CAPRIN2

CAPRIN2 (RNG140/Caprin-2) is a dual-function protein that acts both as a positive regulator of canonical Wnt/β-catenin signaling and as an RNA-binding translational repressor (PMID:18762581, PMID:32839273). In Wnt signaling, it binds the LRP5/6 co-receptors, stabilizes cytosolic β-catenin, enhances Axin–LRP5/6 association, and facilitates GSK3-dependent LRP5/6 phosphorylation to promote LEF1/TCF-dependent transcription, with knockdown in zebrafish causing a dorsalized phenotype (PMID:18762581). It additionally drives constitutive LRP5/6 Ser-1490 phosphorylation by assembling a quaternary complex with CDK14, Cyclin Y, and LRP5/6 during G2/M (PMID:27821587). This signaling activity depends on two structurally defined self-association modules: a C-terminal C1q-related domain that forms a calcium-stabilized homotrimer required for promoting LRP5/6 phosphorylation (PMID:25331957), and an HR1 domain that forms a 'scissors'-like homodimer whose basic residues R200/R201 direct plasma membrane localization essential for Wnt activity (PMID:39159816, PMID:30304999). As an RNA-binding protein, CAPRIN2 binds mRNAs and the translation initiation factor eIF3 to suppress translation initiation, selectively repressing long mRNAs while sparing short crystallin transcripts during lens differentiation (PMID:20516077, PMID:32839273). It binds AVP mRNA in the hypothalamus to control poly(A) tail length and abundance, governing the central osmotic defense response (PMID:26559902). CAPRIN2 localizes to dendritic RNA granules distinct from RNG105-containing granules and is required for dendrite length and spine density (PMID:20516077), and is required in vivo for lens fiber cell morphogenesis downstream of FGF8 signaling (PMID:26177727, PMID:19275872).

1. 2008 High

   Established CAPRIN2 as a positive regulator of canonical Wnt signaling, answering how a novel LRP5/6-binding protein influences β-catenin stability.

   Evidence Co-IP, reporter assays, LRP5/6 phosphorylation assays in mammalian cells and morpholino knockdown in zebrafish

   PMID:18762581

   Open questions at the time

   • Did not define the structural basis of LRP5/6 binding
   • Mechanism linking CAPRIN2 to Axin recruitment not resolved
2. 2009 Medium

   Placed CAPRIN2 downstream of FGF receptor signaling in lens differentiation, defining an upstream inducer of its expression.

   Evidence In vitro lens fiber differentiation with FGF8 gain/loss and in situ hybridization in mouse and chick

   PMID:19275872

   Open questions at the time

   • Transcriptional intermediates between FGF8 and CAPRIN2 not identified
   • Whether CAPRIN2's lens role is RNA-binding or Wnt-related not addressed
3. 2010 High

   Revealed CAPRIN2 as an RNA-binding translational repressor in neurons, distinguishing its dendritic granule role from the paralog RNG105.

   Evidence In vitro translation assays, RNA granule induction, immunofluorescence, and shRNA knockdown with morphological readout in cultured neurons

   PMID:20516077

   Open questions at the time

   • mRNA targets in neurons not identified
   • Molecular mechanism of translation inhibition not yet defined
4. 2014 High

   Defined the C1q-related domain homotrimer as the structural unit required for Wnt function, separating assembly from calcium binding.

   Evidence X-ray crystallography of human and zebrafish domains with mutagenesis and LRP5/6 phosphorylation assay

   PMID:25331957

   Open questions at the time

   • How trimerization couples to LRP5/6 phosphorylation mechanistically unclear
   • Full-length assembly state not determined
5. 2015 High

   Demonstrated CAPRIN2 controls AVP mRNA polyadenylation and stability, linking its RNA-binding activity to systemic osmotic homeostasis.

