SIPA1L3

SIPA1L3 (SPAR3) is a Rap GTPase-activating protein (RapGAP) that governs epithelial cell polarity, actin cytoskeletal organization, and adherens junction formation during morphogenesis, with its RapGAP domain required for function (PMID:26231217, PMID:25804400). Loss-of-function across human translocation, mouse knockout, zebrafish knockdown, and an epithelial cell-line missense variant consistently disrupts actin stress-fibre organization and junction assembly (PMID:26231217), and truncating variants that compromise the Rap-GAP domain cause autosomal recessive congenital cataract in humans and juvenile cataract in mice, establishing a requirement for SIPA1L3 in lens development (PMID:25804400, PMID:28951961). In the developing eye, SIPA1L3 acts in a complex with EphA4 downstream of EphA4 to suppress canonical Wnt/β-catenin signaling, as depletion of either upregulates the Wnt target axin2 and the phenotype is rescued by blocking Wnt/β-catenin signaling (PMID:27993984). Beyond epithelial development, SIPA1L3 functions as a synaptic scaffold: it localizes to excitatory postsynapses where its C-terminus binds the Fezzin protein ProSAPiP1/Lzts3 (PMID:26364583), and to electrical synapses in retinal neurons where it interacts with the gap junction scaffolds ZO-1, ZO-2, and Connexin 36 (PMID:42159345, PMID:39651118). In NSCLC, SIPA1L3 uses its PDZ domain to bind AMOT and block the AMOT–PATJ tight-junction interaction, promoting proliferation and invasion (PMID:41088697).

1. 2015 High

   Established SIPA1L3 as a determinant of epithelial morphogenesis by linking its loss to disrupted polarity, actin organization, and adherens junctions.

   Evidence Germline translocation mapping, siRNA knockdown in 3D culture, Sipa1l3-/- mouse, zebrafish knockdown, and missense variant analysis in epithelial cells

   PMID:26231217

   Open questions at the time

   • Does not define the direct molecular substrate or GAP target driving the junction phenotype
   • Mechanism connecting actin disorganization to junction loss not resolved
2. 2015 Medium

   Identified the protein as a RapGAP whose domain integrity is required, tying truncating variants to recessive congenital cataract.

   Evidence Linkage analysis, whole-exome sequencing of a consanguineous family, and domain architecture analysis

   PMID:25804400

   Open questions at the time

   • RapGAP enzymatic activity inferred from domain homology, not measured in vitro
   • Specific Rap substrate(s) not identified
3. 2015 Medium

   Showed SIPA1L3 is also a synaptic RapGAP by localizing it to excitatory postsynapses and mapping its C-terminus as a ProSAPiP1/Lzts3 interaction module.

   Evidence Immunofluorescence in rat brain neurons, C-terminal deletion constructs, and co-IP with ProSAPiP1/Lzts3

   PMID:26364583

   Open questions at the time

   • Functional consequence of the postsynaptic interaction not tested
   • Single-lab interaction without reciprocal validation across systems
4. 2016 High

   Placed SIPA1L3 in a defined signaling axis by showing it acts downstream of EphA4 to inhibit canonical Wnt/β-catenin signaling during ocular development.

   Evidence Xenopus morpholino knockdown, direct Epha4-Sipa1l3 interaction assay, epistasis/rescue, axin2 expression, and Wnt inhibitor/activator rescue

   PMID:27993984

   Open questions at the time

   • Biochemical link between RapGAP activity and Wnt pathway suppression not defined
   • Whether this axis operates in mammalian lens not directly tested
5. 2017 Medium

   Confirmed Rap-GAP domain integrity is required for lens development via an independent truncating mouse allele.

   Evidence Homozygosity mapping and characterization of a spontaneous 16.7 kb deletion removing the first 14 exons, causing juvenile cataract

   PMID:28951961

   Open questions at the time

   • Domain consequence inferred from sequence, not enzymatic assay
   • Does not isolate the RapGAP function from loss of other deleted domains
6. 2021 Low

   Used structural modelling to argue a cataract-associated variant impairs the Rap·GTP regulatory interface.

   Evidence Whole-exome sequencing with Sanger validation and homology modelling on the Rap1-Rap1GAP complex structure

   PMID:34603379

   Open questions at the time

   • Mechanism is computational only; no in vitro GAP activity assay performed
   • Effect of p.Lys624Arg on Rap binding not experimentally measured
7. 2025 Medium

   Defined a PDZ-domain-dependent function in cancer, blocking AMOT-PATJ tight junction interactions to promote proliferation and invasion.

   Evidence Western blotting, reciprocal co-IP, PDZ-domain mutant analysis, and siRNA knockdown with proliferation/invasion assays in vitro and in vivo

   PMID:41088697

   Open questions at the time

   • Single-lab study
   • Relationship between PDZ/AMOT function and RapGAP activity not integrated
8. 2025 Medium

   Identified SIPA1L3 as a scaffold component of electrical synapses by demonstrating interactions with gap junction proteins in retina.

   Evidence In vivo BioID (TurboID) in mouse AII amacrine cells and zebrafish retina, immunofluorescence, and binding assays with ZO-1, ZO-2, and Cx36

   PMID:39651118 PMID:42159345

   Open questions at the time

   • Functional impact on electrical synapse transmission not established
   • How RapGAP activity relates to the scaffolding role unknown

• Direct biochemical RapGAP activity and the specific Rap substrate(s) unifying SIPA1L3's roles across epithelia, synapses, and cancer remain undefined.
• No in vitro GAP activity assay reported
• Substrate Rap GTPase(s) not identified
• Mechanistic link between RapGAP activity and the PDZ/scaffold functions not established