LIMD1

id: Q9UGP4
gene_symbol: LIMD1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'LIMD1 encodes a multi-domain LIM zinc-binding adaptor/scaffold protein that
  assembles regulatory complexes at adherens junctions, P-bodies, cytoplasmic HIF degradation
  machinery, and the nucleus. Its best-supported functions include mechanosensitive Hippo/LATS-YAP
  regulation, miRISC-mediated translational repression, PHD2-VHL-dependent HIF-alpha degradation,
  and pRB/E2F transcriptional corepression.'
existing_annotations:
  - term:
      id: GO:0003714
      label: transcription corepressor activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Transcription corepressor activity is supported by pRB/E2F repression and
        related corepressor interactions.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 binds **pRB** and represses **E2F-driven
            transcription**, coupling LIMD1 to cell-cycle control.'
  - term:
      id: GO:0005912
      label: adherens junction
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: adherens junction localization is supported for LIMD1 scaffold function
        across junctional, cytoplasmic/P-body, and nuclear compartments.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a **mechanosensitive scaffold**
            controlling the **subcellular localization** (and functional availability) of
            **LATS1/2** kinases at adherens junctions, thereby influencing YAP/TAZ phosphorylation
            state and nuclear localization.'
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Localization:** LIMD1 colocalizes with GW182/TNRC6 and other
            miRISC components in **P-bodies**.'
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Cytoplasm. Nucleus. Cytoplasm, P-body. Cell junction,
            adherens junction. Cell junction, focal adhesion.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: nucleus localization is supported for LIMD1 scaffold function across
        junctional, cytoplasmic/P-body, and nuclear compartments.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a **mechanosensitive scaffold**
            controlling the **subcellular localization** (and functional availability) of
            **LATS1/2** kinases at adherens junctions, thereby influencing YAP/TAZ phosphorylation
            state and nuclear localization.'
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Localization:** LIMD1 colocalizes with GW182/TNRC6 and other
            miRISC components in **P-bodies**.'
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Cytoplasm. Nucleus. Cytoplasm, P-body. Cell junction,
            adherens junction. Cell junction, focal adhesion.
  - term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Regulation of DNA-templated transcription is correct but too broad; LIMD1
        evidence supports negative transcriptional regulation/corepression.
      action: MODIFY
      reason: Use the directionally specific transcriptional repression term.
      proposed_replacement_terms:
        - id: GO:0045892
          label: negative regulation of DNA-templated transcription
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 binds **pRB** and represses **E2F-driven
            transcription**, coupling LIMD1 to cell-cycle control.'
  - term:
      id: GO:0007010
      label: cytoskeleton organization
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Cytoskeleton organization is a broad downstream description; the
        mechanistic evidence is more specifically adherens-junction/F-actin tension
        sensing for Hippo signaling.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a **mechanosensitive scaffold**
            controlling the **subcellular localization** (and functional availability) of
            **LATS1/2** kinases at adherens junctions, thereby influencing YAP/TAZ phosphorylation
            state and nuclear localization.'
  - term:
      id: GO:0035331
      label: negative regulation of hippo signaling
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Negative regulation of Hippo signaling is supported by LIMD1-mediated
        LATS1/2 recruitment/localization at adherens junctions and consequent YAP/TAZ
        regulation.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a **mechanosensitive scaffold**
            controlling the **subcellular localization** (and functional availability) of
            **LATS1/2** kinases at adherens junctions, thereby influencing YAP/TAZ phosphorylation
            state and nuclear localization.'
  - term:
      id: GO:0000932
      label: P-body
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: P-body localization is supported for LIMD1 scaffold function across
        junctional, cytoplasmic/P-body, and nuclear compartments.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a **mechanosensitive scaffold**
            controlling the **subcellular localization** (and functional availability) of
            **LATS1/2** kinases at adherens junctions, thereby influencing YAP/TAZ phosphorylation
            state and nuclear localization.'
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Localization:** LIMD1 colocalizes with GW182/TNRC6 and other
            miRISC components in **P-bodies**.'
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Cytoplasm. Nucleus. Cytoplasm, P-body. Cell junction,
            adherens junction. Cell junction, focal adhesion.
  - term:
      id: GO:0001666
      label: response to hypoxia
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Response to hypoxia is supported by LIMD1 induction and by LIMD1
        scaffolding of PHD2/VHL complexes for HIF-alpha degradation.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a scaffold for the oxygen-sensing
            degradation machinery by bridging **PHD2** and **VHL** to promote efficient **HIF‑α
            degradation**, and is itself **HIF-1 inducible**, creating a negative-feedback
            loop limiting pro-tumorigenic hypoxia signaling.'
  - term:
      id: GO:0005667
      label: transcription regulator complex
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Transcription regulator complex is retained as a non-core complex context
        for pRB/E2F and SNAI-associated repression, but the more informative annotation
        is transcription corepressor activity.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 binds **pRB** and represses **E2F-driven
            transcription**, coupling LIMD1 to cell-cycle control.'
  - term:
      id: GO:0000932
      label: P-body
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: P-body localization is supported for LIMD1 scaffold function across
        junctional, cytoplasmic/P-body, and nuclear compartments.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a **mechanosensitive scaffold**
            controlling the **subcellular localization** (and functional availability) of
            **LATS1/2** kinases at adherens junctions, thereby influencing YAP/TAZ phosphorylation
            state and nuclear localization.'
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Localization:** LIMD1 colocalizes with GW182/TNRC6 and other
            miRISC components in **P-bodies**.'
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Cytoplasm. Nucleus. Cytoplasm, P-body. Cell junction,
            adherens junction. Cell junction, focal adhesion.
  - term:
      id: GO:0001666
      label: response to hypoxia
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: Response to hypoxia is supported by LIMD1 induction and by LIMD1
        scaffolding of PHD2/VHL complexes for HIF-alpha degradation.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a scaffold for the oxygen-sensing
            degradation machinery by bridging **PHD2** and **VHL** to promote efficient **HIF‑α
            degradation**, and is itself **HIF-1 inducible**, creating a negative-feedback
            loop limiting pro-tumorigenic hypoxia signaling.'
