Affinage

LZTR1

Leucine-zipper-like transcriptional regulator 1 · UniProt Q8N653

Length
840 aa
Mass
94.7 kDa
Annotated
2026-04-28
69 papers in source corpus 25 papers cited in narrative 25 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LZTR1 is a substrate-recognition adaptor for the CUL3-RING E3 ubiquitin ligase complex that functions as a central negative regulator of RAS/MAPK signaling by directing ubiquitination and degradation of multiple RAS family GTPases. LZTR1 ubiquitinates KRAS, HRAS, NRAS, MRAS, and RIT1—with RIT1 demonstrated as the preferred in vivo substrate, as Rit1 deletion rescues embryonic lethality of Lztr1-null mice—at conserved lysine residues (e.g., K170 of KRAS), promoting proteasomal degradation or membrane dissociation (PMID:30442762, PMID:31337872, PMID:35467524). Beyond RAS GTPases, LZTR1 ubiquitinates the ESCRT-III component CHMP1B to regulate VEGFR2 endosomal trafficking (PMID:32175818) and targets EGFR and AXL receptor tyrosine kinases for lysosomal degradation (PMID:36445254), and also modulates MHC-I transcription via NF-κB1/p50 co-translational biogenesis independently of ubiquitin ligase activity (PMID:41162356). Germline LZTR1 mutations cause Noonan syndrome through dominant-negative disruption of substrate recognition via the Kelch domain or impaired dimerization, leading to RAS accumulation and MAPK hyperactivation, while biallelic loss-of-function mutations cause recessive Noonan syndrome with cardiac hypertrophy and vascular defects (PMID:30481304, PMID:39352760, PMID:31883238).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2005 High

    The initial characterization of LZTR1 established its subcellular localization and regulated turnover, revealing it as a Golgi-associated BTB-domain protein subject to apoptosis-triggered degradation—setting the stage for later identification of its E3 ligase adaptor function.

    Evidence Confocal microscopy with Golgi markers, BTB domain deletion constructs, and caspase/proteasome inhibitor rescue in mammalian cells

    PMID:16356934

    Open questions at the time
    • No substrates or E3 ligase complex identified at this stage
    • Functional significance of Golgi localization not resolved
    • Upstream signals triggering tyrosine phosphorylation unknown
  2. 2018 High

    Two landmark studies simultaneously identified LZTR1 as a CUL3 E3 ligase adaptor that ubiquitinates RAS GTPases at K170, establishing the first direct biochemical mechanism linking LZTR1 to RAS/MAPK pathway suppression and explaining how disease mutations disrupt either CUL3 binding or RAS recognition.

    Evidence Complex trapping, ubiquitome MS with K170 site mapping, plasma membrane fractionation, disease mutation co-IP, and Drosophila genetic screen in mammalian cells

    PMID:30442762 PMID:30442766

    Open questions at the time
    • Relative substrate preference among RAS isoforms not determined
    • Structural basis of Kelch-RAS interaction unresolved
    • Contribution of different ubiquitin chain types not characterized
  3. 2019 High

    The substrate repertoire and degradation mechanism were expanded: LZTR1 was shown to polyubiquitinate multiple RAS GTPases via K48/K63/K33 chains for proteasomal degradation, and RIT1 was identified as a key interactor whose pathogenic mutations escape LZTR1-mediated turnover, while Noonan syndrome-causing Kelch domain mutations were mapped to the substrate-binding surface.

    Evidence In vivo ubiquitination assays with chain-type analysis, RIT1 MS interactome in knock-in mice, growth factor signaling assays, co-IP of LZTR1-CUL3 with disease mutants

    PMID:30481304 PMID:30872527 PMID:31337872

    Open questions at the time
    • No high-resolution structure of LZTR1-RAS or LZTR1-CUL3 complex
    • Functional hierarchy among RAS substrates in vivo not established
    • Mechanism of mixed ubiquitin chain assembly unknown
  4. 2020 High

    LZTR1 was shown to have non-RAS substrates: ubiquitination of the ESCRT-III component CHMP1B controls endosomal VEGFR2 trafficking, and Lztr1 whole-body knockout causes perinatal lethality from cardiovascular dysfunction, broadening LZTR1 biology beyond RAS proteostasis.

