| 2001 |
A heterodimeric complex of APC2 (the cullin subunit) and APC11 (the RING subunit) constitutes the minimal ubiquitin ligase module of the human APC/C; in combination with Ubc4 or UbcH10 this module is sufficient to catalyze ubiquitination of securin and cyclin B1, though without substrate specificity. APC11 and UbcH10 both bind the C-terminal cullin homology domain of APC2, while Ubc4 interacts with APC11 directly. |
Baculoviral reconstitution of human APC2/APC11 complex, in vitro ubiquitination assay with securin and cyclin B1, mutagenesis of APC11 RING finger Zn2+-binding residues, binding domain mapping |
Molecular biology of the cell |
High |
11739784
|
| 1998 |
Budding yeast RSI1/APC2 is an essential subunit of the APC/C; temperature-sensitive rsi1/apc2 mutants arrest in metaphase, fail to degrade Clb2p, and this arrest is relieved by deletion of PDS1 (securin). Rsi1p/Apc2p co-immunoprecipitates with the known APC subunit Cdc23p, demonstrating its physical association with the complex. |
Genetic screen (SIC1 synthetic lethality), temperature-sensitive mutant analysis, cyclin B degradation assay, co-immunoprecipitation with Cdc23p, PDS1 epistasis rescue |
The EMBO journal |
High |
9430641
|
| 1999 |
Mammalian APC2 contains two SAMP domains both required for binding to conductin (Axin2), and functions like APC to regulate the formation of active β-catenin–TCF complexes, as demonstrated in APC−/− colon carcinoma cells. Human APC2 maps to chromosome 19p13.3. |
Domain deletion analysis, transient transcriptional activation (TOP-FLASH) assays in APC-null colon carcinoma cells, SAMP-domain mutagenesis, chromosomal mapping |
Current biology : CB |
High |
10021369
|
| 1999 |
Drosophila APC2 (dAPC2) binds Armadillo (β-catenin homolog) and negatively regulates Wingless signaling in the embryonic epidermis; it colocalizes with actin in many cellular contexts and shows striking asymmetric distribution in neuroblasts. Genetically, the dAPC2 allele acts downstream of wg and upstream of arm, dTCF, and dishevelled, suggesting a role as a mediator of Wg effects on the cytoskeleton. |
Genetic epistasis analysis, loss-of-function mutation characterization, immunolocalization (colocalization with actin/microtubules), protein–protein binding assay (Armadillo binding) |
The Journal of cell biology |
High |
10491393
|
| 2001 |
Drosophila APC2 and Armadillo (β-catenin) both localize to sites of cortical spindle attachment during syncytial mitoses and play roles in spindle anchoring. APC2–Armadillo complexes often co-localize with interphase microtubules. Zeste-white 3 kinase (GSK-3β homolog), which phosphorylates Armadillo and APC, is required for spindle positioning and regulates the localization of APC2–Armadillo complexes. |
Live imaging and immunofluorescence in Drosophila embryos, genetic loss-of-function analysis, epistasis with zw3 kinase, co-localization with α-catenin and cortical actin markers |
Nature cell biology |
High |
11584277
|
| 2002 |
Simultaneous loss of both Drosophila Apc1 and Apc2 causes global nuclear accumulation of Armadillo (β-catenin) and constitutive activation of Wg/Wnt transduction throughout all tissues, revealing that Apc1 and Apc2 act redundantly to maintain tight regulation of β-catenin–mediated transcriptional activation in all cells. |
Double-mutant genetic analysis, immunolocalization of β-catenin/Armadillo, Wingless target gene expression assays |
Development (Cambridge, England) |
High |
11923210
|
| 2002 |
Drosophila APC2 and APC1 play overlapping roles in regulating Wingless signaling in the embryonic epidermis and imaginal discs, with APC1 functioning even at very low expression levels; the two paralogs differ dramatically in intracellular localization yet still exhibit functional redundancy. |
Single and double loss-of-function mutant analysis, Wingless target gene expression assays, immunolocalization |
Developmental biology |
High |
12297098
|
| 2002 |
