Affinage

LIN7A

Protein lin-7 homolog A · UniProt O14910

Length
233 aa
Mass
26.0 kDa
Annotated
2026-06-10
12 papers in source corpus 7 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LIN7A (MALS-1/Veli-1) is a PDZ-domain scaffold protein that assembles membrane-associated multiprotein complexes at neuronal synapses and epithelial cell-cell contacts (PMID:11311936, PMID:27793718). It binds the MAGUK family member VAM-1 directly through a conserved domain (PMID:11311936), and in brain synaptosomes it captures the α2/β1 form of nitric oxide-sensitive guanylyl cyclase, directing this heterodimer (but not the α1/β1 form) to calcium-insensitive cell-cell contacts via the α2 subunit PDZ-binding motif, an event also requiring MPP3 (PMID:27793718). In neurons, LIN7A is enriched in the presynaptic fraction, and its transcription is controlled by the Ca²⁺/calcineurin pathway downstream of voltage- and ligand-operated Ca²⁺ channels (PMID:12393911, PMID:24658322). Functionally, LIN7A is required for proper cortical neuronal migration and interhemispheric axon development in vivo (PMID:24658322), and it maintains epithelial apico-basal polarity as a Crumbs-complex component whose dysregulation drives polarity inversion, hyperproliferation, and invasion (PMID:26887652).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2001 Medium

    Establishing that LIN7A physically engages a MAGUK partner defined it as a scaffold that nucleates multiprotein assemblies rather than acting alone.

    Evidence GST pull-down and blot overlay assays with VAM-1 in heterologous transfection

    PMID:11311936

    Open questions at the time
    • Functional consequence of the VAM-1/LIN7A complex not tested
    • Endogenous interaction in native tissue not shown
    • Domain on LIN7A mediating binding not mapped
  2. 2002 Medium

    Identifying Ca²⁺/calcineurin-dependent transcriptional control answered how LIN7A levels are set in neurons in response to activity.

    Evidence Pharmacological Ca²⁺-channel and calcineurin perturbation in cerebellar granule cells with reporter and mRNA-stability assays

    PMID:12393911

    Open questions at the time
    • Transcription factors linking calcineurin to the LIN7A promoter not identified
    • Physiological stimulus driving this regulation in vivo unresolved
  3. 2014 Medium

    In vivo loss-of-function established that LIN7A is required for neuronal migration and axon development, moving it from a binding partner to a developmental effector.

    Evidence Synaptosome fractionation plus in utero electroporation RNAi in mouse cortex with histological migration/axon readouts

    PMID:24658322

    Open questions at the time
    • Molecular partners mediating the migration phenotype not defined
    • RNAi specificity not confirmed by rescue
    • Mechanism connecting presynaptic localization to migration unclear
  4. 2016 Medium

    Mapping the α2/β1 guanylyl cyclase interaction to the α2 PDZ motif and requiring MPP3 demonstrated how LIN7A targets specific signaling enzymes to cell-cell contacts.

    Evidence Co-precipitation from brain synaptosomes plus HEK293 localization and truncation mapping

    PMID:27793718

    Open questions at the time
    • Functional output of guanylyl cyclase localization at contacts not measured
    • Architecture of the LIN7A/MPP3/cyclase complex unresolved
  5. 2016 Medium

    Gain-of-function in breast epithelium tied LIN7A to apico-basal polarity maintenance and the Crumbs complex, explaining how its dysregulation drives invasive carcinoma.

    Evidence Overexpression with 3D lumen, invasion and proliferation assays plus clinical expression profiling

    PMID:26887652

    Open questions at the time
    • Direct LIN7A interactions within the Crumbs complex not biochemically mapped
    • Whether the phenotype reflects dosage versus mislocalization unresolved
  6. 2018 Low

    Placing LIN7A downstream of miR-501-3p connected its expression level to proliferation, migration and EMT control in liver cancer cells.

    Evidence Reporter assay, gain/loss-of-function and rescue in HCC cell lines

    PMID:29749382

    Open questions at the time
    • Direct targeting rests on a single reporter approach
    • Not independently confirmed
    • Mechanism by which LIN7A acts in this context not defined
  7. 2025 Low

    Knockdown in glioblastoma linked LIN7A to suppression of invasion via restraint of the β-catenin pathway, implicating it as an invasion brake in tumor cells.

    Evidence Lentiviral RNAi in U87 cells with invasion assays, zymography, β-catenin imaging and orthotopic xenografts

    PMID:40021783

    Open questions at the time
    • Cytoplasmic β-catenin increase reported as not statistically significant
    • Direct molecular link between LIN7A and β-catenin not established
    • Single lab, single study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the same scaffold reconciles its presynaptic/migration role with its epithelial polarity and tumor-invasion functions remains unresolved.
  • No unified structural model of LIN7A complexes across tissues
  • Direct partners in the polarity/Crumbs and β-catenin contexts not biochemically mapped
  • Whether neuronal and epithelial phenotypes share a common molecular mechanism unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2
Localization
GO:0005634 nucleus 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 1
Partners
MPP3VAM-1
Complex memberships
Crumbs polarity complex