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: nucleus localization is supported for LIMD1 scaffold function across
        junctional, cytoplasmic/P-body, and nuclear compartments.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a **mechanosensitive scaffold**
            controlling the **subcellular localization** (and functional availability) of
            **LATS1/2** kinases at adherens junctions, thereby influencing YAP/TAZ phosphorylation
            state and nuclear localization.'
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Localization:** LIMD1 colocalizes with GW182/TNRC6 and other
            miRISC components in **P-bodies**.'
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Cytoplasm. Nucleus. Cytoplasm, P-body. Cell junction,
            adherens junction. Cell junction, focal adhesion.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: cytoplasm localization is supported for LIMD1 scaffold function across
        junctional, cytoplasmic/P-body, and nuclear compartments.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a **mechanosensitive scaffold**
            controlling the **subcellular localization** (and functional availability) of
            **LATS1/2** kinases at adherens junctions, thereby influencing YAP/TAZ phosphorylation
            state and nuclear localization.'
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Localization:** LIMD1 colocalizes with GW182/TNRC6 and other
            miRISC components in **P-bodies**.'
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Cytoplasm. Nucleus. Cytoplasm, P-body. Cell junction,
            adherens junction. Cell junction, focal adhesion.
  - term:
      id: GO:0005912
      label: adherens junction
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: adherens junction localization is supported for LIMD1 scaffold function
        across junctional, cytoplasmic/P-body, and nuclear compartments.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a **mechanosensitive scaffold**
            controlling the **subcellular localization** (and functional availability) of
            **LATS1/2** kinases at adherens junctions, thereby influencing YAP/TAZ phosphorylation
            state and nuclear localization.'
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Localization:** LIMD1 colocalizes with GW182/TNRC6 and other
            miRISC components in **P-bodies**.'
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Cytoplasm. Nucleus. Cytoplasm, P-body. Cell junction,
            adherens junction. Cell junction, focal adhesion.
  - term:
      id: GO:0005925
      label: focal adhesion
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: Focal adhesion localization is supported by UniProt/subcellular evidence,
        but the strongest mechanistic Hippo evidence centers on adherens junctions under
        tension.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Cytoplasm. Nucleus. Cytoplasm, P-body. Cell junction,
            adherens junction. Cell junction, focal adhesion.
  - term:
      id: GO:0031047
      label: regulatory ncRNA-mediated gene silencing
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: Regulatory ncRNA-mediated gene silencing is supported but should be
        represented more specifically as miRNA-mediated post-transcriptional silencing.
      action: MODIFY
      reason: The evidence is specifically miRISC/miRNA-mediated silencing.
      proposed_replacement_terms:
        - id: GO:0035195
          label: miRNA-mediated post-transcriptional gene silencing
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 is a **miRISC adaptor/scaffold** that
            promotes productive AGO-dependent silencing by coupling Argonaute to GW182/TNRC6
            and downstream effector complexes, and by linking silencing to translation initiation
            control at the 5′ cap.'
  - term:
      id: GO:0035278
      label: miRNA-mediated gene silencing by inhibition of translation
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: miRNA-mediated gene silencing by inhibition of translation is supported
        by LIMD1 function as a miRISC/P-body scaffold linking AGO proteins, GW182/TNRC6,
        DDX6, and cap-associated translation repression.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 is a **miRISC adaptor/scaffold** that
            promotes productive AGO-dependent silencing by coupling Argonaute to GW182/TNRC6
            and downstream effector complexes, and by linking silencing to translation initiation
            control at the 5′ cap.'
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Localization:** LIMD1 colocalizes with GW182/TNRC6 and other
            miRISC components in **P-bodies**.'
  - term:
      id: GO:0035331
      label: negative regulation of hippo signaling
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: Negative regulation of Hippo signaling is supported by LIMD1-mediated
        LATS1/2 recruitment/localization at adherens junctions and consequent YAP/TAZ
        regulation.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a **mechanosensitive scaffold**
            controlling the **subcellular localization** (and functional availability) of
            **LATS1/2** kinases at adherens junctions, thereby influencing YAP/TAZ phosphorylation
            state and nuclear localization.'
  - term:
      id: GO:0046872
      label: metal ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: The metal-binding evidence is specifically zinc binding by LIM domains,
        so this broad metal ion binding term should be replaced by zinc ion binding.
      action: MODIFY
      reason: LIM domains are zinc-binding modules; use the specific zinc ion binding
        term.
      proposed_replacement_terms:
        - id: GO:0008270
          label: zinc ion binding
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**LIMD1 is a multi-domain adaptor/scaffold protein**, not an enzyme.
            Its biological roles derive from assembling protein complexes and controlling
            where/when those complexes form—particularly at **cell junctions**, **P-bodies**,
            and in **oxygen-sensing (HIF) degradation complexes**. LIM domains are zinc-binding
            modules (~55–65 aa) that act as protein-interaction interfaces; LIMD1 contains
            **three tandem LIM domains** at its C‑terminus.'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22190034
    review:
      summary: Generic protein binding is over-broad for LIMD1. Specific
        adaptor/scaffold roles with AGO/TNRC6/DDX6, LATS1/2, PHD/VHL, and pRB are more
        informative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Avoid generic protein binding when specific complex/adaptor mechanisms are
        known.
      supported_by:
        - reference_id: PMID:22190034
          supporting_text: Global landscape of HIV-human protein complexes.
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: LIMD1 (Q9UGP4) is best understood as a **multi-compartment
            scaffold** that (i) couples **mechanical tension** at adherens junctions to
            **Hippo pathway kinase (LATS) localization**, (ii) enables efficient
            **miRNA-mediated translational repression** by scaffolding Argonaute and
            GW182/TNRC6 and engaging the cap complex, (iii) promotes **HIF‑α
            degradation** by scaffolding PHD2–VHL complexes and participating in a
            HIF-driven negative feedback loop, and (iv) exerts tumor suppressor
            functions via **pRB/E2F repression** and via maintaining homeostatic control
            over hypoxia and mechanotransduction outputs.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28683311
    review:
      summary: Generic protein binding is over-broad for LIMD1. Specific
        adaptor/scaffold roles with AGO/TNRC6/DDX6, LATS1/2, PHD/VHL, and pRB are more
        informative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Avoid generic protein binding when specific complex/adaptor mechanisms are
        known.
      supported_by:
        - reference_id: PMID:28683311
          supporting_text: Argonaute Utilization for miRNA Silencing Is Determined by
            Phosphorylation-Dependent Recruitment of LIM-Domain-Containing Proteins.
