Affinage

CLIP2

CAP-Gly domain-containing linker protein 2 · UniProt Q9UDT6

Length
1046 aa
Mass
115.8 kDa
Annotated
2026-06-09
20 papers in source corpus 7 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CLIP2 (CLIP-115) is a cytoplasmic linker protein that tracks growing microtubule plus-ends and couples regional microtubule dynamics to organelle positioning and cell morphogenesis (PMID:9427243, PMID:10825300). Microtubule binding requires its conserved MTB domains together with flanking basic, serine-rich regions, is sensitive to phosphorylation, and is supported by disulfide-bridged homodimerization in which Cysteine-391 governs microtubule-bundling activity; the protein initially accumulates at distal microtubule ends together with CLIP-170 (PMID:10825300). At these tips CLIP2 associates with the microtubule-stabilizing CLASP proteins, linking it to a module that redistributes to leading-edge microtubules under PI3-kinase- and GSK-3β-dependent control (PMID:11290329). Genetic reduction of CLIP2 increases the accumulation of CLIP-170 and dynactin at microtubule tips, indicating that CLIP2 normally limits these factors at plus-ends and thereby modulates dynein regulation (PMID:12195424). Functionally, CLIP2 mediates the microtubule-dependent localization of dendritic lamellar bodies in neurons (PMID:9427243), facilitates trafficking of Aquaporin 5 to the plasma membrane in salivary gland cells through a CAP-Gly-type interaction (PMID:41184862), and is required for osteocyte maturation, osteocyte-specific gene expression, and dendrite morphology (PMID:42055327, PMID:41279202).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 1997 Medium

    Established CLIP2 as a brain-enriched microtubule-associated linker and gave it a first cellular job: tethering dendritic lamellar bodies to microtubules.

    Evidence cDNA characterization, microtubule-binding and immunolocalization in neurons, plus local microtubule depolymerization causing transient DLB loss

    PMID:9427243

    Open questions at the time
    • Molecular nature of the organelle-microtubule link not defined
    • No direct binding partner identified for DLB tethering
  2. 2000 High

    Defined the molecular determinants of CLIP2 microtubule binding and oligomerization, showing binding needs MTB domains plus flanking basic/serine-rich regions and is phosphoregulated, and that the protein dimerizes via disulfide bridges.

    Evidence In vitro microtubule-binding assays, MTB and cysteine mutagenesis, phosphorylation-sensitivity assays, and GFP-construct localization in COS-1 cells

    PMID:10825300

    Open questions at the time
    • Physiological kinase(s) controlling phosphorylation not identified
    • In vivo relevance of disulfide dimerization and Cys-391 bundling unresolved
  3. 2001 High

    Placed CLIP2 in a plus-end module by showing it associates with CLASPs, connecting it to PI3K/GSK-3β-controlled microtubule stabilization at the leading edge.

    Evidence Co-immunoprecipitation, colocalization microscopy, antibody injection, and transfection stabilization assays

    PMID:11290329

    Open questions at the time
    • Direct vs. indirect nature of the CLIP2-CLASP interaction not separated from CLIP-170
    • CLIP2-specific contribution to CLASP recruitment not isolated
  4. 2002 High

    Demonstrated a regulatory role at microtubule tips: reducing CLIP2 dosage raises CLIP-170 and dynactin at plus-ends, implying CLIP2 competes for tip occupancy and influences dynein control.

    Evidence Heterozygous Cyln2 knockout mouse with immunofluorescence quantification of tip proteins and behavioral/neuroanatomical phenotyping

    PMID:12195424

    Open questions at the time
    • Direct competition mechanism not biochemically reconstituted
    • Causal link between tip redistribution and behavioral phenotype not established
  5. 2025 Medium

    Extended CLIP2 function beyond neurons by linking it to membrane-protein trafficking, identifying AQP5 as an interactor required for its plasma-membrane delivery.

