Affinage

LZTR1

Leucine-zipper-like transcriptional regulator 1 · UniProt Q8N653

Length
840 aa
Mass
94.7 kDa
Annotated
2026-06-10
69 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LZTR1 is a BTB-Kelch substrate-specific adaptor for a CUL3 RING E3 ubiquitin ligase that restrains RAS-MAPK signaling by targeting RAS-family GTPases for ubiquitin-dependent degradation (PMID:30442762, PMID:30442766). As the adaptor of the CRL3-LZTR1 complex, it ubiquitinates KRAS, HRAS, NRAS, and MRAS at conserved lysines (HRAS K170, MRAS K127), promoting their proteasomal turnover, attenuating their plasma-membrane association, and thereby dampening ERK1/2 activation and proliferation (PMID:30442762, PMID:31337872); in vivo across flies and mice, RIT1 emerges as the genetically preferred substrate, since deletion of Rit1 rescues the lethality of Lztr1 loss (PMID:30872527, PMID:35467524). Substrate engagement is gated by the GTPase nucleotide/mutational state and by post-translational marks: oncogenic KRAS mutations (G12D, G13D, Q61H, A146) abrogate LZTR1 capture and turnover (PMID:38453365, PMID:41542462), while a PAK1/2-phosphorylated/PP1C-dephosphorylated T148 switch and a GSK3-dependent input control RAS stability through LZTR1 (PMID:35114566, PMID:41542462). Beyond RAS, LZTR1 directs CUL3-dependent lysosomal degradation of the receptor tyrosine kinases EGFR and AXL (PMID:36445254) and controls vesicular trafficking by ubiquitinating the ESCRT-III component CHMP1B to regulate recycling-endosome dynamics and VEGFR2 signaling (PMID:32175818). Disease-associated mutations act through distinct mechanisms—disrupting substrate binding at the Kelch surface, CUL3 interaction, or LZTR1 dimerization—and dominant-negative variants poison wild-type LZTR1, causing accumulation of RAS/RIT1/MRAS and MAPK hyperactivation that underlies Noonan syndrome, schwannomatosis-like tumors, and cardiomyopathy, with MEK inhibition (trametinib) reversing cardiac phenotypes in mutant mice (PMID:30481304, PMID:36445254, PMID:39003740, PMID:39352760). LZTR1 localizes to the cytoplasmic face of the Golgi via its second BTB domain (PMID:16356934).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2005 Medium

    Established the first cellular context for LZTR1, defining where it resides before any enzymatic role was known.

    Evidence Confocal microscopy with Golgi markers, brefeldin A, and domain-deletion analysis in mammalian cells

    PMID:16356934

    Open questions at the time
    • No molecular activity assigned at this stage
    • Functional consequence of Golgi localization for later-defined substrates unresolved
    • Tyrosine-phosphorylation/caspase degradation pathway not connected to ubiquitin ligase function
  2. 2018 High

    Resolved the core biochemical function: LZTR1 is a CUL3 adaptor that ubiquitinates RAS GTPases at defined lysines to limit membrane association and MAPK output.

    Evidence Complex trapping, ubiquitome MS, site-directed mutagenesis (HRAS K170, MRAS K127), membrane-localization assays, and mouse haploinsufficiency model; corroborated by genetic screens and endogenous reciprocal Co-IP plus Drosophila epistasis

    PMID:30442762 PMID:30442766

    Open questions at the time
    • Ubiquitin chain linkage composition not yet defined
    • Relative ranking of RAS isoform substrates in vivo unresolved
    • Endosomal/RTK substrates not yet known
  3. 2018 Medium

    Connected LZTR1 to RAF1 phosphorylation, indicating it modulates signaling at additional nodes of the RAS/MAPK cascade.

    Evidence Endogenous Co-IP of LZTR1 with RAF1-PPP1CB and siRNA knockdown with phospho-RAF1 (Ser259) immunoblot

    PMID:30368668

    Open questions at the time
    • Direct vs indirect effect on RAF1 phosphorylation not distinguished
    • No ubiquitination of RAF1 demonstrated
    • Single lab, two methods
  4. 2019 High

    Defined the degradation route and chain chemistry and identified RIT1 as a substrate, broadening the GTPase repertoire LZTR1 controls.