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: LIMD1 (Q9UGP4) is best understood as a **multi-compartment
            scaffold** that (i) couples **mechanical tension** at adherens junctions to
            **Hippo pathway kinase (LATS) localization**, (ii) enables efficient
            **miRNA-mediated translational repression** by scaffolding Argonaute and
            GW182/TNRC6 and engaging the cap complex, (iii) promotes **HIF‑α
            degradation** by scaffolding PHD2–VHL complexes and participating in a
            HIF-driven negative feedback loop, and (iv) exerts tumor suppressor
            functions via **pRB/E2F repression** and via maintaining homeostatic control
            over hypoxia and mechanotransduction outputs.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: Generic protein binding is over-broad for LIMD1. Specific
        adaptor/scaffold roles with AGO/TNRC6/DDX6, LATS1/2, PHD/VHL, and pRB are more
        informative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Avoid generic protein binding when specific complex/adaptor mechanisms are
        known.
      supported_by:
        - reference_id: PMID:33961781
          supporting_text: 2021 May 6. Dual proteome-scale networks reveal cell-specific
            remodeling of the human interactome.
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: LIMD1 (Q9UGP4) is best understood as a **multi-compartment
            scaffold** that (i) couples **mechanical tension** at adherens junctions to
            **Hippo pathway kinase (LATS) localization**, (ii) enables efficient
            **miRNA-mediated translational repression** by scaffolding Argonaute and
            GW182/TNRC6 and engaging the cap complex, (iii) promotes **HIF‑α
            degradation** by scaffolding PHD2–VHL complexes and participating in a
            HIF-driven negative feedback loop, and (iv) exerts tumor suppressor
            functions via **pRB/E2F repression** and via maintaining homeostatic control
            over hypoxia and mechanotransduction outputs.
  - term:
      id: GO:0002076
      label: osteoblast development
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: osteoblast development is retained as a non-core osteoblast/Wnt-related
        role supported by UniProt-curated literature, but it is peripheral to the main
        LIMD1 scaffold functions synthesized here.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Regulates osteoblast development, function, differentiation
            and stress osteoclastogenesis. Enhances the ability of TRAF6 to activate
            adapter protein complex 1 (AP-1) and negatively regulates the canonical Wnt
            receptor signaling pathway in osteoblasts.
  - term:
      id: GO:0003714
      label: transcription corepressor activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Transcription corepressor activity is supported by pRB/E2F repression and
        related corepressor interactions.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 binds **pRB** and represses **E2F-driven
            transcription**, coupling LIMD1 to cell-cycle control.'
  - term:
      id: GO:0045668
      label: negative regulation of osteoblast differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: negative regulation of osteoblast differentiation is retained as a
        non-core osteoblast/Wnt-related role supported by UniProt-curated literature,
        but it is peripheral to the main LIMD1 scaffold functions synthesized here.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Regulates osteoblast development, function, differentiation
            and stress osteoclastogenesis. Enhances the ability of TRAF6 to activate
            adapter protein complex 1 (AP-1) and negatively regulates the canonical Wnt
            receptor signaling pathway in osteoblasts.
  - term:
      id: GO:0090090
      label: negative regulation of canonical Wnt signaling pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: negative regulation of canonical Wnt signaling pathway is retained as a
        non-core osteoblast/Wnt-related role supported by UniProt-curated literature,
        but it is peripheral to the main LIMD1 scaffold functions synthesized here.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Regulates osteoblast development, function, differentiation
            and stress osteoclastogenesis. Enhances the ability of TRAF6 to activate
            adapter protein complex 1 (AP-1) and negatively regulates the canonical Wnt
            receptor signaling pathway in osteoblasts.
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: nucleoplasm localization is supported for LIMD1 scaffold function across
        junctional, cytoplasmic/P-body, and nuclear compartments.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a **mechanosensitive scaffold**
            controlling the **subcellular localization** (and functional availability) of
            **LATS1/2** kinases at adherens junctions, thereby influencing YAP/TAZ phosphorylation
            state and nuclear localization.'
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Localization:** LIMD1 colocalizes with GW182/TNRC6 and other
            miRISC components in **P-bodies**.'
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Cytoplasm. Nucleus. Cytoplasm, P-body. Cell junction,
            adherens junction. Cell junction, focal adhesion.
  - term:
      id: GO:0005925
      label: focal adhesion
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: Focal adhesion localization is supported by UniProt/subcellular evidence,
        but the strongest mechanistic Hippo evidence centers on adherens junctions under
        tension.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Cytoplasm. Nucleus. Cytoplasm, P-body. Cell junction,
            adherens junction. Cell junction, focal adhesion.
  - term:
      id: GO:0035278
      label: miRNA-mediated gene silencing by inhibition of translation
    evidence_type: IMP
    original_reference_id: PMID:20616046
    review:
      summary: miRNA-mediated gene silencing by inhibition of translation is supported
        by LIMD1 function as a miRISC/P-body scaffold linking AGO proteins, GW182/TNRC6,
        DDX6, and cap-associated translation repression.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:20616046
          supporting_text: LIM-domain proteins, LIMD1, Ajuba, and WTIP are required for
            microRNA-mediated gene silencing.
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 is a **miRISC adaptor/scaffold** that
            promotes productive AGO-dependent silencing by coupling Argonaute to GW182/TNRC6
            and downstream effector complexes, and by linking silencing to translation initiation
            control at the 5′ cap.'
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Localization:** LIMD1 colocalizes with GW182/TNRC6 and other
            miRISC components in **P-bodies**.'
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1234159
    review:
      summary: cytosol localization is supported for LIMD1 scaffold function across
        junctional, cytoplasmic/P-body, and nuclear compartments.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a **mechanosensitive scaffold**
            controlling the **subcellular localization** (and functional availability) of
            **LATS1/2** kinases at adherens junctions, thereby influencing YAP/TAZ phosphorylation
            state and nuclear localization.'