    Evidence Whole-body and vascular-specific Lztr1 KO mice, CHMP1B ubiquitination assays, VEGFR2 activation measurements, and cediranib pharmacological rescue

    PMID:32175818

    Open questions at the time
    • Relative contribution of CHMP1B vs. RAS dysregulation to cardiovascular lethality unclear
    • Whether CHMP1B recognition uses the same Kelch surface as RAS not tested
  5. 2021 Medium

    Brain-specific Lztr1 deletion revealed a role in neural development, with MAPK hyperactivation in white matter disrupting oligodendrocyte differentiation and promoting astrogliosis, connecting LZTR1 loss to neurodevelopmental features of Noonan syndrome.

    Evidence Conditional Lztr1 knockout (Foxg1-Cre) in mouse telencephalon with pERK and lineage-marker immunostaining

    PMID:34222248

    Open questions at the time
    • Which specific RAS isoform drives the oligodendrocyte phenotype not identified
    • Behavioral or cognitive consequences not assessed
    • Rescue experiments not performed
  6. 2022 High

    Genetic epistasis in mice definitively established RIT1 as the primary in vivo substrate of LZTR1: Rit1 deletion fully rescued the embryonic lethality of Lztr1-null animals, resolving the substrate hierarchy question among multiple RAS family members.

    Evidence Lztr1/Rit1 double-knockout mouse embryonic viability rescue, cross-species validation in Drosophila, and biochemical ubiquitination assays

    PMID:35467524

    Open questions at the time
    • Whether RIT1 dominance applies in all tissues or is context-dependent not resolved
    • Mechanism of LZTR1 selectivity for RIT1 over other RAS isoforms structurally unexplained
  7. 2022 Medium

    GSK3 was identified as an upstream regulator of LZTR1-mediated RAS turnover, with GSK3 inhibition accelerating RAS degradation in an LZTR1-dependent manner, introducing a kinase-level regulatory input into the pathway.

    Evidence GSK3 inhibitor and siRNA in pancreatic cancer cells with cycloheximide chase, proteasome inhibitor, and LZTR1 knockdown epistasis

    PMID:35114566

    Open questions at the time
    • Direct phosphorylation of LZTR1 by GSK3 not demonstrated
    • Whether GSK3 acts on LZTR1 stability, activity, or localization unknown
    • Relevance beyond pancreatic cancer cells not tested
  8. 2023 High

    The substrate scope of LZTR1 was further expanded to include receptor tyrosine kinases EGFR and AXL, targeted for lysosomal (not proteasomal) degradation, revealing a therapeutically actionable vulnerability in LZTR1-deleted schwannoma tumors.

    Evidence Unbiased biochemical substrate screens, ubiquitination assays, lysosome inhibitor treatment, conditional Lztr1/Cdkn2a KO mouse schwannoma model, and pharmacological co-inhibition of EGFR/AXL

    PMID:36445254

    Open questions at the time
    • How LZTR1 routes some substrates to proteasome vs. lysosome not mechanistically explained
    • Whether EGFR/AXL degradation is Kelch-domain dependent not shown
  9. 2023 Medium

    A RAS-independent function was uncovered: LZTR1 inhibits KLHL12-mediated ubiquitination of COPII component SEC31A, thereby suppressing collagen secretion and ECM deposition, linking LZTR1 loss to metastasis through a non-RAS pathway.

    Evidence Co-IP of LZTR1-KLHL12, SEC31A ubiquitination assays, collagen secretion quantification, and xenograft lung metastasis models

    PMID:37626065

    Open questions at the time
    • Whether LZTR1 directly ubiquitinates KLHL12 or inhibits it by competitive binding not distinguished
    • Independent replication needed
    • Relevance to Noonan syndrome phenotypes unexplored
  10. 2024 High

    Multiple studies refined the disease mechanism: oncogenic KRAS mutations abrogate LZTR1 interaction, dominant NS-causing LZTR1 mutations act as dominant negatives that fail to bind RIT1, and a dimerization-altering LZTR1 variant (L580P) forms aberrant polymers causing cardiomyocyte hypertrophy with tissue-specific degradation pathway preferences for MRAS vs. RIT1.

    Evidence APEX2 proximity labeling of KRAS mutants, Lztr1 knock-in mouse models with MEK inhibitor rescue, patient iPSC-derived cardiomyocytes with CRISPR correction

    PMID:38453365 PMID:39003740 PMID:39352760

    Open questions at the time
    • High-resolution structure of LZTR1 dimer and polymer forms still absent
    • How tissue context determines proteasomal vs. non-proteasomal degradation not defined
    • Whether all dominant LZTR1 mutations act via dominant-negative mechanism not established
  11. 2025 Medium

    Emerging evidence expanded LZTR1 functions beyond classical E3 ligase activity: LZTR1 regulates MHC-I transcription by modulating NF-κB1/p50 co-translational biogenesis in a ubiquitination-independent but proteasome-dependent manner, and cardiac-specific loss activates RAP1/MAPK/AKT causing dilated cardiomyopathy.

