Affinage

LAD1

Ladinin-1 · UniProt O00515

Length
517 aa
Mass
57.1 kDa
Annotated
2026-06-10
30 papers in source corpus 8 papers cited in narrative 8 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

LAD1 (Ladinin-1) is a 120-kDa anchoring filament protein originally characterized as a keratinocyte-secreted component of the dermal-epidermal junction, where antibody-induced disruption causes dermal-epidermal separation, establishing its role in maintaining dermal-epidermal cohesion (PMID:8618013). In skin it assembles as a homotrimeric complex distinct from BP180 (PMID:9886264), and its loss accompanies abnormal BP180 expression in generalized atrophic benign epidermolysis bullosa patients (PMID:9284104). Beyond its structural role, LAD1 acts as an intracellular signaling adaptor downstream of EGF: it binds MEKK2 in a calcium-dependent manner to enable MEKK2 nuclear translocation, tyrosine phosphorylation, and ERK5 activation (PMID:20830310), and is itself transcriptionally induced and phosphorylated by EGF signaling, binding actin-crosslinking filamin proteins and co-localizing with actin stress fibers together with 14-3-3σ to drive cell proliferation and migration (PMID:29382783). In cancer, LAD1 promotes migratory and metastatic behavior — its depletion blocks colorectal cancer migration, invasion, and liver metastasis without affecting proliferation (PMID:33267790) — and it stabilizes Vimentin by competitively blocking the MAEA E3 ligase, reducing K48-linked ubiquitination and degradation of Vimentin in gastric cancer (PMID:37718450).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1996 High

    Establishing whether LAD1 is a structural component of the dermal-epidermal junction defined its founding role in skin cohesion.

    Evidence Immunoelectron microscopy, radioimmunoprecipitation, and in situ antibody-induced blistering in human skin and primary keratinocytes

    PMID:8618013

    Open questions at the time
    • Molecular partners at the anchoring filament not defined
    • Mechanism of secretion and assembly not addressed
  2. 1997 Medium

    Linking LAD1 loss to a blistering disease phenotype tested its functional importance in vivo in humans.

    Evidence Indirect immunofluorescence and radioimmunoprecipitation across a cohort of GABEB patient keratinocyte cultures

    PMID:9284104

    Open questions at the time
    • Co-occurrence with BP180 abnormality leaves causality unresolved
    • No causative LAD1 mutation defined
  3. 1999 Medium

    Determining the oligomeric state showed LAD1 forms its own homotrimer rather than mixing with the related BP180.

    Evidence Two-dimensional SDS-PAGE under temperature-controlled dissociation with immunoblotting in human skin and keratinocytes

    PMID:9886264

    Open questions at the time
    • Structural basis of trimerization not determined
    • Functional consequence of trimerization untested
  4. 2010 Medium

    Identifying LAD1 as a MEKK2 adaptor revealed an intracellular signaling function distinct from its structural role.

    Evidence Reciprocal co-immunoprecipitation, in vitro direct binding assay, calcium modulation, and nuclear translocation imaging

    PMID:20830310

    Open questions at the time
    • Calcium-dependence mechanism not resolved at residue level
    • Connection to LAD1's structural pool unclear
  5. 2018 High

    Connecting LAD1 to EGF-induced filamin binding and actin dynamics established it as an effector linking EGF signaling to cytoskeletal regulation and proliferation/migration.

    Evidence SILAC phosphoproteomics, yeast two-hybrid, proximity ligation, co-IP, cosedimentation, shRNA knockdown, and xenograft tumor model in mammary cells

    PMID:29382783

    Open questions at the time
    • Phosphosite functional roles not fully mapped
    • Relationship between filamin and MEKK2 binding modes unaddressed
  6. 2020 Medium

    Loss-of-function in colorectal cancer separated LAD1's role in metastasis from proliferation, defining a specific pro-migratory function.

    Evidence shRNA depletion with migration/invasion assays and an in vivo spleen-to-liver metastasis mouse model

    PMID:33267790

    Open questions at the time
    • Molecular effectors in colorectal context not identified
    • No rescue with catalytically/structurally defined mutants
  7. 2023 Medium

    Identifying competitive Vimentin binding gave a molecular mechanism for how LAD1 stabilizes an EMT effector to promote cancer progression.

    Evidence MS interactome, co-IP, ubiquitination assays, and PDX/CDX xenograft gain/loss experiments in gastric cancer

    PMID:37718450

    Open questions at the time
    • Binding interface with Vimentin/MAEA not mapped
    • Whether this mechanism operates in non-gastric contexts untested
  8. 2025 Low

    Coupling LAD1 to cortactin/N-WASP phosphorylation and PI3K/AKT extended its cytoskeletal-remodeling role to esophageal carcinoma.