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Localization:** LIMD1 colocalizes with GW182/TNRC6 and other
            miRISC components in **P-bodies**.'
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Cytoplasm. Nucleus. Cytoplasm, P-body. Cell junction,
            adherens junction. Cell junction, focal adhesion.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1234163
    review:
      summary: cytosol localization is supported for LIMD1 scaffold function across
        junctional, cytoplasmic/P-body, and nuclear compartments.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a **mechanosensitive scaffold**
            controlling the **subcellular localization** (and functional availability) of
            **LATS1/2** kinases at adherens junctions, thereby influencing YAP/TAZ phosphorylation
            state and nuclear localization.'
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Localization:** LIMD1 colocalizes with GW182/TNRC6 and other
            miRISC components in **P-bodies**.'
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Cytoplasm. Nucleus. Cytoplasm, P-body. Cell junction,
            adherens junction. Cell junction, focal adhesion.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1234173
    review:
      summary: cytosol localization is supported for LIMD1 scaffold function across
        junctional, cytoplasmic/P-body, and nuclear compartments.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a **mechanosensitive scaffold**
            controlling the **subcellular localization** (and functional availability) of
            **LATS1/2** kinases at adherens junctions, thereby influencing YAP/TAZ phosphorylation
            state and nuclear localization.'
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Localization:** LIMD1 colocalizes with GW182/TNRC6 and other
            miRISC components in **P-bodies**.'
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Cytoplasm. Nucleus. Cytoplasm, P-body. Cell junction,
            adherens junction. Cell junction, focal adhesion.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1234177
    review:
      summary: cytosol localization is supported for LIMD1 scaffold function across
        junctional, cytoplasmic/P-body, and nuclear compartments.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a **mechanosensitive scaffold**
            controlling the **subcellular localization** (and functional availability) of
            **LATS1/2** kinases at adherens junctions, thereby influencing YAP/TAZ phosphorylation
            state and nuclear localization.'
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Localization:** LIMD1 colocalizes with GW182/TNRC6 and other
            miRISC components in **P-bodies**.'
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Cytoplasm. Nucleus. Cytoplasm, P-body. Cell junction,
            adherens junction. Cell junction, focal adhesion.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-1234183
    review:
      summary: cytosol localization is supported for LIMD1 scaffold function across
        junctional, cytoplasmic/P-body, and nuclear compartments.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a **mechanosensitive scaffold**
            controlling the **subcellular localization** (and functional availability) of
            **LATS1/2** kinases at adherens junctions, thereby influencing YAP/TAZ phosphorylation
            state and nuclear localization.'
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Localization:** LIMD1 colocalizes with GW182/TNRC6 and other
            miRISC components in **P-bodies**.'
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Cytoplasm. Nucleus. Cytoplasm, P-body. Cell junction,
            adherens junction. Cell junction, focal adhesion.
  - term:
      id: GO:0003714
      label: transcription corepressor activity
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: Transcription corepressor activity is supported by pRB/E2F repression and
        related corepressor interactions.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 binds **pRB** and represses **E2F-driven
            transcription**, coupling LIMD1 to cell-cycle control.'
  - term:
      id: GO:0002076
      label: osteoblast development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: osteoblast development is retained as a non-core osteoblast/Wnt-related
        role supported by UniProt-curated literature, but it is peripheral to the main
        LIMD1 scaffold functions synthesized here.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Regulates osteoblast development, function, differentiation
            and stress osteoclastogenesis. Enhances the ability of TRAF6 to activate
            adapter protein complex 1 (AP-1) and negatively regulates the canonical Wnt
            receptor signaling pathway in osteoblasts.
  - term:
      id: GO:0045668
      label: negative regulation of osteoblast differentiation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: negative regulation of osteoblast differentiation is retained as a
        non-core osteoblast/Wnt-related role supported by UniProt-curated literature,
        but it is peripheral to the main LIMD1 scaffold functions synthesized here.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Regulates osteoblast development, function, differentiation
            and stress osteoclastogenesis. Enhances the ability of TRAF6 to activate
            adapter protein complex 1 (AP-1) and negatively regulates the canonical Wnt
            receptor signaling pathway in osteoblasts.
  - term:
      id: GO:0090090
      label: negative regulation of canonical Wnt signaling pathway
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: negative regulation of canonical Wnt signaling pathway is retained as a
        non-core osteoblast/Wnt-related role supported by UniProt-curated literature,
        but it is peripheral to the main LIMD1 scaffold functions synthesized here.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Regulates osteoblast development, function, differentiation
            and stress osteoclastogenesis. Enhances the ability of TRAF6 to activate
            adapter protein complex 1 (AP-1) and negatively regulates the canonical Wnt
            receptor signaling pathway in osteoblasts.
  - term:
      id: GO:0001666
      label: response to hypoxia
    evidence_type: IDA
    original_reference_id: PMID:22286099
    review:
      summary: Response to hypoxia is supported by LIMD1 induction and by LIMD1
        scaffolding of PHD2/VHL complexes for HIF-alpha degradation.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:22286099
          supporting_text: The LIMD1 protein bridges an association between the prolyl
            hydroxylases and VHL to repress HIF-1 activity.
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a scaffold for the oxygen-sensing
            degradation machinery by bridging **PHD2** and **VHL** to promote efficient **HIF‑α
            degradation**, and is itself **HIF-1 inducible**, creating a negative-feedback
            loop limiting pro-tumorigenic hypoxia signaling.'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18331720
    review:
      summary: Generic protein binding is over-broad for LIMD1. Specific
        adaptor/scaffold roles with AGO/TNRC6/DDX6, LATS1/2, PHD/VHL, and pRB are more
        informative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Avoid generic protein binding when specific complex/adaptor mechanisms are
        known.
      supported_by:
        - reference_id: PMID:18331720
          supporting_text: Ajuba LIM proteins are snail/slug corepressors required for
            neural crest development in Xenopus.