    Evidence LZTR1 KO in epithelial cells with ribosome/proteasome co-IP and in vivo CD8+ T cell phenotyping; cardiac-specific Lztr1 knockdown via CASAAV with transcriptomics and Ca2+ handling assays

    PMID:40967536 PMID:41162356

    Open questions at the time
    • Mechanism of LZTR1-ribosome-proteasome interaction in NF-κB1 biogenesis not structurally defined
    • Whether the MHC-I regulatory function is CUL3-independent not formally tested
    • Contribution of RAP1 vs. classical RAS isoforms in cardiomyopathy not distinguished

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: the high-resolution structural basis of LZTR1 Kelch domain–substrate recognition and dimerization; how LZTR1 differentially routes substrates to proteasomal vs. lysosomal degradation; the mechanism by which GSK3 and PAK1/2-PP1C phosphorylation cascades regulate LZTR1-mediated RAS turnover; and whether ubiquitination-independent functions (MHC-I regulation, KLHL12 inhibition) represent core LZTR1 biology or context-dependent activities.
  • No crystal or cryo-EM structure of LZTR1 or LZTR1-substrate complex
  • Substrate routing mechanism (proteasome vs. lysosome) not defined
  • Integration of upstream kinase/phosphatase regulation with substrate selectivity not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 7 GO:0098772 molecular function regulator activity 4
Localization
GO:0005829 cytosol 2 GO:0005768 endosome 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-168256 Immune System 1
Partners
CHMP1BCUL3HRASKLHL12KRASMRASNRASRIT1
Complex memberships
CUL3-RING E3 ubiquitin ligase complex