    Evidence Co-IP of a LAD1-LINC01305 interaction, phosphorylation and EMT marker assays, and migration/invasion functional readouts in ESCC

    PMID:39835575

    Open questions at the time
    • Limited mechanistic detail without full reconstitution
    • Direct vs indirect LAD1-lncRNA binding not validated reciprocally
    • Causal ordering of phosphorylation events unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How LAD1's secreted structural anchoring function mechanistically relates to its intracellular signaling/adaptor roles remains unresolved.
  • No structure of LAD1 or its complexes
  • No unifying account of how one protein performs extracellular anchoring and intracellular adaptor functions
  • Tissue-specific switch between roles undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0060090 molecular adaptor activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005576 extracellular region 1 GO:0005856 cytoskeleton 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1474244 Extracellular matrix organization 1
Partners
CTTNFLNAFLNBMAEAMEKK2SFNVIM
Complex memberships
LAD1 homotrimer

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 LAD-1 (Ladinin-1) is a novel 120-kDa anchoring filament protein synthesized and secreted by epidermal keratinocytes, localizing exclusively to anchoring filaments at the dermal-epidermal junction as determined by immunoelectron microscopy. A monoclonal antibody against LAD-1 induced dermal-epidermal separation of human skin in situ, establishing its role in maintaining dermal-epidermal cohesion. Radioimmunoprecipitation, immunoelectron microscopy, immunoblot, in situ antibody-induced blistering assay, primary keratinocyte culture The Journal of investigative dermatology High 8618013
1999 LAD-1 exists as a high-molecular-mass homotrimeric complex (analogous to BP180 trimers) in human skin and keratinocytes, and does not form mixed complexes with BP180, as shown by two-dimensional electrophoresis under temperature-dissociation conditions. Two-dimensional SDS-PAGE with temperature-controlled dissociation, immunoblotting, silver staining The Journal of investigative dermatology Medium 9886264
1997 LAD-1 protein expression is absent or greatly reduced in the majority of generalized atrophic benign epidermolysis bullosa (GABEB) patients, and this defect co-occurs with abnormal BP180 expression, as confirmed by indirect immunofluorescence and radioimmunoprecipitation from cultured keratinocytes. Indirect immunofluorescence microscopy, radioimmunoprecipitation from keratinocyte cultures The Journal of investigative dermatology Medium 9284104
2010 LAD1 (Ladinin-1) functions as an adaptor protein in the EGF-to-ERK5 signaling pathway: EGF stimulation increases MEKK2 binding to LAD1 in a calcium-dependent manner, and this direct interaction (demonstrated by in vitro binding assay) is required for MEKK2 nuclear translocation and full tyrosine phosphorylation of MEKK2, thereby enabling ERK5 activation. Co-immunoprecipitation, in vitro binding assay, intracellular calcium modifiers, nuclear translocation imaging PloS one Medium 20830310
2018 LAD1 (Ladinin-1) is transcriptionally induced by EGF, phosphorylated downstream of EGF signaling, and binds to actin-crosslinking filamin proteins; it co-localizes with actin stress fibers and participates in actin dynamics in collaboration with 14-3-3σ (SFN), mediating mammary cell proliferation and migration. Phosphoproteomics (SILAC), yeast two-hybrid, proximity ligation assay, co-immunoprecipitation, cosedimentation assay, shRNA knockdown, xenograft tumor model Science signaling High 29382783
2023 LAD1 promotes gastric cancer progression by competitively binding to Vimentin, preventing Vimentin's interaction with the E3 ubiquitin ligase MAEA, thereby reducing K48-linked ubiquitination and degradation of Vimentin, leading to increased Vimentin protein levels. Mass spectrometry (interactome), co-immunoprecipitation, ubiquitination assay, in vitro and in vivo functional gain/loss experiments (PDX and CDX xenograft models) Journal of translational medicine Medium 37718450
2025 LAD1 (Ladinin-1) co-regulates cortactin (CTTN) and N-WASP phosphorylation to mediate cytoskeletal reorganization in esophageal squamous cell carcinoma (ESCC), and together with LINC01305 promotes EMT via activation of the PI3K/AKT signaling pathway. Co-IP (LAD1-LINC01305 binding), phosphorylation assays for CTTN and N-WASP, EMT marker analysis, PI3K/AKT pathway assays, functional migration/invasion assays Molecular carcinogenesis Low 39835575
2020 LAD1 depletion inhibits migration and invasion of colorectal cancer cells (SW620, Caco-2) and reduces liver metastasis in a spleen-to-liver mouse model, without affecting cell proliferation, indicating a specific role in metastatic behavior. shRNA-mediated LAD1 depletion, migration/invasion assays, in vivo spleen-to-liver metastasis mouse model, immunohistochemistry BMC cancer Medium 33267790