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: LIMD1 (Q9UGP4) is best understood as a **multi-compartment
            scaffold** that (i) couples **mechanical tension** at adherens junctions to
            **Hippo pathway kinase (LATS) localization**, (ii) enables efficient
            **miRNA-mediated translational repression** by scaffolding Argonaute and
            GW182/TNRC6 and engaging the cap complex, (iii) promotes **HIF‑α
            degradation** by scaffolding PHD2–VHL complexes and participating in a
            HIF-driven negative feedback loop, and (iv) exerts tumor suppressor
            functions via **pRB/E2F repression** and via maintaining homeostatic control
            over hypoxia and mechanotransduction outputs.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20616046
    review:
      summary: Generic protein binding is over-broad for LIMD1. Specific
        adaptor/scaffold roles with AGO/TNRC6/DDX6, LATS1/2, PHD/VHL, and pRB are more
        informative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Avoid generic protein binding when specific complex/adaptor mechanisms are
        known.
      supported_by:
        - reference_id: PMID:20616046
          supporting_text: LIM-domain proteins, LIMD1, Ajuba, and WTIP are required for
            microRNA-mediated gene silencing.
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: LIMD1 (Q9UGP4) is best understood as a **multi-compartment
            scaffold** that (i) couples **mechanical tension** at adherens junctions to
            **Hippo pathway kinase (LATS) localization**, (ii) enables efficient
            **miRNA-mediated translational repression** by scaffolding Argonaute and
            GW182/TNRC6 and engaging the cap complex, (iii) promotes **HIF‑α
            degradation** by scaffolding PHD2–VHL complexes and participating in a
            HIF-driven negative feedback loop, and (iv) exerts tumor suppressor
            functions via **pRB/E2F repression** and via maintaining homeostatic control
            over hypoxia and mechanotransduction outputs.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22286099
    review:
      summary: Generic protein binding is over-broad for LIMD1. Specific
        adaptor/scaffold roles with AGO/TNRC6/DDX6, LATS1/2, PHD/VHL, and pRB are more
        informative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Avoid generic protein binding when specific complex/adaptor mechanisms are
        known.
      supported_by:
        - reference_id: PMID:22286099
          supporting_text: The LIMD1 protein bridges an association between the prolyl
            hydroxylases and VHL to repress HIF-1 activity.
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: LIMD1 (Q9UGP4) is best understood as a **multi-compartment
            scaffold** that (i) couples **mechanical tension** at adherens junctions to
            **Hippo pathway kinase (LATS) localization**, (ii) enables efficient
            **miRNA-mediated translational repression** by scaffolding Argonaute and
            GW182/TNRC6 and engaging the cap complex, (iii) promotes **HIF‑α
            degradation** by scaffolding PHD2–VHL complexes and participating in a
            HIF-driven negative feedback loop, and (iv) exerts tumor suppressor
            functions via **pRB/E2F repression** and via maintaining homeostatic control
            over hypoxia and mechanotransduction outputs.
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: IMP
    original_reference_id: PMID:22286099
    review:
      summary: Negative regulation of DNA-templated transcription is supported by both
        pRB/E2F repression and HIF pathway repression through enhanced HIF-alpha
        degradation.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:22286099
          supporting_text: The LIMD1 protein bridges an association between the prolyl
            hydroxylases and VHL to repress HIF-1 activity.
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 binds **pRB** and represses **E2F-driven
            transcription**, coupling LIMD1 to cell-cycle control.'
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a scaffold for the oxygen-sensing
            degradation machinery by bridging **PHD2** and **VHL** to promote efficient **HIF‑α
            degradation**, and is itself **HIF-1 inducible**, creating a negative-feedback
            loop limiting pro-tumorigenic hypoxia signaling.'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20303269
    review:
      summary: Generic protein binding is over-broad for LIMD1. Specific
        adaptor/scaffold roles with AGO/TNRC6/DDX6, LATS1/2, PHD/VHL, and pRB are more
        informative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Avoid generic protein binding when specific complex/adaptor mechanisms are
        known.
      supported_by:
        - reference_id: PMID:20303269
          supporting_text: Mar 18. Ajuba LIM proteins are negative regulators of the
            Hippo signaling pathway.
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: LIMD1 (Q9UGP4) is best understood as a **multi-compartment
            scaffold** that (i) couples **mechanical tension** at adherens junctions to
            **Hippo pathway kinase (LATS) localization**, (ii) enables efficient
            **miRNA-mediated translational repression** by scaffolding Argonaute and
            GW182/TNRC6 and engaging the cap complex, (iii) promotes **HIF‑α
            degradation** by scaffolding PHD2–VHL complexes and participating in a
            HIF-driven negative feedback loop, and (iv) exerts tumor suppressor
            functions via **pRB/E2F repression** and via maintaining homeostatic control
            over hypoxia and mechanotransduction outputs.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:18439753
    review:
      summary: nucleus localization is supported for LIMD1 scaffold function across
        junctional, cytoplasmic/P-body, and nuclear compartments.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:18439753
          supporting_text: 2008 Apr 24. Cell cycle regulated phosphorylation of LIMD1 in
            cell lines and expression in human breast cancers.
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a **mechanosensitive scaffold**
            controlling the **subcellular localization** (and functional availability) of
            **LATS1/2** kinases at adherens junctions, thereby influencing YAP/TAZ phosphorylation
            state and nuclear localization.'
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Localization:** LIMD1 colocalizes with GW182/TNRC6 and other
            miRISC components in **P-bodies**.'
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Cytoplasm. Nucleus. Cytoplasm, P-body. Cell junction,
            adherens junction. Cell junction, focal adhesion.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:18439753
    review:
      summary: cytoplasm localization is supported for LIMD1 scaffold function across
        junctional, cytoplasmic/P-body, and nuclear compartments.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:18439753
          supporting_text: 2008 Apr 24. Cell cycle regulated phosphorylation of LIMD1 in
            cell lines and expression in human breast cancers.
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a **mechanosensitive scaffold**
            controlling the **subcellular localization** (and functional availability) of
            **LATS1/2** kinases at adherens junctions, thereby influencing YAP/TAZ phosphorylation
            state and nuclear localization.'
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Localization:** LIMD1 colocalizes with GW182/TNRC6 and other
            miRISC components in **P-bodies**.'
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Cytoplasm. Nucleus. Cytoplasm, P-body. Cell junction,
            adherens junction. Cell junction, focal adhesion.