In the Drosophila larval brain, APC2 localizes dynamically and asymmetrically to the cell cortex of neuroblasts through the cell cycle, while APC1 localizes to centrosomes and microtubules. Despite different localizations, both proteins redundantly maintain neuroblast numbers without misregulating Wg signaling, suggesting a cytoskeletal or adhesive rather than Wnt-signaling role in this tissue. |
Immunolocalization, single and double mutant analysis, neuroblast quantification, Wg target gene expression assays |
Developmental biology |
Medium |
12297097
|
| 2002 |
Inversin interacts with the APC/C subunit APC2; this interaction is mediated by destruction-box (D-box) motifs in inversin, and site-directed mutagenesis of conserved D-box residues abolishes inversin–APC2 interaction, identifying inversin as an APC2-interacting protein regulated in a cell-cycle-dependent manner. |
Co-immunoprecipitation, site-directed mutagenesis of D-box residues, cell-cycle expression analysis with inversin-specific antibody |
Human molecular genetics |
Medium |
12471060
|
| 2005 |
Cryo-EM analysis of vertebrate APC/C localized Cdh1 (coactivator) and Apc2 (cullin subunit) to the same side of the asymmetric complex, implying that substrate ubiquitination occurs on this face. Cdh1 binding induces a conformational change in a large flexible domain of APC/C, suggesting Cdh1 activates APC/C both by recruiting substrates and by inducing structural rearrangements. |
Cryo-EM with angular reconstitution and random conical tilt, STEM mass measurement, antibody-based subunit mapping of Cdh1 and Apc2 positions |
Molecular cell |
High |
16364912
|
| 2009 |
APC2 is expressed preferentially in the nervous system and is distributed along microtubules in growth cones and axon shafts of retinal axons. Overexpression of APC2 stabilizes microtubules in cultured cells, while shRNA knockdown in chick retinas reduces microtubule stability, impairs growth cone responses to ephrin-A2, and causes drastic alterations in retinotectal topographic projections in vivo. |
Immunohistochemistry, shRNA knockdown in chick retina, microtubule stability assay, in vitro ephrin-A2 response assay, in vivo retinotectal projection analysis |
The Journal of neuroscience |
High |
19759310
|
| 2011 |
In Drosophila S2 cells and the embryo, the Armadillo repeats and a novel C-terminal 30 amino acid (C30) domain of APC2 are both necessary and together sufficient for cortical localization; neither domain alone is sufficient. The Armadillo repeats mediate self-association of APC2. Cortical localization is required for APC2's role in actin organization but dispensable for its role in Wnt/Wg signaling. |
Domain deletion analysis, rescue experiments in APC mutant embryos, S2 cell localization assays, actin organization phenotypic assay, Wnt reporter assay |
Journal of cell science |
High |
21486956
|
| 2013 |
In Drosophila embryos, APC2 loss leads to increased chromosome segregation errors through a cascade beginning with incomplete centrosome separation, which triggers ectopic cleavage furrow formation, mitotic defects, and DNA damage. APC2 functions at the embryonic cortex together with Axin to promote mitotic fidelity through cytoskeletal regulation. |
Loss-of-function genetics, live imaging of mitosis, centrosome separation assays, DNA damage marker analysis, epistasis with Axin |
Development (Cambridge, England) |
High |
24026117
|
| 2014 |
The spliceosome subunit SNW1 is required for proper splicing of APC2 pre-mRNA; SNW1 depletion reduces APC2 protein levels, decreases APC/C activity, and indirectly contributes to sister chromatid cohesion defects by delaying mitosis and causing cohesion fatigue. Simultaneous expression of sororin and APC2 from intron-less cDNAs rescues cohesion in SNW1-depleted cells. |
RNAi depletion, transcriptome-wide splicing analysis, APC/C activity assay, sister chromatid cohesion assay, intron-less cDNA rescue experiment |
The EMBO journal |
High |
25257309
|
| 2015 |
