Affinage

ACAP2

Arf-GAP with coiled-coil, ANK repeat and PH domain-containing protein 2 · UniProt Q15057

Length
778 aa
Mass
88.0 kDa
Annotated
2026-06-09
15 papers in source corpus 7 papers cited in narrative 7 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

ACAP2 (centaurin-β2) is an ARF6 GTPase-activating protein that operates as a downstream effector of GTP-bound Rab35 to locally inactivate Arf6 and thereby couple membrane trafficking to actin-dependent cellular remodeling (PMID:22344257, PMID:22045739). Rab35 accumulates at Arf6-positive endosomes and the phagocytic cup and recruits ACAP2 in a GTP-Rab35-dependent manner, and ACAP2's Arf6-GAP activity at these sites drives NGF-induced neurite outgrowth and FcγR-mediated phagosome formation (PMID:22344257, PMID:22045739). This Rab35–ACAP2–Arf6 axis is also deployed as a negative regulator of oligodendrocyte differentiation and myelination, where ACAP2 opposes the Arf6-GEF cytohesin-2 (PMID:24600047). The direct Rab35–ACAP2 interaction is highly specific, requiring Thr-76/Thr-81 in the Rab35 switch II region and Asn-610/Asn-691 within the minimal Rab35-binding domain of ACAP2, and binding-deficient mutants of either protein fail to support neurite outgrowth (PMID:25694427). Independent of its GAP function, ACAP2 (the human homolog of C. elegans CNT-1) carries a phosphoinositide-binding-dependent pro-apoptotic activity, as its knockdown blocks 5-fluorouracil-induced apoptosis (PMID:25853217). ACAP2 protein levels are set by ubiquitin-mediated proteasomal degradation through the E3 ligase RNF126 (PMID:40251363).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2011 High

    Established that Rab35 acts upstream of ACAP2 by recruiting this Arf6-GAP to a defined membrane site, the phagocytic cup, to control actin-dependent membrane remodeling.

    Evidence Live-cell imaging, RNAi, GTP/GDP-locked Rab35 mutants and overexpression synergy in macrophage phagocytosis assays

    PMID:22045739

    Open questions at the time
    • Did not define the residues mediating the Rab35–ACAP2 interaction
    • Direct demonstration of Arf6 inactivation at the cup vs. correlative recruitment
  2. 2012 High

    Generalized the Rab35–ACAP2–Arf6 module to a second process, showing ACAP2's Arf6-GAP activity at Rab35/Arf6-positive endosomes is indispensable for NGF-induced neurite outgrowth.

    Evidence Live-cell imaging, colocalization, knockdown-rescue and GTPase activity assays in PC12 cells

    PMID:22344257

    Open questions at the time
    • Downstream actin effectors regulated by Arf6 inactivation not defined
    • How Rab35 itself is activated by NGF not addressed
  3. 2014 High

    Extended the pathway to development by defining a full epistatic circuit in which ACAP2/Rab35 negatively regulate oligodendrocyte differentiation by inactivating Arf6, opposed by the Arf6-GEF cytohesin-2.

    Evidence siRNA knockdown, cytohesin-2 pharmacological inhibition, myelination co-culture and GTPase assays

    PMID:24600047

    Open questions at the time
    • Membrane compartment of ACAP2 action in oligodendrocytes not pinpointed
    • In vivo myelination requirement not tested
  4. 2015 High

    Resolved the structural basis and specificity of the interaction, defining the exact Rab35 and ACAP2 residues required and proving the direct contact is functionally essential.

    Evidence Deletion and point mutagenesis, binding assays, knockdown-rescue in PC12 cells

    PMID:25694427

    Open questions at the time
    • No high-resolution co-structure of the complex
    • Whether the same residues govern recruitment in phagocytosis/myelination not tested
  5. 2015 Medium

    Identified a GAP-independent role by showing ACAP2 is the human CNT-1 homolog with a phosphoinositide-binding pro-apoptotic function required for chemotherapy-induced cell death.

