canonical cell-cycle control, ANAPC2 directs substrate ubiquitination in diverse contexts: it can target KRAS for proteasomal degradation in colorectal cancer cells (PMID:35305671), and is hijacked by the Mycobacterium tuberculosis effector Rv0222, attaching K11-linked ubiquitin chains to Rv0222 to recruit SHP1 to TRAF6 and suppress proinflammatory signaling (PMID:31942069). Its catalytic activity is held in check by the inhibitor FBXO43/Emi2, which binds ANAPC2 directly through its post-ZBR region (PMID:25161877, PMID:34595750). Physiologically, ANAPC2 is essential for hematopoietic stem and progenitor cell quiescence; its loss drives quiescent HSPCs into mitosis and apoptosis with dysregulation of Skp2, p27, Cdk2 and Cyclin E1, causing fatal bone marrow failure (PMID:28968996).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2009 High

    Established that ANAPC2/APC/C acts upstream of Dishevelled in planar cell polarity, answering how APC/C activity links to a developmental patterning output beyond classical mitotic control.

    Evidence Morpholino knockdown in Xenopus embryos with D-box mapping and ubiquitylation assay of Dvl, plus live imaging of cilia polarity and fluid flow

    PMID:19805045

    Open questions at the time
    • Does not resolve whether Dvl ubiquitylation triggers degradation or non-degradative regulation
    • Coactivator (Cdc20/Cdh1) dependence of Dvl recognition not defined
  2. 2014 High

    Defined the enzymatic core of APC/C catalysis and a mechanism of inhibition, showing the ANAPC2-ANAPC11 module elongates ubiquitin chains with UBE2C and is directly inhibited by Emi2's post-ZBR region binding ANAPC2.

    Evidence In vitro ubiquitin chain elongation assay with reconstituted ANAPC2-ANAPC11 subcomplex and Emi2 ZBR domain mutagenesis with interaction mapping

    PMID:25161877

    Open questions at the time
    • Structural basis of the Emi2-ANAPC2 contact not resolved
    • Does not address physiological substrate selectivity within intact APC/C
  3. 2017 High

    Demonstrated a non-redundant physiological requirement for ANAPC2 in maintaining stem cell quiescence, answering whether APC/C is needed to keep HSPCs out of cycle.

    Evidence Inducible Anapc2 knockout mouse with BrdU label-retention, colony assays, and cell-cycle regulator profiling

    PMID:28968996

    Open questions at the time
    • Direct APC/C substrates responsible for quiescence not pinpointed
    • Whether Skp2/p27/Cdk2/Cyclin E1 changes are direct or downstream is unresolved
  4. 2020 High

    Revealed that a bacterial pathogen exploits ANAPC2 for immune evasion, establishing that ANAPC2 can mediate K11-linked ubiquitination of a non-host substrate to dampen innate signaling.

    Evidence Reciprocal Co-IP, shRNA knockdown, mutagenesis of the Rv0222 ubiquitination site, and a mouse infection model

    PMID:31942069

    Open questions at the time
    • Which APC/C coactivator/adaptor recognizes Rv0222 is unknown
    • Whether host substrates are co-regulated during infection not addressed
  5. 2021 Medium

    Corroborated FBXO43/Emi2 as a physical APC/C inhibitor in a native tissue context, extending the in vitro Emi2-ANAPC2 interaction to endogenous complexes.

    Evidence Co-immunoprecipitation from mouse testicular extracts across ANAPC2, ANAPC8 and ANAPC10, validated by Western blot

    PMID:34595750

    Open questions at the time
    • Single Co-IP method without reciprocal functional assay in this system
    • Does not map which subunit contact is rate-limiting for inhibition in vivo
  6. 2022 Medium

    Identified KRAS as a target whose levels ANAPC2 controls via the ubiquitin-proteasome pathway, linking ANAPC2 to oncogene turnover in colorectal cancer.

    Evidence ANAPC2 overexpression and knockdown with MG132 rescue, Western blot, and xenograft/IHC validation

    PMID:35305671

    Open questions at the time
    • Direct ubiquitination of KRAS by ANAPC2 not demonstrated in vitro
    • Degron/D-box on KRAS and coactivator requirement undefined
  7. 2023 Low

    Raised the possibility that ANAPC2 participates in collective cell migration through a LINKIN/ITFG1-dependent adhesion process, linking it to a non-canonical adhesion function.