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 LZTR1 localizes exclusively to the cytoplasmic surface of the Golgi network, with this localization mediated by its second BTB/POZ domain. Upon induction of apoptosis, LZTR1 is phosphorylated on tyrosine residues and subsequently degraded via caspase- and proteasome-dependent mechanisms. Confocal microscopy with Golgi markers (GM130, Golgin-97, TGN46), brefeldin A treatment, BTB domain deletion constructs, caspase inhibitor (Z-VAD-fmk) and proteasome inhibitor (lactacystin, MG132) rescue experiments The Journal of biological chemistry High 16356934
2018 LZTR1 acts as an adaptor for the CUL3 E3 ubiquitin ligase complex and directly associates with RAS GTPases (KRAS, HRAS, NRAS, MRAS). LZTR1-mediated ubiquitination of RAS (at K170 of KRAS) inhibits RAS signaling by attenuating its plasma membrane association. Disease-associated LZTR1 mutations disrupt either LZTR1-CUL3 complex formation or its interaction with RAS. LZTR1 complex trapping from intact mammalian cells, ubiquitome mass spectrometry analysis, plasma membrane fractionation, site-directed mutagenesis of RAS K170, co-immunoprecipitation, Drosophila genetic screen (knockdown of CG3711/LZTR1 ortholog causing Ras-dependent phenotype) Science (New York, N.Y.) High 30442762 30442766
2018 LZTR1 loss abrogates RAS ubiquitination at lysine-170 (K170), leading to decreased ubiquitination and enhanced plasma membrane localization of endogenous KRAS, with consequent enhanced MAPK pathway activity. Ubiquitome analysis by mass spectrometry in Lztr1 knockout vs. wild-type cells, subcellular fractionation, immunoprecipitation Science (New York, N.Y.) High 30442762
2019 LZTR1 facilitates polyubiquitination and proteasomal degradation of multiple RAS GTPases (KRAS, HRAS, NRAS, MRAS, and oncogenic RAS mutants). Ubiquitination occurs at MRAS-K127 and HRAS-K170, with polyubiquitin chains containing K48, K63, and K33 linkages. LZTR1-mediated RAS degradation is primarily via the ubiquitin-proteasome pathway, with minimal contribution from autophagy. In vivo ubiquitination assay, immunoprecipitation, western blotting, site-directed mutagenesis of ubiquitination sites, chloroquine treatment, LC3B lipidation assay, proteasome inhibitor treatment Cell death and differentiation High 31337872
2019 LZTR1 acts as an adaptor for protein degradation of the RAS GTPase RIT1. Pathogenic mutations in either RIT1 (near the switch II domain) or LZTR1 result in incomplete degradation of RIT1, causing RIT1 accumulation and dysregulated growth factor signaling. RIT1 is identified as an LZTR1 interactor by mass spectrometry. Mass spectrometry interactome of RIT1, isogenic germline knock-in mouse model of RIT1 mutation, western blotting for RIT1 protein levels, growth factor signaling assays Science (New York, N.Y.) High 30872527
2019 Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the surface of the Kelch domain mediating substrate binding, do not perturb LZTR1 binding to CUL3, and enhance stimulus-dependent RAS-MAPK signaling associated with an increased RAS protein pool. Recessive NS missense mutations differ mechanistically from dominant mutations. Co-immunoprecipitation of LZTR1-CUL3, RAS protein quantification by western blot, ERK phosphorylation assays after growth factor stimulation, subcellular localization imaging, computational structural prediction of Kelch domain surface mutations Human molecular genetics Medium 30481304
2018 LZTR1 binds to the RAF1-PPP1CB complex, as shown by immunoprecipitation of endogenous LZTR1. LZTR1 knockdown leads to decreased levels of RAF1 phosphorylated at Ser259, indicating LZTR1 participates in regulation of RAF1 activity within the RAS/MAPK pathway. Co-immunoprecipitation of endogenous LZTR1 followed by western blotting; siRNA knockdown of LZTR1 with assessment of RAF1-pSer259 phosphorylation Human genetics Medium 30368668
2020 LZTR1 controls ubiquitination of the ESCRT-III component CHMP1B, affecting the dynamics of fusion and fission of recycling endosomes. LZTR1-mediated dysregulation of CHMP1B ubiquitination triggers endosomal accumulation and subsequent activation of VEGFR2, leading to vascular leakage. NS-associated LZTR1 mutations diminish CHMP1B ubiquitination. Whole-body Lztr1 knockout causes perinatal lethality due to cardiovascular dysfunction. Whole-body and vascular-specific Lztr1 knockout mice, endothelial cell knockdown, ubiquitination assays of CHMP1B, VEGFR2 activation assays, recycling endosome dynamics imaging, VEGFR2 inhibitor (cediranib) rescue, ELISA for soluble VEGFR2 Circulation research High 32175818
