Affinage

AMOTL1

Angiomotin-like protein 1 · UniProt Q8IY63

Length
956 aa
Mass
106.6 kDa
Annotated
2026-06-09
21 papers in source corpus 13 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AMOTL1 is a peripheral membrane scaffold protein of tight junctions that acts as a central regulator of Hippo/YAP signaling, coupling junctional integrity to the cytoplasmic-to-nuclear shuttling of the transcriptional co-activator YAP1 (PMID:11733531, PMID:32313226). First identified as a tight-junction protein of exocrine epithelia containing a coiled-coil domain and a C-terminal PDZ-binding motif (PMID:11733531), it is anchored at junctions through interactions with the multi-PDZ scaffolds MUPP1 and Patj (PMID:17397395). Mechanistically, AMOTL1 binds YAP1 in the cytoplasm, mutually protecting each protein from ubiquitin-mediated degradation, and promotes YAP1 nuclear translocation to drive transcription of targets such as CTGF, thereby supporting proliferation, migration, and oncogenic properties (PMID:32313226). AMOTL1 abundance is tightly controlled by competing ubiquitin-pathway inputs: NEDD4-1 engages three AMOTL1 PPxY motifs cooperatively through its WW domains to promote degradation, while KIBRA binds the C-terminal PPxY motif to protect AMOTL1 (PMID:41580069); the tumor suppressor Merlin drives AMOTL1 degradation via NEDD family ligases (PMID:26806348); HECW2 stabilizes AMOTL1 through K63-linked ubiquitination, and its loss relieves junctional integrity and triggers YAP nuclear translocation and angiogenic sprouting (PMID:27498087); and Tankyrase-mediated PARylation marks AMOTL1 for RNF146-dependent proteasomal degradation (PMID:42012498). AMOTL1 output is further tuned upstream by Fat4, which sequesters AMOTL1 out of the nucleus to restrict cardiomyocyte proliferation (PMID:28239148), and by SRSF3-directed alternative splicing that generates a long isoform with enhanced intracellular YAP1-translocating activity (PMID:37558679). Patient-derived hotspot mutations R157C and P160L in the Tankyrase-binding motif abolish Tankyrase/RNF146 binding, prevent AMOTL1 turnover, and cause cytoplasmic accumulation that disrupts cell junctions and focal adhesions, impairs migration, and produces craniofacial, cardiac, and skeletal muscle defects in zebrafish (PMID:42012498).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2001 Medium

    Established AMOTL1's basal identity by showing it is a tight-junction-associated peripheral membrane protein rather than a soluble or transmembrane factor, defining the cellular compartment where it operates.

    Evidence Localization expression cloning and immunofluorescence in exocrine cells and MDCK/L cells

    PMID:11733531

    Open questions at the time
    • Did not define junctional targeting partners
    • No functional role beyond localization established
  2. 2007 Medium

    Addressed how AMOTL1 is held at junctions by showing it binds the multi-PDZ scaffolds MUPP1 and Patj via its PDZ-binding motif, while revealing this interaction is not the sole determinant of tight-junction targeting.

    Evidence Yeast two-hybrid, immunofluorescence, and biochemical fractionation in epithelial cells

    PMID:17397395

    Open questions at the time
    • Alternative TJ-targeting mechanism unresolved
    • No link to signaling output
  3. 2016 High

    Connected AMOTL1 stability to Hippo signaling and junction integrity by identifying opposing E3-ligase inputs: HECW2 stabilizes AMOTL1 via K63-linked ubiquitination, whereas Merlin drives its NEDD-ligase-dependent degradation.

    Evidence Reciprocal Co-IP, ubiquitination assays, siRNA knockdown with YAP-localization and angiogenic sprouting readouts (HECW2); Co-IP and proteasome assays with migration/c-Src readouts (Merlin)

    PMID:26806348 PMID:27498087

    Open questions at the time
    • Did not resolve how AMOTL1 mechanically links junctions to YAP
    • Direct YAP-AMOTL1 binding not yet demonstrated in these studies
  4. 2017 High

    Placed AMOTL1 in an in vivo non-canonical Hippo axis by showing Fat4 sequesters AMOTL1 from the nucleus to restrict cardiomyocyte proliferation, establishing AMOTL1 as a YAP1 co-translocating intermediate.

    Evidence Fat4 mutant mouse genetics, immunofluorescence localization, and genetic epistasis

    PMID:28239148

    Open questions at the time
    • Molecular basis of Fat4-mediated sequestration not defined
    • Whether the same axis operates in other tissues unclear
  5. 2020 Medium

    Defined the core mechanistic node by showing AMOTL1 directly binds YAP1 in the cytoplasm, mutually stabilizes it against degradation, and promotes its nuclear translocation to activate CTGF and oncogenic programs.

