ACAP3

ACAP3 is a GTPase-activating protein (GAP) selective for the small GTPase Arf6 that governs cell morphological dynamics in both neural development and epithelial cancers (PMID:27330119). In neurons, ACAP3 drives neurite outgrowth by cycling Arf6 between its GTP- and GDP-bound states; loss of ACAP3 raises GTP-bound Arf6 and abolishes outgrowth, a defect rescued by wild-type but not GAP-inactive ACAP3 (PMID:27330119), and the same GAP-dependent activity is required for cortical neuronal migration in vivo (PMID:28919417). In cancer cells, ACAP3 acts as a tumour suppressor: in lung adenocarcinoma it inhibits EGFR signalling by impairing EGFR recycling and accelerating lysosome-mediated EGFR degradation in a GAP-activity-dependent manner, suppressing proliferation (PMID:41520057), and in papillary thyroid carcinoma it suppresses viability, migration, and invasion while promoting apoptosis through modulation of AKT and p53 signalling (PMID:39098591). ACAP3 expression is held down epigenetically, via Myc-driven DNA hypermethylation and deacetylation in lung adenocarcinoma (PMID:41520057) and via HDAC2 in papillary thyroid carcinoma (PMID:39098591).

1. 2016 High

   Established ACAP3 as an Arf6-specific GAP whose nucleotide-cycling activity is mechanistically required for neurite outgrowth, defining its core molecular function.

   Evidence Primary hippocampal neuron knockdown with wild-type vs. GAP-inactive rescue, Arf6-GTP pulldown, fast-cycle mutant complementation, and HEK-293T GAP assay

   PMID:27330119

   Open questions at the time

   • Does not identify the cognate Arf6 GEF that partners ACAP3 in cycling
   • Downstream effectors linking Arf6 cycling to outgrowth not defined
2. 2017 High

   Extended ACAP3's GAP function from cultured neurons to in vivo brain development, showing it is required for cortical neuronal migration through the same Arf6 GAP activity.

   Evidence In utero electroporation knockdown in mouse cortex with wild-type vs. GAP-inactive rescue and histological layering analysis

   PMID:28919417

   Open questions at the time

   • Molecular link between Arf6 cycling and migration machinery unresolved
   • Single lab, single phenotypic readout
3. 2024 Medium

   Identified ACAP3 as a tumour suppressor negatively regulated by HDAC2 in papillary thyroid carcinoma, linking its expression to AKT and p53 signalling control of proliferation and apoptosis.

   Evidence Functional assays (proliferation, migration, invasion, apoptosis), Western blot, and oe-ACAP3 + oe-HDAC2 rescue in PTC cell lines

   PMID:39098591

   Open questions at the time

   • No direct demonstration that HDAC2 binds or deacetylates the ACAP3 promoter
   • Whether tumour suppression requires Arf6 GAP activity not tested in this system
   • Cell-line only, no in vivo validation
4. 2026 Medium

   Connected ACAP3's GAP activity to EGFR trafficking control in lung adenocarcinoma and showed Myc enforces its epigenetic silencing, defining a receptor-recycling mechanism for tumour suppression.

   Evidence RRBS epigenome profiling, EGFR recycling and lysosomal degradation assays, GAP-deficient mutant comparison, in vitro and in vivo proliferation assays

   PMID:41520057

   Open questions at the time

   • Abstract-level detail only
   • Direct biochemical link between Arf6 and EGFR sorting endosomes not shown
   • Whether Myc acts directly on the ACAP3 locus unresolved

• How ACAP3-controlled Arf6 cycling is mechanistically coupled to its distinct outputs — neurite outgrowth, neuronal migration, and EGFR sorting — and what GEF and effector partners operate in each context remain open.
• Cognate Arf6 GEF unidentified
• No structural model of the ACAP3-Arf6 interaction
• Unified mechanism across neural and cancer contexts not established