Source papers

Stage 0 corpus · 30 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 LAD-1, the linear IgA bullous dermatosis autoantigen, is a novel 120-kDa anchoring filament protein synthesized by epidermal cells. The Journal of investigative dermatology 186 8618013
2001 LAD-1, the Caenorhabditis elegans L1CAM homologue, participates in embryonic and gonadal morphogenesis and is a substrate for fibroblast growth factor receptor pathway-dependent phosphotyrosine-based signaling. The Journal of cell biology 100 11502758
2000 Genetic analysis of integrin function in man: LAD-1 and other syndromes. Matrix biology : journal of the International Society for Matrix Biology 81 10936446
2015 Long-Term Balancing Selection in LAD1 Maintains a Missense Trans-Species Polymorphism in Humans, Chimpanzees, and Bonobos. Molecular biology and evolution 67 25605789
2007 Reversion mutations in patients with leukocyte adhesion deficiency type-1 (LAD-1). Blood 61 17875809
2003 D-xylose metabolism in Hypocrea jecorina: loss of the xylitol dehydrogenase step can be partially compensated for by lad1-encoded L-arabinitol-4-dehydrogenase. Eukaryotic cell 51 14555469
2018 SILAC identifies LAD1 as a filamin-binding regulator of actin dynamics in response to EGF and a marker of aggressive breast tumors. Science signaling 48 29382783
2016 A Four-Gene Promoter Methylation Marker Panel Consisting of GREM1, NEURL, LAD1, and NEFH Predicts Survival of Clear Cell Renal Cell Cancer Patients. Clinical cancer research : an official journal of the American Association for Cancer Research 45 27756787
2011 Reduced-intensity conditioning hematopoietic SCT for pediatric patients with LAD-1: clinical efficacy and importance of chimerism. Bone marrow transplantation 28 21743503
2018 Long term outcome of eight patients with type 1 Leukocyte Adhesion Deficiency (LAD-1): Not only infections, but high risk of autoimmune complications. Clinical immunology (Orlando, Fla.) 27 29548898
2006 Dendritic cell-mediated HIV-1 transmission to T cells of LAD-1 patients is impaired due to the defect in LFA-1. Retrovirology 26 17078873
2020 MSCs rescue impaired wound healing in a murine LAD1 model by adaptive responses to low TGF-β1 levels. EMBO reports 23 32080965
1997 LAD-1 is absent in a subset of junctional epidermolysis bullosa patients. The Journal of investigative dermatology 23 9284104
2020 Autoantibody Profile of a Cohort of 54 Italian Patients with Linear IgA Bullous Dermatosis: LAD-1 Denoted as a Major Auto-antigen of the Lamina Lucida Subtype. Acta dermato-venereologica 21 32011724
2002 Defective migration of monocyte-derived dendritic cells in LAD-1 immunodeficiency. Journal of leukocyte biology 21 12377933
2010 Calcium regulation of EGF-induced ERK5 activation: role of Lad1-MEKK2 interaction. PloS one 19 20830310
2021 circ-ANXA7 facilitates lung adenocarcinoma progression via miR-331/LAD1 axis. Cancer cell international 18 33536022
2020 LAD1 expression is associated with the metastatic potential of colorectal cancer cells. BMC cancer 18 33267790
2023 LAD1 promotes malignant progression by diminishing ubiquitin-dependent degradation of vimentin in gastric cancer. Journal of translational medicine 15 37718450
2020 β2 Integrin Gene (ITGB2) mutation spectra in Pakistani families with leukocyte adhesion deficiency type 1 (LAD1). Immunobiology 15 32279896
2015 Successful adjunctive immunoglobulin treatment in patients affected by leukocyte adhesion deficiency type 1 (LAD-1). Immunologic research 14 25527966
1999 Type XVII collagen (BP180) and LAD-1 are present as separate trimeric complexes. The Journal of investigative dermatology 13 9886264
2014 Characterization of single amino acid substitutions in the β2 integrin subunit of patients with leukocyte adhesion deficiency (LAD)-1. Blood cells, molecules & diseases 12 25514840
2021 High expression of ladinin-1 (LAD1) predicts adverse outcomes: a new candidate docetaxel resistance gene for prostatic cancer (PCa). Bioengineered 11 34516317
2010 A novel 3' splice-site mutation and a novel gross deletion in leukocyte adhesion deficiency (LAD)-1. Biochemical and biophysical research communications 11 21195692
2014 Successful anti-TNF-α treatment in a girl with LAD-1 disease and autoimmune manifestations. Journal of clinical immunology 10 25135596
2011 A Case of Chronic Bullous Disease of Childhood That Was Reactive to the Antigen of 120 kDa (LAD-1). Annals of dermatology 3 21747622
2005 In vivo tumouricidal effects of LAD-1 monoclonal antibody on murine RL-male-1 lymphoma mediated by enhanced phagocytosis. Clinical and experimental immunology 2 15958070
2025 LINC01305 and LAD1 Co-Regulate CTTN and N-WASP Phosphorylation, Mediating Cytoskeletal Reorganization to Promote ESCC Metastasis. Molecular carcinogenesis 1 39835575
2023 Circ_0060937 Contributes to the Development of Lung Cancer via Positively Regulating LAD1 Expression by Binding to miR-1304-5p. Biochemical genetics 0 36633773

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