    Evidence Co-IP, immunofluorescence, siRNA knockdown, CTGF reporter, and xenograft assays in gastric cancer

    PMID:32313226

    Open questions at the time
    • Structural basis of the YAP1 interaction not resolved
    • Single tumor context
  6. 2023 Medium

    Explained isoform-level tuning of AMOTL1 activity by showing SRSF3-directed inclusion of exon 12 generates a long isoform that localizes intracellularly and more robustly translocates YAP1, enhancing proliferation and migration.

    Evidence SRSF3 knockdown, RRM-binding analysis, RT-PCR isoform analysis, isoform-specific Co-IP with YAP1, and functional rescue in NPC cells

    PMID:37558679

    Open questions at the time
    • Upstream control of SRSF3 in this context unknown
    • Quantitative contribution of each isoform in normal tissue unclear
  7. 2024 High

    Identified an RNA-modification layer of control, showing Nat10-mediated ac4C modification stabilizes Amotl1 mRNA to amplify Amotl1-Yap interaction and fibrogenic signaling after myocardial infarction.

    Evidence ac4C-RIP-seq, Nat10 knockdown/overexpression, fibroblast-specific Nat10 KO/OE mice, Co-IP, and verteporfin rescue

    PMID:38839936

    Open questions at the time
    • Whether ac4C control of AMOTL1 generalizes beyond cardiac fibroblasts unknown
    • Did not map ac4C sites functionally
  8. 2026 High

    Resolved the biophysical logic of AMOTL1 turnover by quantifying how its three PPxY motifs cooperatively recruit NEDD4-1 (promoting degradation) versus high-affinity C-terminal binding by KIBRA (protecting it), defining a competitive WW-domain switch.

    Evidence Isothermal titration calorimetry and NMR with quantitative affinity measurements of PPxY interactions

    PMID:41580069

    Open questions at the time
    • In vitro biophysics not validated in cells
    • Functional consequence of the affinity differences on YAP output not measured
  9. 2026 High

    Established disease causation by showing hotspot TBM mutations R157C and P160L abolish Tankyrase/RNF146 binding, block AMOTL1 degradation, and cause cytoplasmic accumulation that disrupts junctions and migration with developmental defects in vivo.

    Evidence Co-IP, ubiquitination and stability assays, junction/focal-adhesion immunofluorescence, migration assays, and zebrafish expression of R157C

    PMID:42012498

    Open questions at the time
    • Human patient phenotype-genotype correlation beyond the mutations not detailed
    • Downstream transcriptional consequences in affected tissues unmapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple converging stability inputs (Tankyrase/RNF146 PARylation-degradation, NEDD4-1/KIBRA WW competition, HECW2 protection, Merlin degradation) are integrated to set net AMOTL1 levels and YAP output in a given cell remains unresolved.
  • No unified quantitative model of competing E3/regulator inputs
  • Tissue-specific dominance of each regulator unknown
  • Structural model of the AMOTL1-YAP1 complex absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-392499 Metabolism of proteins 3 R-HSA-162582 Signal Transduction 2
Partners
HECW2KIBRAMUPP1NEDD4-1NF2PATJTNKSYAP1