    Evidence IP-MS in HEK293T cells identifying ANAPC2 as an ITFG1 interactor plus C. elegans apc-2/lnkn-1 migration phenotype (preprint)

    PMID:36798316

    Open questions at the time
    • Single IP-MS hit without reciprocal or functional validation of the interaction
    • No demonstration that ANAPC2 ubiquitin ligase activity underlies the migration phenotype
  8. 2024 Low

    Suggested a role for ANAPC2 in adipocyte differentiation, indicating a possible metabolic/developmental function.

    Evidence Lentiviral overexpression of ANAPC2 in human subcutaneous pre-adipocytes with adipogenesis readout

    PMID:38702075

    Open questions at the time
    • Single gain-of-function experiment in one cell type
    • No substrate or pathway mechanism for the anti-adipogenic effect identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ANAPC2/APC/C achieves substrate selectivity across its disparate targets (cell-cycle regulators, Dvl, KRAS, bacterial effectors) and how coactivators direct these context-specific functions remain unresolved.
  • No unified structural model of substrate engagement across contexts
  • Coactivator (Cdc20/Cdh1) usage for non-canonical substrates undefined
  • Direct in vitro ubiquitination not shown for KRAS

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 3 GO:0140096 catalytic activity, acting on a protein 3
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-1640170 Cell Cycle 1
Partners
ANAPC10ANAPC11ANAPC8FBXO43ITFG1UBE2C
Complex memberships
APC/C

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 ANAPC2, as a core subunit of the APC/C E3 ubiquitin ligase, interacts with the mycobacterial protein Rv0222 and promotes attachment of lysine-11-linked ubiquitin chains to lysine 76 of Rv0222, which facilitates recruitment of the protein tyrosine phosphatase SHP1 to the adaptor protein TRAF6, preventing lysine-63-linked ubiquitination and activation of TRAF6, thereby suppressing proinflammatory cytokine expression. Co-immunoprecipitation, shRNA knockdown of ANAPC2, site-directed mutagenesis of Rv0222 ubiquitination site, mouse infection model Nature High 31942069
2014 The ANAPC2-ANAPC11 subcomplex (the cullin-RING ligase module of APC/C) catalyzes ubiquitin chain elongation in combination with the E2 UBE2C/UbcH10, and the post-ZBR region of Emi2 interacts directly with the cullin subunit ANAPC2 to inhibit this activity. In vitro ubiquitin chain elongation assay with reconstituted ANAPC2-ANAPC11 subcomplex, domain mutagenesis of Emi2 ZBR, pulldown/interaction mapping FEBS open bio High 25161877
2009 Knockdown of the ANAPC2 subunit in Xenopus disrupts the polarity of motile cilia and alters the directionality of fluid movement along the epidermis; mechanistically, the APC/C recognizes a D-box motif on Dishevelled (Dvl) and ubiquitylates Dvl on a conserved lysine residue, placing ANAPC2/APC/C upstream of Dvl in the planar cell polarity pathway required for cilia orientation. Morpholino knockdown of ANAPC2 in Xenopus embryos, D-box motif identification, ubiquitylation assay of Dvl, live imaging of cilia polarity and fluid flow Proceedings of the National Academy of Sciences of the United States of America High 19805045
2017 Inducible knockout of Anapc2 in mice causes fatal bone marrow failure within 7 days, with rapid loss of hematopoietic stem and progenitor cells (HSPCs); cell cycle analysis showed that quiescent HSPCs shift from quiescence to mitosis followed by apoptosis, associated with dysregulation of Skp2, P27, Cdk2, and Cyclin E1, establishing ANAPC2/APC/C as essential for HSPC quiescence maintenance. Inducible Anapc2 knockout mouse model, BrdU label-retaining cell assay, colony formation assay, cell cycle regulator protein analysis, bone marrow failure phenotyping Oncotarget High 28968996
2021 ANAPC2, along with ANAPC8 and ANAPC10, directly interacts with FBXO43 (Emi2) in mouse testicular protein extracts, confirming that FBXO43 is a direct inhibitor of the APC/C complex through physical association with core APC/C subunits including ANAPC2. Co-immunoprecipitation from mouse testicular protein extracts, validated by Western blot Clinical genetics Medium 34595750
2022 Overexpression of ANAPC2 significantly reduces KRAS protein levels in colorectal cancer cells via the ubiquitin-proteasome pathway (reversed by MG132), and knockdown of ANAPC2 abolishes the KRAS-reducing effect of combined artesunate/WNT974 treatment, establishing ANAPC2 as an E3 ligase that can target KRAS for proteasomal degradation. ANAPC2 overexpression, shRNA knockdown, MG132 proteasome inhibitor rescue, Western blot, xenograft mouse model, IHC Cell communication and signaling : CCS Medium 35305671
2023 In C. elegans, loss of function of apc-2 (ANAPC2 ortholog) produces a migratory detachment phenotype similar to loss of lnkn-1 (LINKIN/ITFG1), and ANAPC2 was identified as a potential interactor of ITFG1 by IP-MS in human HEK293T cells, suggesting ANAPC2 participates in LINKIN-dependent cell adhesion during collective cell migration. IP-MS in human HEK293T cells, C. elegans lnkn-1/apc-2 loss-of-function genetic analysis with migration phenotype readout bioRxivpreprint Low 36798316
2024 Overexpression of ANAPC2 in human subcutaneous pre-adipocytes inhibits adipogenesis, establishing a functional role for ANAPC2 in regulating adipocyte differentiation. Lentiviral overexpression of ANAPC2 in human subcutaneous pre-adipocytes with adipogenesis readout Life science alliance Low 38702075