    Evidence In vivo ubiquitination assays with K48/K63/K33 linkage and site mutagenesis; MS identification of RIT1 interaction with isogenic knock-in mouse model

    PMID:30872527 PMID:31337872

    Open questions at the time
    • Autophagy contribution minor but not fully delineated
    • Why RIT1 vs classical RAS preference unresolved at this stage
  5. 2019 Medium

    Distinguished dominant from recessive disease mechanisms, showing dominant Noonan mutations spare CUL3 binding and stability but impair substrate recognition.

    Evidence Transfection of NS-associated mutants with phospho-ERK, RAS level, CUL3 Co-IP, stability/localization assays, and Kelch-domain modeling

    PMID:30481304

    Open questions at the time
    • No in vivo validation
    • Structural modeling not experimentally confirmed
    • Mechanism of dominant effect not fully resolved here
  6. 2020 High

    Extended LZTR1 substrate scope beyond RAS to CHMP1B, linking it to endosomal trafficking and cardiovascular VEGFR2 control.

    Evidence Conditional/whole-body and endothelial Lztr1 knockout mice, CHMP1B ubiquitination assays, VEGFR2 readouts, and cediranib rescue

    PMID:32175818

    Open questions at the time
    • Relationship between RAS and CHMP1B substrate pathways unresolved
    • Structural basis of CHMP1B recognition unknown
  7. 2020 Medium

    Demonstrated conserved organismal physiology for LZTR1 RAS regulation, linking it to NF1 and GABAergic sleep control.

    Evidence Drosophila nowl loss-of-function, genetic epistasis with Nf1, tissue-specific knockdown, and GABAA pharmacological rescue

    PMID:32339168

    Open questions at the time
    • Mammalian relevance of sleep phenotype untested
    • Direct substrate driving phenotype not identified
  8. 2021 Medium

    Showed LZTR1 loss perturbs CNS cell-fate decisions through MAPK hyperactivation, relevant to its tumor and developmental phenotypes.

    Evidence Foxg1-Cre conditional Lztr1 knockout mice with oligodendrocyte lineage marker analysis and phospho-ERK measurement

    PMID:34222248

    Open questions at the time
    • Substrate driving lineage block not identified
    • Single lab descriptive phenotype
  9. 2022 High

    Established RIT1 orthologs as the genetically preferred in vivo substrate by rescuing lethality, ranking substrates physiologically.

    Evidence Lztr1 loss-of-function in fly and mouse with Rit1 knockout rescue and biochemical substrate-preference assays

    PMID:35467524

    Open questions at the time
    • Biochemical basis of RIT1 preference vs classical RAS unresolved
    • Tissue-specific substrate hierarchy not mapped
  10. 2022 Medium

    Identified additional non-RAS roles—repression of KLHL12/SEC31A-mediated collagen secretion and a GSK3-dependent input controlling RAS stability.

    Evidence LZTR1 knockout in lung adenocarcinoma cells with KLHL12 Co-IP and SEC31A ubiquitination assays; GSK3 inhibition/knockdown with LZTR1-dependent half-life and proteasome-rescue assays in pancreatic cancer cells

    PMID:35114566 PMID:37626065

    Open questions at the time
    • Mechanism by which GSK3 acts on the LZTR1-RAS axis undefined
    • KLHL12 repression mechanism single lab
  11. 2022 High

    Expanded substrate scope to receptor tyrosine kinases, showing LZTR1 routes EGFR and AXL to lysosomal degradation and that cancer mutations fail to do so.

    Evidence Unbiased Co-IP/MS, ubiquitination/degradation and lysosomal-pathway assays, and Lztr1/Cdkn2a conditional schwannoma mouse model with EGFR+AXL co-inhibition

    PMID:36445254

    Open questions at the time
    • Why these substrates go to lysosome vs proteasome unresolved
    • CUL3-dependence of RTK degradation step not fully dissected
  12. 2024 Medium

    Showed substrate capture is gated by KRAS mutational state, explaining how oncogenic mutants evade LZTR1-mediated turnover.