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 AMOTL1 (JEAP) was identified as a novel peripheral membrane protein localized at tight junctions (TJs) specifically in exocrine cells (pancreas, submandibular gland, lacrimal gland, parotid gland, sublingual gland), but not at TJs of intestinal epithelial or endothelial cells. It contains a coiled-coil domain and a C-terminal PDZ-binding motif. Fluorescence localization-based expression cloning; immunofluorescence microscopy; exogenous expression in MDCK and L cells The Journal of biological chemistry Medium 11733531
2007 AMOTL1 (JEAP) physically interacts with the multi-PDZ scaffold proteins MUPP1 and Patj via its C-terminal PDZ-binding motif (PDZ3 of MUPP1 responsible for JEAP interaction). AMOTL1 co-localizes with MUPP1 at tight junctions and apical membranes in epithelial cells and behaves as a peripheral (not transmembrane) membrane protein. The PDZ-binding motif is not strictly required for TJ localization, indicating MUPP1/Patj interaction is not solely responsible for AMOTL1's TJ targeting. Yeast two-hybrid screening; immunofluorescence microscopy; biochemical fractionation; dominant-negative MUPP1/Patj expression Genes to cells : devoted to molecular & cellular mechanisms Medium 17397395
2014 miR-124 represses AMOTL1 expression by directly targeting its 3′UTR, thereby suppressing vasculogenic mimicry, migration, invasion, and EMT in cervical cancer cells. 3′UTR reporter assays; gain/loss-of-function experiments in HeLa and C33A cells; migration and invasion assays Cancer letters Medium 25218344
2016 The E3 ubiquitin ligase HECW2 physically interacts with AMOTL1 and stabilizes it via K63-linked ubiquitination in endothelial cells. HECW2 depletion reduces AMOTL1 stability, loosens cell-to-cell junctions, and causes nuclear translocation of YAP, leading to increased angiogenic sprouting. Co-immunoprecipitation; ubiquitination assays; siRNA knockdown; immunofluorescence for YAP localization; sprouting angiogenesis assay Cellular signalling High 27498087
2016 The tumor suppressor Merlin directly interacts with AMOTL1 and triggers its proteasomal degradation via NEDD family ubiquitin ligases. YAP activity conversely stimulates AMOTL1 expression. AMOTL1 expression is sufficient to trigger tumor cell migration and stimulates proliferation by activating c-Src. Co-immunoprecipitation; proteasome inhibitor assays; siRNA/overexpression functional assays; migration and proliferation assays; c-Src activation measurement Neoplasia (New York, N.Y.) Medium 26806348
2017 In the mouse heart, Fat4 sequesters AMOTL1 out of the nucleus; loss of Fat4 allows nuclear translocation of AMOTL1 together with YAP1, promoting cardiomyocyte proliferation and heart overgrowth. AMOTL1 acts as a mammalian intermediate for non-canonical Hippo signaling downstream of Fat4, restricting heart growth at birth. Fat4 mutant mouse genetics; cardiomyocyte proliferation/size measurements; immunofluorescence for AMOTL1 and YAP1 localization; genetic epistasis analysis Nature communications High 28239148
2020 AMOTL1 physically interacts with YAP1 in the cytoplasm, protecting each other from ubiquitin-mediated degradation. AMOTL1 promotes YAP1 translocation into the nucleus to activate downstream targets such as CTGF. Knockdown of AMOTL1 impairs gastric oncogenic properties. Co-immunoprecipitation; immunofluorescence; siRNA knockdown; xenograft assays; CTGF reporter assays Oncogene Medium 32313226
2023 The splicing factor SRSF3 directly binds exon 12 of AMOTL1 via its RRM domain to promote inclusion of exon 12, generating a long isoform (AMOTL1-L). AMOTL1-L preferentially localizes intracellularly rather than at the cell membrane and more robustly interacts with YAP1, promoting its nuclear translocation and NPC cell proliferation and migration; the short isoform AMOTL1-S lacks these properties. Transcriptome analysis; SRSF3 knockdown; RT-PCR isoform analysis; immunofluorescence for localization; co-immunoprecipitation of AMOTL1-L/S with YAP1; functional rescue assays Cell death & disease Medium 37558679
2024 N-acetyltransferase 10 (Nat10) mediates N4-acetylcytidine (ac4C) modification of Amotl1 mRNA, increasing its stability and translation in cardiac fibroblasts. This leads to increased Amotl1–Yap interaction and Yap nuclear translocation, promoting cardiac fibroblast proliferation and differentiation into myofibroblasts, contributing to cardiac fibrosis after myocardial infarction. ac4C-RIP-seq; Nat10 siRNA/overexpression; fibroblast-specific Nat10 KO and OE mice; echocardiography; co-immunoprecipitation of AMOTL1-YAP; verteporfin (YAP inhibitor) treatment Acta pharmacologica Sinica High 38839936
2026 AMOTL1 contains three PPxY motifs that engage NEDD4-1 and KIBRA through distinct cooperative binding mechanisms. NEDD4-1 binds all three PPxY motifs cooperatively (using three of its four WW domains), yielding ~10-fold enhanced affinity and promoting AMOTL1 degradation. KIBRA binds primarily through the C-terminal PPxY motif with high affinity and protects AMOTL1 from degradation; secondary KIBRA interactions at other PPxY sites do not enhance overall affinity. Isothermal titration calorimetry (ITC); nuclear magnetic resonance (NMR) spectroscopy; quantitative molecular biophysical analyses Journal of molecular biology High 41580069
2026 Patient-derived hotspot mutations R157C and P160L in the Tankyrase-binding motif (TBM) of AMOTL1 abolish interaction with Tankyrase 1/2 and RNF146, preventing poly-ADP-ribosylation, ubiquitination, and proteasomal degradation of AMOTL1. The stabilized mutants accumulate in the cytoplasm, disrupt cell junctions and focal adhesions, inhibit cell migration velocity and persistence, and cause craniofacial malformations and cardiac/skeletal muscle defects in zebrafish. Co-immunoprecipitation; ubiquitination assays; protein stability assays; immunofluorescence for junction and focal adhesion markers; cell migration assays; zebrafish embryo expression of R157C mutant Bioscience reports High 42012498
2026 PFKP directly binds AMOTL1 and inhibits its ubiquitin-mediated degradation. PFKP-driven aerobic glycolysis and EMT in head and neck cancer cells are dependent on AMOTL1. PFKP promotes YAP nuclear translocation via AMOTL1, suppressing Hippo pathway activity. Co-immunoprecipitation; ubiquitination analysis; immunofluorescence; siRNA knockdown functional assays (migration, glycolysis); in vivo xenograft Journal of translational internal medicine Medium 41727965
2025 Tankyrase (TNKS1/2) targets AMOTL1 as a direct substrate; pharmacological TNKS inhibition with OM-153 stabilizes AMOTL1 protein in lung fibroblasts, suppresses YAP signaling, and reduces pro-fibrotic ECM expression in multiple preclinical IPF models. Immunoblotting for AMOTL1 protein levels after TNKS inhibitor treatment; RNA sequencing; in vitro fibroblast assays; bleomycin mouse model; precision-cut lung slices bioRxivpreprint Low
2024 AMOTL1 interacts with the androgen receptor (AR) in prostate cancer cells, and this interaction is pivotal for modulating sensitivity to AR antagonists. Co-immunoprecipitation (interaction with AR); pharmacodynamic sensitivity assays with AR antagonists International journal of biological macromolecules Low 39643184