  - term:
      id: GO:0005912
      label: adherens junction
    evidence_type: IDA
    original_reference_id: PMID:20303269
    review:
      summary: adherens junction localization is supported for LIMD1 scaffold function
        across junctional, cytoplasmic/P-body, and nuclear compartments.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:20303269
          supporting_text: Mar 18. Ajuba LIM proteins are negative regulators of the
            Hippo signaling pathway.
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a **mechanosensitive scaffold**
            controlling the **subcellular localization** (and functional availability) of
            **LATS1/2** kinases at adherens junctions, thereby influencing YAP/TAZ phosphorylation
            state and nuclear localization.'
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Localization:** LIMD1 colocalizes with GW182/TNRC6 and other
            miRISC components in **P-bodies**.'
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Cytoplasm. Nucleus. Cytoplasm, P-body. Cell junction,
            adherens junction. Cell junction, focal adhesion.
  - term:
      id: GO:0005925
      label: focal adhesion
    evidence_type: IDA
    original_reference_id: PMID:18439753
    review:
      summary: Focal adhesion localization is supported by UniProt/subcellular evidence,
        but the strongest mechanistic Hippo evidence centers on adherens junctions under
        tension.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: PMID:18439753
          supporting_text: 2008 Apr 24. Cell cycle regulated phosphorylation of LIMD1 in
            cell lines and expression in human breast cancers.
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Cytoplasm. Nucleus. Cytoplasm, P-body. Cell junction,
            adherens junction. Cell junction, focal adhesion.
  - term:
      id: GO:0016310
      label: phosphorylation
    evidence_type: IDA
    original_reference_id: PMID:18439753
    review:
      summary: LIMD1 is a scaffold protein and not a kinase; the cited paper concerns
        phosphorylation of LIMD1 rather than LIMD1 catalyzing phosphorylation.
      action: REMOVE
      reason: Substrate-as-enzyme misannotation.
      supported_by:
        - reference_id: PMID:18439753
          supporting_text: 2008 Apr 24. Cell cycle regulated phosphorylation of LIMD1 in
            cell lines and expression in human breast cancers.
  - term:
      id: GO:0035331
      label: negative regulation of hippo signaling
    evidence_type: IDA
    original_reference_id: PMID:20303269
    review:
      summary: Negative regulation of Hippo signaling is supported by LIMD1-mediated
        LATS1/2 recruitment/localization at adherens junctions and consequent YAP/TAZ
        regulation.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:20303269
          supporting_text: Mar 18. Ajuba LIM proteins are negative regulators of the
            Hippo signaling pathway.
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a **mechanosensitive scaffold**
            controlling the **subcellular localization** (and functional availability) of
            **LATS1/2** kinases at adherens junctions, thereby influencing YAP/TAZ phosphorylation
            state and nuclear localization.'
  - term:
      id: GO:0000932
      label: P-body
    evidence_type: IDA
    original_reference_id: PMID:20616046
    review:
      summary: P-body localization is supported for LIMD1 scaffold function across
        junctional, cytoplasmic/P-body, and nuclear compartments.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:20616046
          supporting_text: LIM-domain proteins, LIMD1, Ajuba, and WTIP are required for
            microRNA-mediated gene silencing.
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a **mechanosensitive scaffold**
            controlling the **subcellular localization** (and functional availability) of
            **LATS1/2** kinases at adherens junctions, thereby influencing YAP/TAZ phosphorylation
            state and nuclear localization.'
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Localization:** LIMD1 colocalizes with GW182/TNRC6 and other
            miRISC components in **P-bodies**.'
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Cytoplasm. Nucleus. Cytoplasm, P-body. Cell junction,
            adherens junction. Cell junction, focal adhesion.
  - term:
      id: GO:0016442
      label: RISC complex
    evidence_type: IDA
    original_reference_id: PMID:20616046
    review:
      summary: RISC complex is supported by LIMD1 function as a miRISC/P-body scaffold
        linking AGO proteins, GW182/TNRC6, DDX6, and cap-associated translation
        repression.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:20616046
          supporting_text: LIM-domain proteins, LIMD1, Ajuba, and WTIP are required for
            microRNA-mediated gene silencing.
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 is a **miRISC adaptor/scaffold** that
            promotes productive AGO-dependent silencing by coupling Argonaute to GW182/TNRC6
            and downstream effector complexes, and by linking silencing to translation initiation
            control at the 5′ cap.'
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Localization:** LIMD1 colocalizes with GW182/TNRC6 and other
            miRISC components in **P-bodies**.'
  - term:
      id: GO:0033962
      label: P-body assembly
    evidence_type: IMP
    original_reference_id: PMID:20616046
    review:
      summary: P-body assembly is supported by LIMD1 function as a miRISC/P-body
        scaffold linking AGO proteins, GW182/TNRC6, DDX6, and cap-associated translation
        repression.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:20616046
          supporting_text: LIM-domain proteins, LIMD1, Ajuba, and WTIP are required for
            microRNA-mediated gene silencing.
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 is a **miRISC adaptor/scaffold** that
            promotes productive AGO-dependent silencing by coupling Argonaute to GW182/TNRC6
            and downstream effector complexes, and by linking silencing to translation initiation
            control at the 5′ cap.'
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Localization:** LIMD1 colocalizes with GW182/TNRC6 and other
            miRISC components in **P-bodies**.'
  - term:
      id: GO:0035195
      label: miRNA-mediated post-transcriptional gene silencing
    evidence_type: IMP
    original_reference_id: PMID:20616046
    review:
      summary: miRNA-mediated post-transcriptional gene silencing is supported by LIMD1
        function as a miRISC/P-body scaffold linking AGO proteins, GW182/TNRC6, DDX6,
        and cap-associated translation repression.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:20616046
          supporting_text: LIM-domain proteins, LIMD1, Ajuba, and WTIP are required for
            microRNA-mediated gene silencing.
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 is a **miRISC adaptor/scaffold** that
            promotes productive AGO-dependent silencing by coupling Argonaute to GW182/TNRC6
            and downstream effector complexes, and by linking silencing to translation initiation
            control at the 5′ cap.'