    Evidence siRNA knockdown, apoptosis assays and phosphoinositide-binding assays in cancer cells

    PMID:25853217

    Open questions at the time
    • Single lab with limited downstream mechanistic depth
    • Link between phosphoinositide binding and the apoptotic effector pathway not established
  6. 2006 Medium

    Identified ACAP2 as a binding partner of vaccinia virus K1L while showing this interaction is separable from K1L's host-range function.

    Evidence Ankyrin repeat mutagenesis, binding assays and viral replication assays in HeLa and RK13 cells

    PMID:16806385

    Open questions at the time
    • Functional consequence of K1L–ACAP2 binding for the host or virus not defined
    • Single-lab interaction without reciprocal validation in subsequent work
  7. 2025 Medium

    Defined a post-translational control of ACAP2 abundance, showing the E3 ligase RNF126 ubiquitinates ACAP2 to drive its proteasomal degradation in ovarian cancer.

    Evidence Co-IP, cycloheximide chase, RT-qPCR/Western and xenograft assays

    PMID:40251363

    Open questions at the time
    • Ubiquitination site(s) on ACAP2 not mapped
    • Whether degradation affects the Rab35/Arf6 trafficking functions not tested
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ACAP2's distinct GAP-dependent trafficking role and GAP-independent pro-apoptotic role are coordinated, and whether its degradation by RNF126 regulates either, remains unresolved.
  • No unifying model linking trafficking and apoptotic functions
  • No structural model of ACAP2 in complex with Rab35 or substrates
  • Upstream signals controlling ACAP2 recruitment vs. degradation not integrated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0008289 lipid binding 1
Localization
GO:0005768 endosome 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-168256 Immune System 1 R-HSA-5357801 Programmed Cell Death 1
Partners
ARF6K1LRAB35RNF126

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 ACAP2 (centaurin-β2) functions as a Rab35 effector and as an Arf6-GAP during neurite outgrowth. Rab35 accumulates at Arf6-positive endosomes in response to NGF stimulation and recruits ACAP2 to the same compartment; the Arf6-GAP activity of ACAP2 at these endosomes is indispensable for NGF-induced neurite outgrowth in PC12 cells. Live-cell imaging, co-localization, knockdown and rescue experiments in PC12 cells, GTPase activity assays Journal of cell science High 22344257
2011 During FcγR-mediated phagocytosis in macrophages, Rab35 recruits ACAP2 (an ARF6-GAP) to the phagocytic cup in a GTP-Rab35-dependent manner; ACAP2 recruitment downstream of Rab35 controls actin-dependent phagosome formation, and co-overexpression of ACAP2 with GTP-locked Rab35 synergistically inhibits phagocytosis. Live-cell imaging, RNAi knockdown, dominant-negative/constitutively active Rab35 mutants, overexpression, phagocytosis assays in macrophages Journal of cell science High 22045739
2014 ACAP2, acting as an Arf6-GAP downstream of Rab35, negatively regulates oligodendrocyte morphological differentiation and myelination; ACAP2 knockdown promotes differentiation and myelination, while Arf6 (which ACAP2 inactivates) is required for differentiation. Cytohesin-2 (a GEF for Arf6) opposes ACAP2/Rab35 in this pathway. siRNA knockdown, pharmacological inhibition of cytohesin-2, oligodendrocyte-neuronal co-culture myelination assay, GTPase activity measurements Molecular biology of the cell High 24600047
2015 Thr-76 and Thr-81 in the switch II region of Rab35 are required for binding ACAP2, and are dispensable for binding other Rab35-binding proteins. Asn-610 and Asn-691 in ACAP2's minimal Rab35-binding domain are key residues for specific Rab35 recognition. Neither Rab35(T76S/T81A) nor ACAP2(N610A/N691A) binding-deficient mutants support neurite outgrowth, confirming the functional significance of the direct Rab35–ACAP2 interaction. Deletion and point mutagenesis, binding assays, knockdown-rescue experiments in PC12 cells The Journal of biological chemistry High 25694427
2015 ACAP2, the human homolog of C. elegans CNT-1, has a pro-apoptotic function and shares an identical phosphoinositide-binding pattern with tCNT-1. Knockdown of ACAP2 blocks apoptosis in cancer cells in response to 5-fluorouracil treatment. siRNA knockdown, apoptosis assays, phosphoinositide-binding assays Cell cycle (Georgetown, Tex.) Medium 25853217
2006 Vaccinia virus K1L protein binds ACAP2 (an ARF6-GAP); however, ANK mutations that abolish VV replication in human or rabbit cells do not affect K1L's ability to bind ACAP2, indicating that ACAP2 binding is separable from the host-range function of K1L. Ankyrin repeat mutagenesis, binding assays, viral replication assays in HeLa and RK13 cells Virology Medium 16806385
2025 RNF126 (a ubiquitin E3 ligase) physically interacts with ACAP2 and promotes its ubiquitination and proteasomal degradation, thereby reprogramming lipid metabolism and promoting ovarian cancer progression. ACAP2 protein stability is negatively regulated by RNF126. Co-immunoprecipitation, cycloheximide chase assay, RT-qPCR, Western blot, siRNA knockdown, in vivo xenograft Biochemical genetics Medium 40251363