   Evidence RNA-IP, in vivo lentiviral shRNA knockdown, overexpression, poly(A) tail assays, and physiological measurements in hypothalamus

   PMID:26559902

   Open questions at the time

   • Mechanism by which CAPRIN2 promotes poly(A) lengthening unknown
   • Whether eIF3-mediated repression applies to AVP mRNA not tested
6. 2015 Medium

   Established a required in vivo role for CAPRIN2 in lens fiber cell morphogenesis and lens-cornea separation.

   Evidence Lens-specific conditional knockout with WGA staining, scanning electron microscopy, and phenotypic analysis in mouse

   PMID:26177727

   Open questions at the time

   • No molecular mechanism identified for the lens phenotype
   • Low (8%) penetrance of the Peters anomaly-like defect
7. 2015 Medium

   Showed CAPRIN2 can be hijacked by a pathogen, with Chlamydia pneumoniae Cpn1027 recruiting CAPRIN2 and GSK3β to promote β-catenin-dependent apoptosis resistance.

   Evidence Yeast two-hybrid, reciprocal Co-IP, GST pull-down, live-cell imaging of recruitment, and apoptosis assays

   PMID:25996495

   Open questions at the time

   • Physiological relevance to native CAPRIN2 function unclear
   • Whether recruitment alters host Wnt signaling output not quantified
8. 2016 High

   Identified a cell-cycle-coupled mechanism whereby CAPRIN2 scaffolds CDK14/Cyclin Y onto LRP6 to drive constitutive Ser-1490 phosphorylation.

   Evidence Reciprocal Co-IP, cell cycle synchronization, and phosphorylation assays with knockdown readouts

   PMID:27821587

   Open questions at the time

   • Structural basis of the quaternary complex not resolved
   • How signaling and RNA-binding functions are coordinated unknown
9. 2019 Medium

   Resolved the HR1 dimerization fold and noted surface differences from Caprin-1 that may dictate distinct partner interactions.

   Evidence X-ray crystallography and structural comparison

   PMID:30304999

   Open questions at the time

   • Functional consequences of surface differences not experimentally tested
   • Partners differentiated by these surfaces not identified
10. 2020 High

    Defined the mechanism of CAPRIN2 translational repression, showing eIF3 binding selectively suppresses long mRNAs and shapes lens crystallin expression.

    Evidence Co-IP for eIF3 binding, genome-wide ribosome profiling in overexpression and knockout cells, and knockout mouse eye analysis

    PMID:32839273

    Open questions at the time

    • How mRNA length is sensed mechanistically not fully resolved
    • Whether RNA-binding and Wnt functions occur in the same cells unclear
11. 2024 High

    Established that the HR1 basic cluster (R200/R201) directs plasma membrane localization essential for CAPRIN2 Wnt activity.

    Evidence X-ray crystallography, mutagenesis, subcellular localization imaging, and Wnt signaling assays

    PMID:39159816

    Open questions at the time

    • The membrane lipid or partner bound by the basic cluster not identified
    • How HR1 dimerization and C1q trimerization integrate spatially unresolved
12. 2025 Low

    Linked CAPRIN2 to erythropoiesis, with loss boosting erythroid production and overexpression triggering cell cycle arrest and apoptosis.

    Evidence Caprin2 knockout mouse erythroid phenotyping, CAPRIN2 overexpression growth/apoptosis assays in CHO cells, and GATA1 regulation analysis

    PMID:39922087

    Open questions at the time

    • GATA1 transcriptional regulation proposed but not experimentally confirmed
    • mRNA targets mediating the erythroid phenotype not identified
    • Single lab, limited mechanistic follow-up

• It remains unknown how CAPRIN2's two distinct activities—membrane-associated Wnt co-receptor scaffolding and cytoplasmic eIF3-dependent translational repression—are spatially and temporally partitioned within a single cell.
• No study reconciles the membrane-localized Wnt role with the RNA granule/eIF3 translational role
• Direct mRNA target catalog across tissues incomplete