    Evidence Co-IP/mass spectrometry, proximity ligation, microscale thermophoresis, structural modeling, and CRISPR/Cas9 knockout trafficking assay in salivary gland cells

    PMID:41184862

    Open questions at the time
    • Whether trafficking defect is microtubule-dependent not directly tested
    • Structural model of AQP5-CLIP2 interaction not experimentally resolved
  6. 2025 Medium

    Implicated CLIP2 in cell maturation and dendrite morphogenesis outside neurons, showing it is needed for osteocyte differentiation and process formation.

    Evidence Genome-wide CRISPRi screen with CRISPRi knockdown in Ocy454 cells, flow cytometry for surface CD61, qPCR for osteocyte markers, and dendrite morphology imaging

    PMID:41279202 PMID:42055327

    Open questions at the time
    • Direct molecular link between CLIP2 and CD61/osteocyte gene regulation not defined
    • Microtubule-dependence of the osteocyte phenotype inferred rather than directly demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CLIP2's plus-end tracking is mechanistically converted into specific cargo and organelle outcomes (DLBs, AQP5, osteocyte dendrites) across cell types remains unresolved.
  • No unified model linking tip competition with dynein/dynactin to cargo delivery
  • Cell-type-specific partners directing distinct functions not catalogued

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3
Localization
GO:0005856 cytoskeleton 3 GO:0005815 microtubule organizing center 2
Partners
AQP5CLASP1CLIP1DCTN1

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 CLIP-115 (CLIP2) was identified as a brain-specific cytoplasmic linker protein enriched in dendritic lamellar bodies (DLBs); local microtubule depolymerization caused a temporary reduction of DLBs, suggesting CLIP-115 mediates the localization of this organelle by linking it to microtubules. cDNA characterization, microtubule-binding assays, immunolocalization in neurons, microtubule depolymerization experiments Neuron Medium 9427243
2000 Efficient microtubule binding by CLIP-115 requires not only the conserved MTB domains but also the flanking basic, serine-rich regions, and is sensitive to phosphorylation. CLIP-115 forms homodimers linked by disulfide bridges in vitro, and Cysteine-391 controls the microtubule-bundling capacity of certain CLIP-115 mutants. In transfected COS-1 cells, CLIP-115 initially accumulates at distal microtubule ends, coinciding with CLIP-170. In vitro microtubule-binding assays, mutagenesis of MTB domains and cysteine residues, transfection of COS-1 cells with GFP-tagged constructs, phosphorylation-sensitivity assays Journal of cell science High 10825300
2001 CLIP-115 and CLIP-170 associate with CLASPs (CLIP-associating proteins); CLASPs bind CLIPs and microtubules, colocalize with CLIPs at microtubule distal ends, and have microtubule-stabilizing effects. After serum induction, CLASPs redistribute to distal microtubule segments at the leading edge in a PI3-kinase- and GSK-3β-dependent manner. Co-immunoprecipitation, colocalization by fluorescence microscopy, antibody injection, transfection-based stabilization assays Cell High 11290329
2002 Haploinsufficiency of Cyln2 (CLIP-115/CLIP2) in mice leads to increased levels of CLIP-170 and dynactin at the tips of growing microtubules, indicating that CLIP-115 normally competes with or limits the accumulation of these proteins at microtubule ends, potentially affecting dynein motor regulation. Gene-targeting (heterozygous knockout mouse), immunofluorescence quantification of microtubule-tip proteins (CLIP-170, dynactin), behavioral and neuroanatomical phenotyping Nature genetics High 12195424
2025 CLIP2 was identified as a novel interacting partner of Aquaporin 5 (AQP5); structural modeling showed the AQP5-CLIP2 interaction resembles other CAP-Gly domain complexes. CRISPR/Cas9-mediated knockout of CLIP2 in salivary gland cells significantly impaired AQP5 trafficking to the plasma membrane. Co-immunoprecipitation followed by mass spectrometry, proximity ligation assay, microscale thermophoresis, in-silico structural modeling, CRISPR/Cas9 knockout, immunofluorescence trafficking assay Cell communication and signaling : CCS Medium 41184862
2025 CRISPRi-mediated inhibition of Clip2 in osteocyte-like cells (Ocy454) decreased surface CD61 (integrin β3) expression, reduced osteocyte-specific gene expression (Dmp1, Sost), and impaired dendrite morphology, establishing a role for CLIP2 in osteocyte maturation and dendrite development via the microtubule cytoskeleton. Genome-wide CRISPRi screen, flow cytometry (surface CD61 quantification), qPCR for osteocyte marker genes, in vitro dendrite morphology imaging The Journal of biological chemistry Medium 41279202 42055327