    Evidence APEX2 proximity labeling and quantitative proteomics comparing WT and G12D/G13D/Q61H KRAS under starvation/stimulation

    PMID:38453365

    Open questions at the time
    • No direct ubiquitination assay for the mutants in this study
    • Structural basis of impaired capture not shown
  13. 2024 Medium

    Defined two distinct disease-mutation mechanisms—dimerization-disrupting polymer formation and dominant-negative inhibition—both causing RAS/RIT1/MRAS accumulation and reversible by MEK inhibition.

    Evidence Patient/CRISPR-corrected iPSC cardiomyocytes with proteomics and rescue (L580P); Lztr1 G245R/R409C knock-in mice with RIT1 Co-IP, protein-level assays, and trametinib rescue

    PMID:39003740 PMID:39352760

    Open questions at the time
    • Polymer-formation model partly in silico
    • Non-proteasomal MRAS degradation route in cardiomyocytes undefined
    • Single lab per model
  14. 2024 Medium

    Provided a structural/biochemical foothold by reconstituting the CRL3-LZTR1-MRAS complex and demonstrating CUL3-driven stabilization of LZTR1.

    Evidence BacMam expression, purification, and in vitro binding assays comparing MRAS, RIT1, and HRAS

    PMID:40204202

    Open questions at the time
    • No high-resolution structure reported in abstract
    • Discrepancy with in vivo RIT1 preference unresolved
    • Limited functional follow-up
  15. 2024 Medium

    Identified small-molecule fragments that enhance the KRAS-LZTR1 interaction, establishing the complex as a druggable degradation-promoting target.

    Evidence Split-luciferase reporter, BioID, thermal shift, and NMR characterization of fragments C53/Z86

    PMID:39194017

    Open questions at the time
    • No in vivo validation
    • Effect on KRAS degradation not directly demonstrated
  16. 2025 Medium

    Uncovered a phosphorylation switch (PAK1/2-PP1C at RAS T148) and tissue context that set whether LZTR1 can degrade RAS, explaining differential RAS stability across cancers.

    Evidence Multi-omics in multiple myeloma cells, writer/eraser identification (PAK1/2, PP1C), T148 mutagenesis, LZTR1-dependent degradation and stability assays (preprint)

    PMID:41542462

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Structural basis of how T148 phosphorylation blocks LZTR1 capture unknown
  17. 2025 Medium

    Revealed ubiquitination-independent functions—co-translational regulation of NF-kB1/MHC-I via ribosome/proteasome binding and disruption of LZTR1-NOC2L controlling p53 acetylation—broadening LZTR1 mechanism beyond RAS degradation.

    Evidence LZTR1 knockout epithelial organoids with NF-kB1 processing and ribosome/proteasome Co-IP and CD8+ TRM readouts; nanoluciferase PPI, phosphoproteomics, and p53-acetylation assays for NOC2L

    PMID:41162356 PMID:41175093

    Open questions at the time
    • Mechanism of co-translational p50 regulation incompletely defined
    • LZTR1-NOC2L interaction not independently replicated
    • Connection to canonical CUL3 adaptor role unresolved
  18. 2025 Medium

    Documented context-dependent pro-tumorigenic and cardiac roles—ERBB3/PYK2/SRC and actin-cytoskeleton effects in melanoma and RAP1/MAPK/AKT-driven cardiomyopathy—indicating LZTR1 output varies by tissue.

    Evidence BioID/Co-IP-MS with invasion and pathway assays in melanoma; cardiac-specific CASAAV Lztr1 knockdown mice with transcriptomics, Ca2+ handling, and apoptosis assays

    PMID:40885854 PMID:40967536

    Open questions at the time
    • Direct substrates underlying these phenotypes not defined
    • Reconciliation of tumor-suppressive vs pro-invasive roles unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How LZTR1 integrates its many substrate axes—RAS/RIT1 degradation, RTK and CHMP1B turnover, KLHL12 repression, and ubiquitination-independent transcriptional/translational roles—into tissue-specific outputs, and how phosphorylation gating is structurally read out, remains unresolved.
  • No high-resolution structure of substrate-bound CRL3-LZTR1
  • Hierarchy and competition among substrates across cell types unmapped
  • Mechanistic link between Golgi localization and ubiquitin ligase activity unestablished