Loss-of-function mutation in APC2 causes Sotos syndrome features in humans; Apc2-deficient mice show impaired learning/memory and abnormal head shape. Endogenous Apc2 expression is downregulated by Nsd1 knockdown, placing APC2 downstream of NSD1. Nsd1 knockdown impairs cortical neuron migration and laminar positioning similarly to Apc2-/- mice, and forced Apc2 expression rescues this defect, establishing APC2 as an NSD1 downstream effector in neuronal cytoskeletal regulation. |
Whole-exome sequencing (human patients), Apc2-/- mouse generation, behavioral testing, Nsd1 knockdown with cortical neuron migration assay, Apc2 rescue by forced expression in embryonic mouse brain |
Cell reports |
High |
25753423
|
| 2016 |
Tankyrase (TNKS) binds a C-terminal RPQPSG motif in Drosophila APC2 (conserved in human APC2 but absent from human APC1), can be recruited by APC2 into the β-catenin destruction complex, and directly PARylates both Drosophila Axin and APC2. PARylation does not globally regulate APC2 protein levels as it does for Axin, yet TNKS inhibition in colon cancer cells decreases β-catenin signaling beyond what can be explained by Axin stabilization alone, implicating APC2 PARylation as an additional regulatory point. |
Yeast two-hybrid screen, motif mapping, co-immunoprecipitation, in vitro PARylation assay, TNKS inhibitor treatment in colon cancer cells, β-catenin signaling reporter |
The Journal of biological chemistry |
High |
27068743
|
| 2018 |
APC2 promotes dynamics of minus-end-out microtubules in vertebrate dendrites. APC2 localizes as distinct clusters along microtubule bundles in dendrites via LC8-binding and two separate microtubule-interacting domains. APC2 depletion reduces plus-end dynamics of minus-end-out microtubules, increases microtubule sliding, and causes defects in dendritic morphology. |
shRNA knockdown in neurons, live TIRF/spinning-disk microscopy of microtubule dynamics, domain deletion analysis (LC8-binding and MT-interacting domains), dendritic morphology analysis |
Nature communications |
High |
30018294
|
| 2018 |
In Drosophila neurons, APC2 is positioned at dendrite branch points through four independent modules: mitochondrial energy production (via spastin-regulated mitochondria), Nrg/Ank2 membrane scaffold, branched actin generated by Arp2/3, and Frizzled/G protein/Axin Wnt signaling. At branch points, APC2 recruits APC1 to steer growing microtubules, maintaining minus-end-out polarity. |
RNAi screen, secondary candidate RNAi screens, live imaging of APC2-GFP localization, epistasis analysis with Axin, G proteins, Arp2/3, Miro and spastin |
G3 (Bethesda, Md.) |
Medium |
29602811
|
| 2018 |
In Drosophila, Brain Tumor (Brat) regulates the expression and localization of APC2 at microtubule plus ends in commissural axons to promote midline crossing; this function is independent of Wnt/β-catenin transcriptional regulation and instead requires the microtubule-stabilizing role of APC2. |
Genetic analysis (brat and apc2 mutants), epistasis with Netrin/Fra pathway, cell-autonomy assay, localization of APC2 at microtubule plus ends, Wnt reporter assay |
PLoS genetics |
Medium |
29617376
|
| 2018 |
APC2 cortical localization in Drosophila follicular epithelium and nurse cells requires self-association through an N-terminal APC Self-Association Domain (ASAD) and a conserved coiled-coil within the C-terminal C30 domain. APC2 regulates cortical actin dynamics and the distribution of cortical actin at the apical side of follicular epithelium. |
Domain deletion and mutagenesis in S2 cells, immunofluorescence in Drosophila ovary, cortical actin dynamics assay (live imaging), self-association biochemical assay |
Cytoskeleton (Hoboken, N.J.) |
Medium |
30019417
|
| 2019 |
Bi-allelic loss-of-function mutations in APC2 cause a distinct form of lissencephaly with posterior-predominant agyria/pachygyria, subcortical heterotopia, and global developmental delay in humans, linking APC2's established role in integrating actin and microtubule cytoskeletons to neuronal migration defects shared with other lissencephaly proteins (LIS1, CTNNA2). |