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Clasps are CLIP-115 and -170 associating proteins involved in the regional regulation of microtubule dynamics in motile fibroblasts. Cell 401 11290329
2002 Targeted mutation of Cyln2 in the Williams syndrome critical region links CLIP-115 haploinsufficiency to neurodevelopmental abnormalities in mice. Nature genetics 140 12195424
2000 Functional analysis of CLIP-115 and its binding to microtubules. Journal of cell science 102 10825300
1997 CLIP-115, a novel brain-specific cytoplasmic linker protein, mediates the localization of dendritic lamellar bodies. Neuron 93 9427243
2004 LIMK1 and CLIP-115: linking cytoskeletal defects to Williams syndrome. BioEssays : news and reviews in molecular, cellular and developmental biology 67 14745832
2014 CLIP2 as radiation biomarker in papillary thyroid carcinoma. Oncogene 41 25284583
2012 The contribution of CLIP2 haploinsufficiency to the clinical manifestations of the Williams-Beuren syndrome. American journal of human genetics 35 22608712
2015 Dose-dependent expression of CLIP2 in post-Chernobyl papillary thyroid carcinomas. Carcinogenesis 26 25957251
2023 Serpin-1a and serpin-6 regulate the Toll pathway immune homeostasis by synergistically inhibiting the Spätzle-processing enzyme CLIP2 in silkworm, Bombyx mori. PLoS pathogens 20 37851691
2021 Circ_CLIP2 promotes glioma progression through targeting the miR-195-5p/HMGB3 axis. Journal of neuro-oncology 16 34357490
2020 Polypoid Atypical Spitz Tumor With a Fibrosclerotic Stroma, CLIP2-BRAF Fusion, and Homozygous Loss of 9p21. The American Journal of dermatopathology 16 31449064
2020 A glioneuronal tumor with CLIP2-MET fusion. NPJ genomic medicine 8 32550005
2020 Inflammatory myofibroblastic tumor arising from soft tissues of extremities harboring a novel CLIP2-ALK fusion. Pathology international 3 32716129
2020 Transcriptome network of the papillary thyroid carcinoma radiation marker CLIP2. Radiation oncology (London, England) 3 32727620
2024 Clinical, pathologic, and genomic characteristics of two pediatric glioneuronal tumors with a CLIP2::MET fusion. Acta neuropathologica communications 2 38650040
2023 Knockdown of circ_CLIP2 regulates the proliferation, metastasis and apoptosis of glioma cells through miR-641/EPHA3/STAT3 axis. Journal of neurogenetics 2 37129498
2025 Genome-wide CRISPR interference screen identifies Clip2 as a novel regulator of osteocyte maturation and morphology. bioRxiv : the preprint server for biology 1 41279202
2026 A CLIP on the Ear: Spitz Melanocytoma Harbouring a CLIP2-BRAF Gene Fusion. Case reports in dermatological medicine 0 41608505
2026 Genome-wide CRISPR interference screen identifies Clip2 as a novel regulator of osteocyte maturation and morphology. The Journal of biological chemistry 0 42055327
2025 CLIP2: a novel functional player in AQP5 trafficking dynamics and implications for Sjögren's disease. Cell communication and signaling : CCS 0 41184862

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