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0140096 catalytic activity, acting on a protein 4 GO:0016874 ligase activity 3
Localization
GO:0005768 endosome 1 GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-5653656 Vesicle-mediated transport 1
Partners
AXLCHMP1BCUL3EGFRHRASKRASMRASRIT1
Complex memberships
CRL3-LZTR1 (CUL3 RING E3 ligase)

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 LZTR1 (LZTR-1) localizes exclusively to the cytoplasmic surface of the Golgi network, with this localization mediated by its second BTB/POZ domain. Treatment with brefeldin A causes LZTR1 to redistribute into dispersed punctuated structures that co-localize with the Golgi marker GM130, identifying it as a Golgi matrix-associated protein. Upon induction of apoptosis, LZTR1 is phosphorylated on tyrosine residues and subsequently degraded via caspase- and proteasome-dependent pathways. Confocal microscopy with Golgi markers (GM130, Golgin-97, TGN46), brefeldin A treatment, co-localization with actin, caspase inhibitor (Z-VAD-fmk) and proteasome inhibitor (lactacystin, MG132) rescue experiments, domain-deletion analysis The Journal of biological chemistry Medium 16356934
2018 LZTR1 functions as a CUL3 (cullin 3) ubiquitin ligase adaptor that ubiquitinates RAS GTPases (KRAS, HRAS, NRAS, MRAS) at lysine-170 (HRAS) and lysine-127 (MRAS). LZTR1-mediated ubiquitination at K170 inhibits RAS signaling by attenuating RAS association with the plasma membrane. Disease-associated LZTR1 mutations disrupt either LZTR1-CUL3 complex formation or LZTR1 interaction with RAS proteins. LZTR1 complex trapping from intact mammalian cells, ubiquitome mass spectrometry analysis, site-directed mutagenesis (K170 on HRAS, K127 on MRAS), membrane localization assays, mouse haploinsufficiency model recapitulating Noonan syndrome phenotypes, Schwann cell knockout driving dedifferentiation and proliferation Science (New York, N.Y.) High 30442762
2018 Inactivation of LZTR1 (the CUL3 adaptor) in human CML cells leads to enhanced MAPK pathway activity and reduced sensitivity to tyrosine kinase inhibitors. Endogenous human LZTR1 associates with the main RAS isoforms. LZTR1 inactivation causes decreased ubiquitination and enhanced plasma membrane localization of endogenous KRAS. Knockdown of the Drosophila LZTR1 ortholog CG3711 results in a Ras-dependent gain-of-function phenotype. Genetic screens in CML cells, siRNA knockdown in human cells, co-immunoprecipitation of endogenous LZTR1 with RAS isoforms, membrane localization assays, Drosophila CG3711 knockdown with genetic epistasis Science (New York, N.Y.) High 30442766
2019 LZTR1 promotes polyubiquitination and proteasomal degradation of RAS GTPases (HRAS, NRAS, KRAS, MRAS), including oncogenic RAS mutants, via ubiquitin chains containing K48, K63, and K33 linkages. MRAS-K127 and HRAS-K170 are ubiquitination sites. LZTR1-mediated RAS degradation inhibits ERK1/2 activation and cell growth. LZTR1 also interacts with autophagy proteins LC3B and SQSTM1/p62, and co-expression of LZTR1 and RAS increases lipidated LC3B, but long-term chloroquine treatment has minimal effect on RAS levels, indicating autophagy plays a minor role compared to proteasomal degradation. In vivo ubiquitination assays, immunoprecipitation, western blotting, site-directed mutagenesis of ubiquitination sites, chloroquine treatment, LC3B lipidation assay, ERK1/2 activation assays, cell proliferation assays Cell death and differentiation High 31337872
2019 LZTR1 acts as an adaptor for proteasomal degradation of the RAS GTPase RIT1. Pathogenic mutations in either RIT1 (near switch II domain) or LZTR1 result in incomplete degradation of RIT1, causing RIT1 accumulation and dysregulated growth factor signaling. LZTR1 was identified as a RIT1 interactor by mass spectrometry. Mass spectrometry identification of RIT1-LZTR1 interaction, isogenic germline knock-in mouse model (RIT1 mutation), functional degradation assays, growth factor signaling readouts Science (New York, N.Y.) High 30872527