Whole-exome sequencing in 12 individuals from 8 families, brain MRI characterization, genotype-phenotype correlation |
American journal of human genetics |
Medium |
31585108
|
| 2020 |
APC2 (functioning as APC2-CDH1) is enriched at the post-synapse of neuromuscular junctions in postmitotic myotubes and negatively regulates AChR clustering by promoting ubiquitination of the adaptor protein DOK7 at lysine 243, leading to its proteolytic degradation. This requires MuSK kinase activity and phosphorylation of tyrosine 106 in DOK7, revealing a mechanism of negative feedback in agrin-LRP4-MuSK signaling. |
Co-immunoprecipitation, immunofluorescence localization at NMJs, ubiquitination assay, site-directed mutagenesis (K243 and Y106), AChR clustering assay, MuSK kinase-dead controls |
FASEB journal |
High |
32687671
|
| 2010 |
FBG1, an F-box protein, directly interacts with APC2 through a D-box motif within its F-box domain; co-expression with FBG1 increases total APC2 levels but reduces free APC2 by sequestration, inhibiting cell proliferation and inducing S-phase arrest. |
Co-immunoprecipitation, D-box mutagenesis, FACS cell-cycle analysis, protein level quantification by western blot |
Cell cycle (Georgetown, Tex.) |
Medium |
21135578
|
| 1999 |
ROC1 (APC11 homolog) specifically interacts with APC2 (a cullin-related APC subunit), and APC11 immunocomplexes can catalyze ubiquitin isopeptide ligation (polyubiquitin chain formation) in an E1- and E2-dependent manner, establishing the APC2–APC11 pair as the catalytic core of the APC/C. |
Co-immunoprecipitation showing specificity of APC11 for APC2 vs. other cullins, in vitro ubiquitin ligase assay with APC11 immunocomplexes, RING-finger mutagenesis abolishing ligase activity |
Molecular cell |
High |
10230407
|
| 2012 |
In Drosophila, the APC11 subunit (LmgA/Lemming) interacts with Morula/Apc2 and together they form a ternary complex with the E2-C type ubiquitin-conjugating enzyme Vihar, establishing that Lmg/Apc11 recruits the E2 enzyme to the APC/C via Apc2. |
Genetic rescue assays (Drosophila null and yeast ts mutant complementation), protein–protein interaction assays, immunolocalization, mutant phenotype analysis (cyclin accumulation, metaphase arrest) |
Cell division |
Medium |
22417125
|
| 2021 |
FOXO4 functions as a transcription factor that binds the APC2 promoter and upregulates APC2 expression, which in turn increases phosphorylated degradation of β-catenin and suppresses CRC cell migration and metastasis; APC2 knockdown reverses the anti-metastatic effects of FOXO4 overexpression. |
Chromatin immunoprecipitation (ChIP), luciferase reporter for APC2 promoter, FOXO4 overexpression/APC2 knockdown rescue, β-catenin phosphorylation western blot, in vivo xenograft metastasis assay |
Frontiers in cell and developmental biology |
Medium |
34631691
|
| 2024 |
Comparative cryo-EM structures of S. cerevisiae and human APC/C reveal that in human APC/C, coactivator (CDH1) binding induces a conformational change of the catalytic module APC2:APC11 to allow E2 binding, whereas in S. cerevisiae apo-APC/C the catalytic module (Apc2:Apc11) is already pre-positioned to bind E2 without requiring coactivator-induced conformational change—demonstrating a species-specific regulatory difference in how APC2 engages E2 enzymes. |
Cryo-EM structure determination of multiple APC/C states (apo, CDH1-bound, phosphorylated), comparative structural analysis between yeast and human APC/C |
bioRxivpreprint |
Medium |
|
| 2025 |
The BubR1 TPR domain interacts with Apc2 within the MCC–APC/C complex, as identified by cryo-EM structural guidance; this interaction, together with TPR domain contacts with Mad2 and Cdc20-APC/C, promotes MCC assembly and MCC–APC/C binding to enable rapid spindle assembly checkpoint activation. |
cryo-EM structure-guided mutagenesis, biochemical MCC assembly assay, MCC–APC/C binding assay, functional SAC signaling assay |
bioRxivpreprint |
Medium |
|