2020 In Drosophila, the LZTR1 ortholog (night owl/nowl, CG3711) negatively regulates RAS signaling and interacts genetically with Nf1 in sleep regulation. Nowl is required for metabolic homeostasis, and knockdown in GABA-responsive sleep-promoting neurons elicits sleep phenotype rescuable by increased GABAA receptor signaling. Drosophila genetic knockdown, sleep behavior assays, genetic epistasis with Nf1, pharmacological rescue with GABAA receptor agonists PLoS genetics Medium 32339168
2022 In both Drosophila and mice, LZTR1 loss-of-function phenotypes show biochemical preference for RIT1 orthologs as substrates. Embryonic lethality of homozygous Lztr1 null mice can be rescued by deletion of Rit1, demonstrating that RIT1 is the primary functional substrate of LZTR1 in vivo. Lztr1 knockout mice, Rit1 knockout mice, double-knockout (Lztr1/Rit1) mice with embryonic viability rescue, Drosophila genetics, biochemical ubiquitination assays eLife High 35467524
2022 GSK3 kinase regulates the function of LZTR1. Inhibiting or silencing GSK3 in pancreatic cancer cells leads to decreased Ras protein levels (including oncogenic KRAS), a 3-fold decrease in Ras protein half-life that is blocked by proteasome inhibition or LZTR1 knockdown, indicating GSK3 acts upstream of LZTR1 in regulating Ras proteostasis. GSK3 inhibitor and siRNA knockdown, protein half-life measurement by cycloheximide chase, proteasome inhibitor treatment, LZTR1 siRNA rescue, cell proliferation assays Neoplasia (New York, N.Y.) Medium 35114566
2023 LZTR1-CUL3 ubiquitin ligase targets EGFR and AXL receptor tyrosine kinases for ubiquitin-dependent lysosomal degradation. Pathogenic cancer-associated LZTR1 mutations fail to promote EGFR and AXL degradation, resulting in their accumulation and dysregulated growth factor signaling. LZTR1/Cdkn2a-deleted mouse tumors accumulate EGFR and AXL and are vulnerable to co-inhibition of both kinases. Unbiased biochemical screens for LZTR1 substrates, co-immunoprecipitation, ubiquitination assays, lysosome inhibitor treatment, conditional Lztr1/Cdkn2a knockout mouse model of schwannoma-like tumors, pharmacological inhibition of EGFR and AXL Cancer discovery High 36445254
2023 LZTR1 inhibits KLHL12-mediated ubiquitination of SEC31A (a COPII coat component), thereby suppressing collagen secretion. LZTR1 deficiency promotes KLHL12-SEC31A-mediated collagen secretion and ECM deposition, enhancing tumor metastasis independently of RAS regulation. Multi-omics analysis of LZTR1 knockout cells, co-immunoprecipitation of LZTR1 with KLHL12, ubiquitination assays of SEC31A, collagen secretion assays, in vivo xenograft and lung metastasis models Cell death & disease Medium 37626065
2024 KRAS oncogenic mutations (G12D, G13D, Q61H) abrogate KRAS association with LZTR1, thereby preventing LZTR1-mediated turnover of oncogenic KRAS. WT KRAS and LZTR1 interact, while activating mutations disrupt this interaction. APEX2 proximity labeling of KRAS mutants (WT, G12D, G13D, Q61H), quantitative proteomics under starvation and stimulation, co-immunoprecipitation validation Life science alliance Medium 38453365
2024 A homozygous LZTR1 L580P variant alters the binding affinity of LZTR1 dimerization domains, facilitating formation of linear LZTR1 polymers. This complex dysfunction results in accumulation of RAS GTPases and cardiomyocyte hypertrophy. Cardiomyocyte-specific MRAS degradation is mediated by LZTR1 via non-proteasomal pathways, while RIT1 degradation is mediated by both LZTR1-dependent and LZTR1-independent pathways. Patient-specific iPSC-derived cardiomyocytes, CRISPR-Cas9 correction, in silico structural prediction of polymerization, proteomic landscape analysis, RAS GTPase accumulation assays, pathway-specific inhibitor treatments Cell reports Medium 39003740
2024 Autosomal dominant LZTR1 mutations (G245R and R409C, corresponding to human G248R and R412C) cause Noonan syndrome-like phenotypes in knock-in mice. LZTR1 AD mutants do not interact with RIT1 and function as dominant-negative forms of WT LZTR1. MRAS and RIT1 accumulate in the left ventricles of mutant mice, and MEK inhibitor trametinib ameliorates cardiac hypertrophy. LZTR1 knock-in mouse models (Lztr1G245R/+ and Lztr1R409C/+), co-immunoprecipitation of LZTR1 with RIT1, multi-omics analysis of LV tissue, MEK inhibitor treatment JCI insight High 39352760