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 VAM-1, a MAGUK family member, binds directly to human Veli-1 (LIN7A) through a conserved domain, as demonstrated by GST pull-down experiments and blot overlay assays. This interaction suggests LIN7A participates in assembly of multiprotein complexes in neuronal and epithelial cells. GST pull-down, blot overlay assay, heterologous transfection Biochimica et biophysica acta Medium 11311936
2002 MALS-1 (LIN7A) expression in cerebellar granule cells is regulated at the transcriptional level by the Ca²⁺/calcineurin pathway activated through voltage- or ligand-operated Ca²⁺ channels; this regulation does not require de novo protein synthesis and does not occur at the level of mRNA stability. Pharmacological activation/inhibition of Ca²⁺ channels and calcineurin in cultured cerebellar granule cells; transcriptional reporter and mRNA stability assays The Journal of biological chemistry Medium 12393911
2014 LIN7A protein is enriched in the presynaptic fraction of mouse brain (biochemical fractionation). RNAi-mediated knockdown of Lin7A in mouse cortex via in utero electroporation delays neuronal migration (neurons retained in lower cortical plate and intermediate zone at P2) and disrupts interhemispheric axon development. Biochemical fractionation of mouse brain synaptosomes; in utero electroporation-based RNAi knockdown with histological readout of neuronal migration and axon development PloS one Medium 24658322
2016 The α2/β1 form of nitric oxide-sensitive guanylyl cyclase interacts with Lin7a in mouse brain synaptosomes (co-precipitation). In HEK293 cells, the α2/β1 heterodimer (but not the α1/β1 form) is directed to calcium-insensitive cell-cell contacts via the PDZ-binding motif of the α2 subunit; this localization requires heterodimerization with β1 and is mediated through Lin7a and MPP3. Co-precipitation from mouse brain synaptosomes; overexpression and localization analysis in HEK293 cells; truncation constructs to map the PDZ-binding motif Biochemical pharmacology Medium 27793718
2016 LIN7A overexpression in breast epithelial cells causes hyperproliferation, invasion, and complete absence of lumen formation, indicating a direct role in apico-basal polarity maintenance; LIN7A was identified as a Crumbs-complex polarity gene whose dysregulation drives polarity inversion in invasive micropapillary carcinoma. Gain-of-function overexpression in breast epithelial cells with 3D lumen formation assay, invasion assay, and proliferation readout; gene expression profiling of clinical samples Breast cancer research : BCR Medium 26887652
2018 LIN7A is a direct target of miR-501-3p in hepatocellular carcinoma cells; re-expression of LIN7A rescues the suppressive effects of miR-501-3p overexpression on cell proliferation, migration, invasion, and EMT, placing LIN7A downstream of miR-501-3p in mediating these processes. Luciferase reporter assay (implied by 'directly targeted'), gain-of-function and loss-of-function in HCC cell lines, rescue experiments Cell death & disease Low 29749382
2025 Silencing of LIN7A in U87 glioblastoma cells increases invasiveness and MMP-2/MMP-9 protease activity, and leads to nuclear accumulation of β-catenin with increased transcriptional activity of β-catenin target genes, suggesting LIN7A suppresses invasion partly by restraining the β-catenin pathway. Lentiviral RNAi knockdown in U87 cells; real-time cell invasion analysis; zymography for MMP-2/MMP-9; Western blot and immunofluorescence for β-catenin localization; orthotopic xenograft model Scientific reports Low 40021783

Source papers

Stage 0 corpus · 12 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Long noncoding RNA CASC9 promotes LIN7A expression via miR-758-3p to facilitate the malignancy of ovarian cancer. Journal of cellular physiology 55 30537154
2018 microRNA-501-3p suppresses metastasis and progression of hepatocellular carcinoma through targeting LIN7A. Cell death & disease 42 29749382
2001 VAM-1: a new member of the MAGUK family binds to human Veli-1 through a conserved domain. Biochimica et biophysica acta 37 11311936
2016 LIN7A is a major determinant of cell-polarity defects in breast carcinomas. Breast cancer research : BCR 23 26887652
2014 LIN7A depletion disrupts cerebral cortex development, contributing to intellectual disability in 12q21-deletion syndrome. PloS one 23 24658322
2023 DNA methylation landscape reveals LIN7A as a decitabine-responsive marker in patients with t(8;21) acute myeloid leukemia. Clinical epigenetics 9 36864492
2016 Heterodimerization with the β1 subunit directs the α2 subunit of nitric oxide-sensitive guanylyl cyclase to calcium-insensitive cell-cell contacts in HEK293 cells: Interaction with Lin7a. Biochemical pharmacology 7 27793718
2024 Ortholog of autism candidate gene RBM27 regulates mitoribosomal assembly factor MALS-1 to protect against mitochondrial dysfunction and axon degeneration during neurodevelopment. PLoS biology 4 39480871
2025 Impact of LIN7A silencing on U87 cell invasion and its clinical significance in glioblastoma. Scientific reports 2 40021783
2024 Identification and validation of miR-29b-3p and LIN7A as important diagnostic markers for bone non-union by WGCNA. Journal of cellular and molecular medicine 2 38957040
2002 The expression of the PDZ protein MALS-1/velis is regulated by calcium and calcineurin in cerebellar granule cells. The Journal of biological chemistry 2 12393911
2024 Autism candidate gene rbm-26 (RBM26/27) regulates MALS-1 to protect against mitochondrial dysfunction and axon degeneration during neurodevelopment. bioRxiv : the preprint server for biology 0 37873356

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