2019 Dominant Noonan syndrome-causing LZTR1 mutations do not disrupt binding to CUL3 but are predicted to affect the Kelch domain surface mediating substrate binding. These dominant mutations enhance stimulus-dependent RAS-MAPK signaling, at least partly by increasing the RAS protein pool. Dominant NS mutations do not affect LZTR1 protein stability or subcellular localization, unlike missense changes occurring in recessive NS. Transfection of NS-associated LZTR1 mutants, MAPK pathway activation assays (phospho-ERK), RAS protein level measurements, co-immunoprecipitation with CUL3, subcellular localization analysis, protein stability assays, structural modeling of Kelch domain Human molecular genetics Medium 30481304
2018 LZTR1 binds to the RAF1-PPP1CB complex as detected by immunoprecipitation of endogenous LZTR1. Cells transfected with siRNA against LZTR1 show decreased levels of RAF1 phosphorylated at Ser259, indicating LZTR1 modulates RAF1 phosphorylation status within the RAS/MAPK pathway. Endogenous co-immunoprecipitation followed by western blotting, siRNA knockdown of LZTR1, phospho-RAF1 (Ser259) western blotting Human genetics Medium 30368668
2020 LZTR1 (night owl/nowl) negatively regulates Ras signaling and interacts genetically with Neurofibromin-1 (Nf1) in the control of night-time sleep in Drosophila. Knockdown of nowl or Nf1 in GABA-responsive sleep-promoting neurons elicits a sleep phenotype that can be rescued by increased GABAA receptor signaling, indicating Nowl regulates sleep through modulation of GABA signaling. Nowl is also required for metabolic homeostasis. Drosophila genetic loss-of-function (nowl knockdown), genetic epistasis with Nf1 mutants, tissue-specific knockdown in GABAergic neurons, GABAA receptor pharmacological rescue, sleep behavior quantification, metabolic assays PLoS genetics Medium 32339168
2020 LZTR1 controls cardiovascular function by regulating vesicular trafficking. LZTR1 affects dynamics of fusion and fission of recycling endosomes by controlling ubiquitination of the ESCRT-III component CHMP1B (charged multivesicular protein 1B). NS-associated LZTR1 mutations diminish CHMP1B ubiquitination. LZTR1-mediated dysregulation of CHMP1B ubiquitination triggers endosomal accumulation and subsequent activation of VEGFR2, and decreases blood levels of soluble VEGFR2. Whole-body and vascular-specific Lztr1 knockout causes perinatal lethality from cardiovascular dysfunction; Lztr1 deletion in adult blood vessels leads to abnormal vascular leakage with defective adherent and tight junctions due to dysregulated vesicular trafficking. Conditional and whole-body Lztr1 knockout mice, endothelial-specific knockout, vascular permeability assays, endosomal trafficking assays, ubiquitination assays for CHMP1B, VEGFR2 activity measurements, ELISA for soluble VEGFR2, cediranib (VEGFR2 inhibitor) rescue experiments Circulation research High 32175818
2022 In both fruit flies and mice, LZTR1 shows a biochemical preference for RIT1 orthologs over classical RAS GTPases. Embryonic lethality of homozygous Lztr1 null mice can be rescued by deletion of Rit1, demonstrating genetic epistasis and establishing RIT1 orthologs as the preferred in vivo substrates of LZTR1. Lztr1 loss-of-function mutants in Drosophila and mice, Rit1 knockout rescue of Lztr1 null lethality, biochemical substrate preference assays, genetic epistasis analysis eLife High 35467524
2022 LZTR1 deficiency increases accumulation of RAS subfamily members and enhances cell proliferation, invasion, and xenograft tumor growth. LZTR1 inhibits KLHL12-mediated ubiquitination of SEC31A (a COPII component), and LZTR1 deficiency promotes collagen secretion via KLHL12. LZTR1-RIT1 and LZTR1-KLHL12 interactions are independent and do not directly interfere with each other. LZTR1 functions as a repressor of BTB-Kelch family member KLHL12. LZTR1 knockout in lung adenocarcinoma cells, multi-omics analysis, co-immunoprecipitation identifying KLHL12 interaction, SEC31A ubiquitination assays, collagen secretion assays, xenograft tumor growth assays, EMT marker analysis under TGF-β1 treatment Cell death & disease Medium 37626065