2024 Small molecule fragments (C53 and Z86) enhance the protein-protein interaction between KRAS and LZTR1. This was established using a split-luciferase reporter assay, proximity biotinylation (BioID), thermal shift assays, and NMR spectroscopy, confirming fragment-dependent enhanced recruitment of endogenous LZTR1 and physical engagement with KRAS. Split-luciferase reporter assay, BioID proximity biotinylation, thermal shift assay, NMR spectroscopy, small fragment library screening ACS chemical biology Medium 39194017
2025 LZTR1 regulates MHC-I transcription by modulating co-translational biogenesis of NF-κB1 (p50) in a ubiquitination-independent but proteasome-dependent manner through direct binding with ribosome and proteasome. Loss of LZTR1 leads to suppression of CD8+ tissue-resident memory T cell activation and reduced IL-17A production. LZTR1 knockout in cutaneous and colonic epithelial cells, co-immunoprecipitation with ribosome and proteasome components, MHC-I and NF-κB1 expression assays, in vivo mouse models of LZTR1 conditional knockout Cell discovery Medium 41162356
2026 The phosphatase PP1C dephosphorylates the conserved T148 residue on RAS, permitting LZTR1-dependent proteasomal degradation. Kinases PAK1 and PAK2 phosphorylate RAS at T148, shielding it from LZTR1-dependent degradation. KRAS A146 gain-of-function mutations (adjacent to T148) abrogate LZTR1-mediated degradation. Multi-omics screen in multiple myeloma cells, phosphatase/kinase identification by functional genomics, RAS T148 site-specific mutagenesis, co-immunoprecipitation, PAK1/2 inhibitor treatment bioRxivpreprint Medium 41542462
2021 Lztr1 deficiency in the mouse telencephalon leads to increased MAPK pathway activation in white matter, altered oligodendrocyte lineage development with increased OPCs and decreased oligodendrocyte differentiation markers, and increased astrocyte marker GFAP expression. Conditional Lztr1 knockout (Foxg1-Cre), pERK immunostaining, stage-specific oligodendrocyte marker immunostaining, GFAP immunostaining Frontiers in cell and developmental biology Medium 34222248
2025 LZTR1 interacts with NOC2L (a histone acetyltransferase inhibitor); this interaction is disrupted by dominant Noonan syndrome LZTR1 variants. LZTR1 variant expression leads to upregulation of NOC2L and impaired p53 acetylation, with consequent reduced apoptosis and compensatory increase in autophagy. Phosphoproteomics of LZTR1 variant vs. WT expressed in mammalian cells, nanoluciferase protein-protein interaction assay, immunoblotting, immunofluorescence, in silico structural modeling The Journal of clinical endocrinology and metabolism Low 41175093
2025 LZTR1 loss in Hep3B hepatocellular carcinoma cells increases phosphorylation across the RAF-MEK-ERK-RSK cascade, remodels EMT-associated markers, and suppresses vimentin expression, leading to impaired cell migration and invasion. LZTR1 CRISPR knockout, immunoblotting for pathway activation, RNA-seq transcriptomics, GSEA, wound closure and transwell migration/invasion assays International journal of molecular sciences Medium 41752002
2025 LZTR1 regulates the ubiquitin proteasome system in melanoma cells and associates with actin-related proteins. Overexpression of LZTR1 activates ERBB3 receptor and its downstream targets PYK2 and SRC tyrosine kinases, enhancing cell invasion and actin cytoskeleton organization. LZTR1 downregulation suppresses autophagy regulators ULK1 and AMBRA1 while upregulating p62/SQSTM1. Proximity biotinylation (BioID) and co-immunoprecipitation with LC-MS/MS proteomics, LZTR1 knockdown and overexpression, ERBB3/PYK2/SRC pathway activation assays, invasion assays Oncogene Medium 40885854
2019 Biallelic loss of lztr1 in zebrafish (CRISPR-Cas9 frameshift) results in ventricular hypertrophy and multiple vascular malformations, phenocopying human recessive Noonan syndrome and supporting a loss-of-function disease mechanism. CRISPR-Cas9 zebrafish knockout, histological analysis, western blotting for RAS/MAPK signaling Molecular genetics & genomic medicine Medium 31883238
2025 Lztr1 deficiency in mouse hearts activates the RAP1/MAPK/AKT signaling pathway, leads to Ca2+ homeostasis disruption, elevated cardiomyocyte apoptosis, and disrupted mitochondrial function, causing dilated cardiomyopathy. CRISPR-Cas9/AAV9-mediated cardiac-specific Lztr1 knockdown (CASAAV), transcriptomic sequencing, western blotting for pathway activation, Ca2+ handling measurements, mitochondrial function assays International journal of biological macromolecules Medium 40967536