Source papers

Stage 0 corpus · 15 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Rab35 regulates Arf6 activity through centaurin-β2 (ACAP2) during neurite outgrowth. Journal of cell science 124 22344257
1994 Prediction of the coding sequences of unidentified human genes. II. The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of cDNA clones from human cell line KG-1. DNA research : an international journal for rapid publication of reports on genes and genomes 122 7584044
2018 The CircRNA-ACAP2/Hsa-miR-21-5p/ Tiam1 Regulatory Feedback Circuit Affects the Proliferation, Migration, and Invasion of Colon Cancer SW480 Cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 113 30212824
2011 Rab35 regulates phagosome formation through recruitment of ACAP2 in macrophages during FcγR-mediated phagocytosis. Journal of cell science 72 22045739
2021 Cancer-associated fibroblasts-derived exosomal miR-3656 promotes the development and progression of esophageal squamous cell carcinoma via the ACAP2/PI3K-AKT signaling pathway. International journal of biological sciences 56 34671193
2006 Vaccinia virus K1L protein supports viral replication in human and rabbit cells through a cell-type-specific set of its ankyrin repeat residues that are distinct from its binding site for ACAP2. Virology 38 16806385
2014 Rab35, acting through ACAP2 switching off Arf6, negatively regulates oligodendrocyte differentiation and myelination. Molecular biology of the cell 37 24600047
2020 CircRNA ACAP2 induces myocardial apoptosis after myocardial infarction by sponging miR-29. Minerva medica 31 32406223
2021 Circ-ACAP2 facilitates the progression of colorectal cancer through mediating miR-143-3p/FZD4 axis. European journal of clinical investigation 29 34085707
2020 CircRNA_ACAP2 Suppresses EMT in Head and Neck Squamous Cell Carcinoma by Targeting the miR-21-5p/STAT3 Signaling Axis. Frontiers in oncology 21 33363013
2021 CircRNA ACAP2 Is Overexpressed in Myocardial Infarction and Promotes the Maturation of miR-532 to Induce the Apoptosis of Cardiomyocyte. Journal of cardiovascular pharmacology 15 34139744
2015 Structure-function analyses of the small GTPase Rab35 and its effector protein centaurin-β2/ACAP2 during neurite outgrowth of PC12 cells. The Journal of biological chemistry 15 25694427
2021 CircRNA-ACAP2 contributes to the invasion, migration, and anti-apoptosis of neuroblastoma cells through targeting the miRNA-143-3p-hexokinase 2 axis. Translational pediatrics 13 35070838
2015 Human ACAP2 is a homolog of C. elegans CNT-1 that promotes apoptosis in cancer cells. Cell cycle (Georgetown, Tex.) 8 25853217
2025 RNF126 Promotes Ovarian Cancer Progression by Reprogramming Lipid Metabolism Through Degradation of ACAP2. Biochemical genetics 1 40251363

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