2022 GSK3 regulates LZTR1 function: inhibiting or silencing GSK3 in pancreatic cancer cells leads to a decline in Ras protein levels (wild-type and oncogenic KRAS) via a 3-fold decrease in Ras protein half-life. This decline is blocked by proteasome inhibition or LZTR1 knockdown, establishing a GSK3-regulated LZTR1-dependent mechanism controlling Ras protein stability and cell proliferation. GSK3 inhibitor treatment and siRNA knockdown in pancreatic cancer cells, LZTR1 siRNA knockdown, protein half-life measurements, proteasome inhibition rescue, cell proliferation assays Neoplasia (New York, N.Y.) Medium 35114566
2023 LZTR1 is the substrate-specific adaptor of a CUL3-dependent ubiquitin ligase that targets EGFR and AXL receptor tyrosine kinases for ubiquitin-dependent degradation in the lysosome. Pathogenic cancer-associated LZTR1 mutations fail to promote EGFR and AXL degradation, resulting in dysregulated growth factor signaling. Conditional inactivation of Lztr1 and Cdkn2a in the mouse nervous system causes schwannoma-like tumors with aberrant accumulation of EGFR and AXL. Unbiased biochemical screens (Co-IP/MS) identifying EGFR and AXL as LZTR1 interactors, ubiquitination and degradation assays, lysosomal pathway determination, Lztr1/Cdkn2a conditional mouse knockout, EGFR+AXL co-inhibition in tumor models Cancer discovery High 36445254
2024 Oncogenic KRAS mutations G12D, G13D, and Q61H abrogate KRAS association with LZTR1, thereby affecting KRAS turnover by the CUL3/LZTR1 E3 ligase complex. Wild-type KRAS but not oncogenic mutants are efficiently captured by LZTR1. APEX2 proximity labeling of WT, G12D, G13D, and Q61H KRAS mutants, quantitative proteomics under starvation and stimulation conditions, differential LZTR1 capture analysis Life science alliance Medium 38453365
2024 A homozygous LZTR1 L580P variant is predicted to alter binding affinity of dimerization domains, facilitating formation of linear LZTR1 polymers. This complex dysfunction results in accumulation of RAS GTPases and global pathological proteomic changes leading to cardiomyocyte hypertrophy. Cardiomyocyte-specific MRAS degradation is mediated by LZTR1 via non-proteasomal pathways, whereas RIT1 degradation is mediated by both LZTR1-dependent and LZTR1-independent pathways. Biallelic genetic correction of LZTR1 L580P rescues the molecular and cellular disease phenotype. Patient-specific and CRISPR-Cas9-corrected iPSC-derived cardiomyocytes, in silico polymer formation prediction, proteomics, RAS accumulation assays, CRISPR rescue experiments, pathway inhibitor studies Cell reports Medium 39003740
2024 LZTR1 autosomal dominant mutations (G245R and R409C, corresponding to human G248R and R412C) cause dominant-negative inhibition of wild-type LZTR1 function. These mutants do not interact with RIT1 and result in accumulation of MRAS and RIT1 in cardiomyocytes, activating the MAPK signaling pathway. MEK inhibitor trametinib treatment ameliorates cardiac hypertrophy in mutant mice. LZTR1 knock-in mice (Lztr1G245R/+ and Lztr1R409C/+), co-immunoprecipitation with RIT1, MRAS and RIT1 protein level assays in left ventricles, multi-omics analysis, trametinib treatment rescue JCI insight Medium 39352760
2024 Novel small-molecule fragments (C53 and Z86) enhance the KRAS-LZTR1 protein-protein interaction in a dose-dependent manner, as shown by split-luciferase reporter assay, proximity biotinylation (BioID), thermal shift assays, and NMR spectroscopy. These fragments increase endogenous LZTR1 recruitment to KRAS. Split-luciferase-based reporter assay for KRAS-LZTR1 interaction, fragment library screen, BioID proximity biotinylation, thermal shift assays, NMR spectroscopy ACS chemical biology Medium 39194017