Source papers

Stage 0 corpus · 69 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas. Nature genetics 229 24362817
2015 Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. Journal of medical genetics 194 25795793
2018 LZTR1 is a regulator of RAS ubiquitination and signaling. Science (New York, N.Y.) 179 30442766
2018 Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination. Science (New York, N.Y.) 168 30442762
2018 Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants. Genetics in medicine : official journal of the American College of Medical Genetics 159 29469822
2016 Revisiting neurofibromatosis type 2 diagnostic criteria to exclude LZTR1-related schwannomatosis. Neurology 99 27856782
2014 Mutations in LZTR1 add to the complex heterogeneity of schwannomatosis. Neurology 97 25480913
2019 LZTR1 facilitates polyubiquitination and degradation of RAS-GTPases. Cell death and differentiation 90 31337872
2019 RIT1 oncoproteins escape LZTR1-mediated proteolysis. Science (New York, N.Y.) 86 30872527
2019 Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the Kelch domain substrate-recognition surface and enhance RAS-MAPK signaling. Human molecular genetics 73 30481304
2014 Expanding the mutational spectrum of LZTR1 in schwannomatosis. European journal of human genetics : EJHG 64 25335493
2005 The BTB-kelch protein LZTR-1 is a novel Golgi protein that is degraded upon induction of apoptosis. The Journal of biological chemistry 63 16356934
2018 Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes. Human genetics 61 30368668
2019 Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome. Clinical genetics 50 30859559
2020 Analysis of genes within the schizophrenia-linked 22q11.2 deletion identifies interaction of night owl/LZTR1 and NF1 in GABAergic sleep control. PLoS genetics 29 32339168
2019 Providing more evidence on LZTR1 variants in Noonan syndrome patients. American journal of medical genetics. Part A 27 31825158
2016 Multifocal nerve lesions and LZTR1 germline mutations in segmental schwannomatosis. Annals of neurology 24 27472264
2021 LZTR1: A promising adaptor of the CUL3 family. Oncology letters 22 34113392
2020 The Noonan Syndrome Gene Lztr1 Controls Cardiovascular Function by Regulating Vesicular Trafficking. Circulation research 21 32175818
2019 Oligo-astrocytoma in LZTR1-related Noonan syndrome. European journal of medical genetics 21 30664951
2023 LZTR1 Mutation Mediates Oncogenesis through Stabilization of EGFR and AXL. Cancer discovery 18 36445254
2023 LZTR1 deficiency exerts high metastatic potential by enhancing sensitivity to EMT induction and controlling KLHL12-mediated collagen secretion. Cell death & disease 18 37626065
2022 Cross-species analysis of LZTR1 loss-of-function mutants demonstrates dependency to RIT1 orthologs. eLife 18 35467524
2022 LZTR1 molecular genetic overlap with clinical implications for Noonan syndrome and schwannomatosis. BMC medical genomics 18 35840934
2019 LZTR1: Genotype Expansion in Noonan Syndrome. Hormone research in paediatrics 16 31533111
2020 Simultaneous Detection of NF1, SPRED1, LZTR1, and NF2 Gene Mutations by Targeted NGS in an Italian Cohort of Suspected NF1 Patients. Genes 13 32575496
2017 Constitutional LZTR1 mutation presenting with a unilateral vestibular schwannoma in a teenager. Clinical genetics 13 28295212
2016 Unilateral vestibular schwannoma in a patient with schwannomatosis in the absence of LZTR1 mutation. Journal of neurosurgery 13 26848914
2021 Expanding the clinical phenotype of RASopathies in 38 Turkish patients, including the rare LZTR1, RAF1, RIT1 variants, and large deletion in NF1. American journal of medical genetics. Part A 12 34184824
2024 Mutation-induced LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome. Cell reports 11 39003740
2022 The GSK3 kinase and LZTR1 protein regulate the stability of Ras family proteins and the proliferation of pancreatic cancer cells. Neoplasia (New York, N.Y.) 11 35114566
2022 Molecular autopsy and clinical family screening in a case of sudden cardiac death reveals ACTN2 mutation related to hypertrophic/dilated cardiomyopathy and a novel LZTR1 variant associated with Noonan syndrome. Molecular genetics & genomic medicine 11 35656879
2024 Dysregulation of RAS proteostasis by autosomal-dominant LZTR1 mutation induces Noonan syndrome-like phenotypes in mice. JCI insight 9 39352760
2022 RASopathy Cohort of Patients Enrolled in a Brazilian Reference Center for Rare Diseases: A Novel Familial LZTR1 Variant and Recurrent Mutations. The application of clinical genetics 9 36304179
2019 Noonan syndrome-associated biallelic LZTR1 mutations cause cardiac hypertrophy and vascular malformations in zebrafish. Molecular genetics & genomic medicine 9 31883238
2019 Further support linking the 22q11.2 microduplication to an increased risk of bladder exstrophy and highlighting LZTR1 as a candidate gene. Molecular genetics & genomic medicine 8 31044557
2024 Oncogenic mutations of KRAS modulate its turnover by the CUL3/LZTR1 E3 ligase complex. Life science alliance 6 38453365