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 Host-mediated ubiquitination of a mycobacterial protein suppresses immunity. Nature 81 31942069
2016 A genome-wide association study of heat stress-associated SNPs in catfish. Animal genetics 50 27476875
2010 Novel medicinal mushroom blend suppresses growth and invasiveness of human breast cancer cells. International journal of oncology 49 21042722
2009 Regulation of ciliary polarity by the APC/C. Proceedings of the National Academy of Sciences of the United States of America 47 19805045
2012 Inhibition of STAT1 sensitizes renal cell carcinoma cells to radiotherapy and chemotherapy. Cancer biology & therapy 37 22262126
2016 Comparison of Genome-Wide and Gene-Specific DNA Methylation Profiling in First-Trimester Chorionic Villi From Pregnancies Conceived With Infertility Treatments. Reproductive sciences (Thousand Oaks, Calif.) 32 28090815
2020 Post translational modifications in tuberculosis: ubiquitination paradox. Autophagy 21 33190592
2022 Combination of artesunate and WNT974 induces KRAS protein degradation by upregulating E3 ligase ANACP2 and β-TrCP in the ubiquitin-proteasome pathway. Cell communication and signaling : CCS 20 35305671
2014 The zinc-binding region (ZBR) fragment of Emi2 can inhibit APC/C by targeting its association with the coactivator Cdc20 and UBE2C-mediated ubiquitylation. FEBS open bio 20 25161877
2014 Activated pregnane X receptor inhibits cervical cancer cell proliferation and tumorigenicity by inducing G2/M cell-cycle arrest. Cancer letters 18 24486740
2012 EGF and HB-EGF enhance the proliferation of programmable cells of monocytic origin (PCMO) through activation of MEK/ERK signaling and improve differentiation of PCMO-derived hepatocyte-like cells. Cell communication and signaling : CCS 15 22873932
2021 A homozygous loss-of-function mutation in FBXO43 causes human non-obstructive azoospermia. Clinical genetics 14 34595750
2022 LncRNA-ANAPC2 and lncRNA-NEFM positively regulates the inflammatory response via the miR-451/npr2/ hdac8 axis in grass carp. Fish & shellfish immunology 8 35843524
2020 In vitro efficacy of liver microenvironment in bone marrow mesenchymal stem cell differentiation. In vitro cellular & developmental biology. Animal 5 32270392
2017 Hard clam extracts induce atypical apoptosis in human gastric cancer cells. Experimental and therapeutic medicine 5 28810604
2022 The role of ubiquitin signaling pathway on liver regeneration in rats. Molecular and cellular biochemistry 4 35750978
2024 Systems genetics analysis of human body fat distribution genes identifies adipocyte processes. Life science alliance 3 38702075
2023 In silico de novo drug design of a therapeutic peptide inhibitor against UBE2C in breast cancer. Journal of bioinformatics and computational biology 3 36775260
2018 Identifying fenofibrate responsive CpG sites. BMC proceedings 3 30275892
2023 Identification of Four Novel Candidate Genes for Non-syndromic Intellectual Disability in Pakistani Families. Biochemical genetics 2 37985543
2017 APC/C is essential for hematopoiesis and impaired in aplastic anemia. Oncotarget 2 28968996
2023 Systems genetics analysis of human body fat distribution genes identifies Wnt signaling and mitochondrial activity in adipocytes. bioRxiv : the preprint server for biology 1 37732278
2022 Multi-CpG linear regression models to accurately predict paclitaxel and docetaxel activity in cancer cell lines. Advances in cancer research 1 36990534
2025 PTTG1 as a common promising target for PCOS, Ovarian Cancer, and Major Depressive Disorder patients. Computational biology and chemistry 0 40925190
2023 LINKIN-associated proteins necessary for tissue integrity during collective cell migration. bioRxiv : the preprint server for biology 0 36798316

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