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Localization:** LIMD1 colocalizes with GW182/TNRC6 and other
            miRISC components in **P-bodies**.'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:15542589
    review:
      summary: Generic protein binding is over-broad for LIMD1. Specific
        adaptor/scaffold roles with AGO/TNRC6/DDX6, LATS1/2, PHD/VHL, and pRB are more
        informative.
      action: MARK_AS_OVER_ANNOTATED
      reason: Avoid generic protein binding when specific complex/adaptor mechanisms are
        known.
      supported_by:
        - reference_id: PMID:15542589
          supporting_text: LIM domains-containing protein 1 (LIMD1), a tumor suppressor
            encoded at chromosome 3p21.3, binds pRB and represses E2F-driven
            transcription.
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: LIMD1 (Q9UGP4) is best understood as a **multi-compartment
            scaffold** that (i) couples **mechanical tension** at adherens junctions to
            **Hippo pathway kinase (LATS) localization**, (ii) enables efficient
            **miRNA-mediated translational repression** by scaffolding Argonaute and
            GW182/TNRC6 and engaging the cap complex, (iii) promotes **HIF‑α
            degradation** by scaffolding PHD2–VHL complexes and participating in a
            HIF-driven negative feedback loop, and (iv) exerts tumor suppressor
            functions via **pRB/E2F repression** and via maintaining homeostatic control
            over hypoxia and mechanotransduction outputs.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:15542589
    review:
      summary: nucleus localization is supported for LIMD1 scaffold function across
        junctional, cytoplasmic/P-body, and nuclear compartments.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:15542589
          supporting_text: LIM domains-containing protein 1 (LIMD1), a tumor suppressor
            encoded at chromosome 3p21.3, binds pRB and represses E2F-driven
            transcription.
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a **mechanosensitive scaffold**
            controlling the **subcellular localization** (and functional availability) of
            **LATS1/2** kinases at adherens junctions, thereby influencing YAP/TAZ phosphorylation
            state and nuclear localization.'
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Localization:** LIMD1 colocalizes with GW182/TNRC6 and other
            miRISC components in **P-bodies**.'
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Cytoplasm. Nucleus. Cytoplasm, P-body. Cell junction,
            adherens junction. Cell junction, focal adhesion.
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:15542589
    review:
      summary: cytoplasm localization is supported for LIMD1 scaffold function across
        junctional, cytoplasmic/P-body, and nuclear compartments.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:15542589
          supporting_text: LIM domains-containing protein 1 (LIMD1), a tumor suppressor
            encoded at chromosome 3p21.3, binds pRB and represses E2F-driven
            transcription.
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a **mechanosensitive scaffold**
            controlling the **subcellular localization** (and functional availability) of
            **LATS1/2** kinases at adherens junctions, thereby influencing YAP/TAZ phosphorylation
            state and nuclear localization.'
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Localization:** LIMD1 colocalizes with GW182/TNRC6 and other
            miRISC components in **P-bodies**.'
        - reference_id: file:human/LIMD1/LIMD1-uniprot.txt
          supporting_text: Cytoplasm. Nucleus. Cytoplasm, P-body. Cell junction,
            adherens junction. Cell junction, focal adhesion.
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:15542589
    review:
      summary: Negative regulation of DNA-templated transcription is supported by both
        pRB/E2F repression and HIF pathway repression through enhanced HIF-alpha
        degradation.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:15542589
          supporting_text: LIM domains-containing protein 1 (LIMD1), a tumor suppressor
            encoded at chromosome 3p21.3, binds pRB and represses E2F-driven
            transcription.
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 binds **pRB** and represses **E2F-driven
            transcription**, coupling LIMD1 to cell-cycle control.'
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**Primary function:** LIMD1 acts as a scaffold for the oxygen-sensing
            degradation machinery by bridging **PHD2** and **VHL** to promote efficient **HIF‑α
            degradation**, and is itself **HIF-1 inducible**, creating a negative-feedback
            loop limiting pro-tumorigenic hypoxia signaling.'
  - term:
      id: GO:0060090
      label: molecular adaptor activity
    evidence_type: IDA
    original_reference_id: PMID:20616046
    review:
      summary: LIMD1 molecular adaptor activity is directly supported by PMID:20616046,
        which shows LIMD1/Ajuba/WTIP linking Ago1/2, eIF4E-cap complexes, and
        miRNA-mediated silencing machinery; this captures the broader scaffold/adaptor
        role synthesized across LIMD1 pathways.
      action: NEW
      reason: The existing GOA annotations capture downstream processes but lack the
        core molecular adaptor/scaffold activity demonstrated by primary mechanistic
        literature.
      supported_by:
        - reference_id: PMID:20616046
          supporting_text: these LIM-domain proteins facilitate miRNA-mediated gene
            silencing by acting as an essential molecular link between the
            translationally inhibited eIF4E-m(7)GTP-5(')cap and Ago1/2 within the miRISC
            complex attached to the 3'-UTR of mRNA, creating an inhibitory closed-loop
            complex.
        - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
          supporting_text: '**LIMD1 is a multi-domain adaptor/scaffold protein**, not an enzyme.
            Its biological roles derive from assembling protein complexes and controlling
            where/when those complexes form—particularly at **cell junctions**, **P-bodies**,
            and in **oxygen-sensing (HIF) degradation complexes**. LIM domains are zinc-binding
            modules (~55–65 aa) that act as protein-interaction interfaces; LIMD1 contains
            **three tandem LIM domains** at its C‑terminus.'
references:
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data to
      orthologs by curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
      vocabulary mapping, accompanied by conservative changes to GO terms applied by
      UniProt
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation data to
      orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:15542589
    title: LIM domains-containing protein 1 (LIMD1), a tumor suppressor encoded at
      chromosome 3p21.3, binds pRB and represses E2F-driven transcription.
    findings: []
  - id: PMID:18331720
    title: Ajuba LIM proteins are snail/slug corepressors required for neural crest
      development in Xenopus.
    findings: []
  - id: PMID:18439753
    title: Cell cycle regulated phosphorylation of LIMD1 in cell lines and expression in
      human breast cancers.
    findings: []
  - id: PMID:20303269
    title: Ajuba LIM proteins are negative regulators of the Hippo signaling pathway.