2021 A Chinese family with Noonan syndrome caused by a heterozygous variant in LZTR1: a case report and literature review. BMC endocrine disorders 6 33407364
2021 Structural Model for Recruitment of RIT1 to the LZTR1 E3 Ligase: Evidences from an Integrated Computational Approach. Journal of chemical information and modeling 5 33792302
2020 LZTR1-related spinal schwannomatosis and 7q11.23 duplication syndrome: A complex phenotype with dual diagnosis. Molecular genetics & genomic medicine 5 33269527
2024 Preclinical evaluation of CRISPR-based therapies for Noonan syndrome caused by deep-intronic LZTR1 variants. Molecular therapy. Nucleic acids 4 38333672
2024 Phenotypic Expansion of Autosomal Dominant LZTR1-Related Disorders with Special Emphasis on Adult-Onset Features. Genes 4 39062695
2025 Novel LZTR1 germline mutation as a mechanism of resistance to osimertinib in EGFR-mutated lung adenocarcinoma: a case report. Translational lung cancer research 3 40114953
2024 Gonadal dysfunction in a man with Noonan syndrome from the LZTR1 variant: case report and review of literature. Frontiers in endocrinology 3 38689733
2024 Heterozygosity for loss-of-function variants in LZTR1 is associated with isolated multiple café-au-lait macules. Genetics in medicine : official journal of the American College of Medical Genetics 3 39140257
2024 Identification and Characterization of Novel Small-Molecule Enhancers of the CUL3LZTR1 E3 Ligase KRAS Complex. ACS chemical biology 3 39194017
2022 A Comprehensive Pan-Cancer Analysis of the Tumorigenic Effect of Leucine-Zipper-Like Transcription Regulator (LZTR1) in Human Cancer. Oxidative medicine and cellular longevity 3 36304963
2021 Concomitant variants in NF1, LZTR1 and GNAZ genes probably contribute to the aggressiveness of plexiform neurofibroma and warrant treatment with MEK inhibitor. Experimental dermatology 3 34913528
2025 Pathogenic Variants and Allele Loss of the NF2 and LZTR1 Gene in Sporadic Vestibular Schwannoma. In vivo (Athens, Greece) 2 40295009
2025 LZTR1 expression as a novel predictive biomarker for early recurrence of hepatocellular carcinoma. European journal of medical research 1 40542439
2025 LZTR1: c.1260+1del Variant as a Significant Predictor of Early-Age Breast Cancer Development: Case Report Combined with In Silico Analysis. International journal of molecular sciences 1 40724954
2025 Lztr1 deficiency contributes to the pathogenesis of dilated cardiomyopathy via RAP1/PI3K/AKT-mediated myocardial Injury. International journal of biological macromolecules 1 40967536
2025 LZTR1 regulates epithelial MHC-I expression via NF-κB1 to modulate CD8+ T cells activation. Cell discovery 1 41162356
2024 LZTR1 loss-of-function variants associated with café au lait macules with or without freckling. Frontiers in neurology 1 39258154
2024 Generation of a human induced pluripotent stem cell line from a female patient carrying LZTR1 gene mutation. Stem cell research 1 39577308
2023 Exome Survey and Candidate Gene Re-Sequencing Identifies Novel Exstrophy Candidate Genes and Implicates LZTR1 in Disease Formation. Biomolecules 1 37509153
2021 Generation of a Mouse Model to Study the Noonan Syndrome Gene Lztr1 in the Telencephalon. Frontiers in cell and developmental biology 1 34222248
2021 Spontaneous resolution of nonimmune hydrops fetalis in a fetus with TP63 gene mutation and LZTR1 gene variants. Clinical case reports 1 34401172
2026 Pathogenesis of Noonan Syndrome is Modulated by NOC2L, a Novel Interactor of LZTR1 Leading to Impaired P53 Signalling. The Journal of clinical endocrinology and metabolism 0 41175093
2026 Central nervous system schwannoma, VGLL-fused (EWSR1::VGLL1 fusion) with neuroblastoma-like cell dense areas in the frontal lobe of a young man with schwannomatosis due to a germline LZTR1 mutation. Free neuropathology 0 41522855
2026 Phosphorylation Protects Oncogenic RAS from LZTR1-Mediated Degradation. bioRxiv : the preprint server for biology 0 41542462
2026 LZTR1 Loss Reduces Vimentin Expression and Motility in Hep3B Hepatocellular Carcinoma Cells. International journal of molecular sciences 0 41752002
2025 The tumor suppressor LZTR1: Its expression, purification and characterization. Protein expression and purification 0 40204202
2025 Protein-losing enteropathy and multiple vasculature dysplasia in LZTR1-related Noonan syndrome: A case report and review of literature. World journal of gastroenterology 0 40521264
2025 Genetic Variants in LZTR1, MAP2K1 and RAF1: Insights into the Role of RAS-MAPK Pathway in Primary Lymphedema. Lymphology 0 40803040
2025 LZTR1 is a melanoma oncogene that promotes invasion and suppresses apoptosis. Oncogene 0 40885854
2025 Homozygous LZTR1 Variant Lacking the Second BTB Domain Associated With Bone Marrow Failure and Multiple Congenital Anomalies Distinct From Those of Noonan Syndrome. Clinical genetics 0 41196194
2025 Novel susceptibility genes for non-NF2-/LZTR1-/SMARCB1-related hereditary schwannomatosis. Familial cancer 0 41286185
2024 Familial schwannomatosis carrying LZTR1 variant p.R340X with brain tumor: A case report. Molecular genetics and metabolism reports 0 38983105