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Amotl1 mediates sequestration of the Hippo effector Yap1 downstream of Fat4 to restrict heart growth. Nature communications 83 28239148
2014 MiR-124 represses vasculogenic mimicry and cell motility by targeting amotL1 in cervical cancer cells. Cancer letters 83 25218344
2007 Molecular characterization of angiomotin/JEAP family proteins: interaction with MUPP1/Patj and their endogenous properties. Genes to cells : devoted to molecular & cellular mechanisms 81 17397395
2019 circAMOTL1 Motivates AMOTL1 Expression to Facilitate Cervical Cancer Growth. Molecular therapy. Nucleic acids 75 31812104
2001 JEAP, a novel component of tight junctions in exocrine cells. The Journal of biological chemistry 59 11733531
2016 The endothelial E3 ligase HECW2 promotes endothelial cell junctions by increasing AMOTL1 protein stability via K63-linked ubiquitination. Cellular signalling 44 27498087
2020 AMOTL1 enhances YAP1 stability and promotes YAP1-driven gastric oncogenesis. Oncogene 38 32313226
2016 AMOTL1 Promotes Breast Cancer Progression and Is Antagonized by Merlin. Neoplasia (New York, N.Y.) 32 26806348
2020 The circ-AMOTL1/ENO1 Axis Implicated in the Tumorigenesis of OLP-Associated Oral Squamous Cell Carcinoma. Cancer management and research 17 32884340
2023 Circ-AMOTL1 enhances cardiac fibrosis through binding with EIF4A3 and stabilizing MARCKS expression in diabetic cardiomyopathy. Cellular signalling 13 37586467
2023 CircAMOTL1 RNA and AMOTL1 Protein: Complex Functions of AMOTL1 Gene Products. International journal of molecular sciences 9 36768425
2024 Acetylcytidine modification of Amotl1 by N-acetyltransferase 10 contributes to cardiac fibrotic expansion in mice after myocardial infarction. Acta pharmacologica Sinica 7 38839936
2023 SRSF3/AMOTL1 splicing axis promotes the tumorigenesis of nasopharyngeal carcinoma through regulating the nucleus translocation of YAP1. Cell death & disease 7 37558679
2024 circ-Amotl1 in extracellular vesicles derived from ADSCs improves wound healing by upregulating SPARC translation. Regenerative therapy 6 38318480
2024 Harnessing machine learning and multi-omics to explore tumor evolutionary characteristics and the role of AMOTL1 in prostate cancer. International journal of biological macromolecules 6 39643184
2023 A mutational hotspot in AMOTL1 defines a new syndrome of orofacial clefting, cardiac anomalies, and tall stature. American journal of medical genetics. Part A 5 36751037
2025 Hsa_circ_0001278 Facilitates Colorectal Cancer Progression via Sponging miR-338-5p and Regulating AMOTL1 Expression. Combinatorial chemistry & high throughput screening 4 38018210
2022 Clinical report: Chronic liver dysfunction in an individual with an AMOTL1 variant. European journal of medical genetics 1 36116699
2026 Multivalent AMOTL1 Engages NEDD4-1 and KIBRA Through Distinct Cooperative Binding Mechanisms. Journal of molecular biology 0 41580069
2026 PFKP binding AMOTL1 promotes tumor aerobic glycolysis and epithelial-mesenchymal transition by modulating Hippo pathway in head and neck cancer. Journal of translational internal medicine 0 41727965
2026 Patient-derived AMOTL1 mutations lead to defective cell migration and tissue development. Bioscience reports 0 42012498

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