    findings: []
  - id: PMID:20616046
    title: LIM-domain proteins, LIMD1, Ajuba, and WTIP are required for
      microRNA-mediated gene silencing.
    findings: []
  - id: PMID:22190034
    title: Global landscape of HIV-human protein complexes.
    findings: []
  - id: PMID:22286099
    title: The LIMD1 protein bridges an association between the prolyl hydroxylases and
      VHL to repress HIF-1 activity.
    findings: []
  - id: PMID:28683311
    title: Argonaute Utilization for miRNA Silencing Is Determined by
      Phosphorylation-Dependent Recruitment of LIM-Domain-Containing Proteins.
    findings: []
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the human
      interactome.
    findings: []
  - id: Reactome:R-HSA-1234159
    title: Proteasome proteolyzes ub-HIF-alpha
    findings: []
  - id: Reactome:R-HSA-1234163
    title: Cytosolic VBC complex ubiquitinylates hydroxyprolyl-HIF-alpha
    findings: []
  - id: Reactome:R-HSA-1234173
    title: Cytosolic PHD2,3 hydroxylates proline residues on HIF3A
    findings: []
  - id: Reactome:R-HSA-1234177
    title: Cytosolic PHD2,3 hydroxylates proline residues on HIF1A
    findings: []
  - id: Reactome:R-HSA-1234183
    title: Cytosolic VHL:EloB,C:CUL2:RBX1 binds hydroxyprolyl-HIF-alpha
    findings: []
  - id: file:human/LIMD1/LIMD1-deep-research-falcon.md
    title: Falcon deep research synthesis for LIMD1
    findings: []
  - id: file:human/LIMD1/LIMD1-uniprot.txt
    title: UniProt record for LIMD1
    findings: []
core_functions:
  - description: Mechanosensitive adaptor activity at adherens junctions that
      recruits/localizes LATS1/2 and negatively regulates Hippo signaling output.
    molecular_function:
      id: GO:0060090
      label: molecular adaptor activity
    directly_involved_in:
      - id: GO:0035331
        label: negative regulation of hippo signaling
    locations:
      - id: GO:0005912
        label: adherens junction
      - id: GO:0005737
        label: cytoplasm
    supported_by:
      - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
        supporting_text: '**Primary function:** LIMD1 acts as a **mechanosensitive scaffold**
          controlling the **subcellular localization** (and functional availability) of **LATS1/2**
          kinases at adherens junctions, thereby influencing YAP/TAZ phosphorylation state
          and nuclear localization.'
      - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
        supporting_text: '**LIMD1 is a multi-domain adaptor/scaffold protein**, not an enzyme.
          Its biological roles derive from assembling protein complexes and controlling where/when
          those complexes form—particularly at **cell junctions**, **P-bodies**, and in **oxygen-sensing
          (HIF) degradation complexes**. LIM domains are zinc-binding modules (~55–65 aa)
          that act as protein-interaction interfaces; LIMD1 contains **three tandem LIM domains**
          at its C‑terminus.'
  - description: miRISC/P-body adaptor activity that promotes miRNA-mediated
      translational repression by coupling Argonaute, TNRC6/GW182, DDX6, and
      cap-associated machinery.
    molecular_function:
      id: GO:0060090
      label: molecular adaptor activity
    directly_involved_in:
      - id: GO:0035195
        label: miRNA-mediated post-transcriptional gene silencing
      - id: GO:0033962
        label: P-body assembly
    locations:
      - id: GO:0000932
        label: P-body
      - id: GO:0005737
        label: cytoplasm
    in_complex:
      id: GO:0016442
      label: RISC complex
    supported_by:
      - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
        supporting_text: '**Primary function:** LIMD1 is a **miRISC adaptor/scaffold** that
          promotes productive AGO-dependent silencing by coupling Argonaute to GW182/TNRC6
          and downstream effector complexes, and by linking silencing to translation initiation
          control at the 5′ cap.'
      - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
        supporting_text: '**Localization:** LIMD1 colocalizes with GW182/TNRC6 and other miRISC
          components in **P-bodies**.'
  - description: Adaptor activity in hypoxia signaling that bridges PHD2/VHL machinery
      to promote HIF-alpha degradation and limit hypoxic transcriptional responses.
    molecular_function:
      id: GO:0060090
      label: molecular adaptor activity
    directly_involved_in:
      - id: GO:0001666
        label: response to hypoxia
      - id: GO:0045892
        label: negative regulation of DNA-templated transcription
    locations:
      - id: GO:0005829
        label: cytosol
      - id: GO:0005737
        label: cytoplasm
    supported_by:
      - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
        supporting_text: '**Primary function:** LIMD1 acts as a scaffold for the oxygen-sensing
          degradation machinery by bridging **PHD2** and **VHL** to promote efficient **HIF‑α
          degradation**, and is itself **HIF-1 inducible**, creating a negative-feedback loop
          limiting pro-tumorigenic hypoxia signaling.'
      - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
        supporting_text: LIMD1 (Q9UGP4) is best understood as a **multi-compartment
          scaffold** that (i) couples **mechanical tension** at adherens junctions to
          **Hippo pathway kinase (LATS) localization**, (ii) enables efficient
          **miRNA-mediated translational repression** by scaffolding Argonaute and
          GW182/TNRC6 and engaging the cap complex, (iii) promotes **HIF‑α degradation**
          by scaffolding PHD2–VHL complexes and participating in a HIF-driven negative
          feedback loop, and (iv) exerts tumor suppressor functions via **pRB/E2F
          repression** and via maintaining homeostatic control over hypoxia and
          mechanotransduction outputs.
  - description: Nuclear transcription corepressor activity through pRB/E2F repression.
    molecular_function:
      id: GO:0003714
      label: transcription corepressor activity
    directly_involved_in:
      - id: GO:0045892
        label: negative regulation of DNA-templated transcription
    locations:
      - id: GO:0005634
        label: nucleus
    supported_by:
      - reference_id: file:human/LIMD1/LIMD1-deep-research-falcon.md
        supporting_text: '**Primary function:** LIMD1 binds **pRB** and represses **E2F-driven
          transcription**, coupling LIMD1 to cell-cycle control.'
proposed_new_terms: []
suggested_questions: []
suggested_experiments: []