2025 PP1C phosphatase dephosphorylates the conserved T148 residue on RAS, which permits LZTR1-dependent proteasomal degradation. Phosphorylation of RAS T148 by PAK1/2 kinases shields RAS from LZTR1-dependent degradation. KRAS A146 gain-of-function mutations (adjacent to T148) render LZTR1 ineffective at promoting degradation. KRAS protein is four-fold less stable in hematologic versus carcinoma cells due to this regulatory circuit. Multi-omics screening in multiple myeloma cells, phosphatase identification (PP1C), kinase identification (PAK1/2), T148 mutagenesis, LZTR1-dependent degradation assays, PAK1/2 inhibitor treatment, protein stability measurements bioRxivpreprint Medium 41542462
2025 LZTR1 regulates MHC-I expression in epithelial cells through an NF-κB1-dependent mechanism. Mechanistically, LZTR1 modulates MHC-I transcription by regulating 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+ TRM activation and proliferation and decreased IL-17A production. LZTR1 knockout in cutaneous and colonic epithelial cells/organoids, NF-κB1 (p50) processing assays, ribosome and proteasome co-immunoprecipitation, MHC-I expression assays, in vivo CD8+ TRM functional readouts Cell discovery Medium 41162356
2025 LZTR1 interacts with NOC2L (a histone acetyltransferase inhibitor), and this interaction is disrupted by dominant Noonan syndrome LZTR1 variants. Loss of LZTR1-NOC2L interaction leads to NOC2L upregulation, impaired p53 acetylation, reduced apoptosis, and compensatory increase in autophagy. LZTR1 variants are thermodynamically stable in vitro and associated with elevated pan-RAS levels and preferential activation of the DNA damage response. Mutagenesis of LZTR1 variants, phosphoproteomics, immunoblotting, immunofluorescence, nanoluciferase assays (PPI), in silico structural modeling, p53 acetylation assays, LC3 and phospho-p70 S6K measurements The Journal of clinical endocrinology and metabolism Medium 41175093
2025 LZTR1 overexpression in melanoma activates ERBB3 receptor and its downstream targets PYK2 and SRC tyrosine kinases, enhancing cell invasion and actin cytoskeleton organization. LZTR1 associates with actin-related proteins. LZTR1 downregulation suppresses the protective autophagy-initiating factors ULK1 and AMBRA1, and upregulates SQSTM1/p62. LZTR1 regulates the ubiquitin proteasome system in melanoma cells. Proximity biotinylation and co-immunoprecipitation combined with LC-MS/MS proteomics, LZTR1 knockdown/overexpression in melanoma cells, invasion assays, ERBB3/PYK2/SRC pathway activation assays, autophagy marker measurements Oncogene Medium 40885854
2025 In a cardiac-specific Lztr1 knockdown mouse model, Lztr1 deficiency activates the RAP1/MAPK/AKT signaling pathway leading to Ca2+ homeostasis disorder and cardiomyocyte apoptosis, recapitulating dilated cardiomyopathy pathology. The transcriptomic analysis identified the RAP1 pathway as a key downstream effector. CRISPR-Cas9/AAV9-mediated cardiac-specific Lztr1 knockdown (CASAAV system), cardiac function assays, transcriptomic sequencing, pathway analysis, mitochondrial and Ca2+ handling assays, apoptosis assays International journal of biological macromolecules Medium 40967536
2025 Full-length CRL3LZTR1-MRAS complex was successfully expressed and purified. MRAS binds tightly to LZTR1, in contrast to RIT1 and HRAS under these in vitro conditions. The presence of CRL3 (Cullin3 RING ligase) stabilizes and homogenizes LZTR1 by facilitating complex formation. BacMam expression system, protein purification and biochemical characterization, in vitro binding assays comparing MRAS, RIT1, and HRAS binding to LZTR1 Protein expression and purification Medium 40204202
2021 Conditional knockout of Lztr1 restricted to the telencephalon results in increased MAPK pathway activation in white matter regions, altered expression of stage-specific oligodendrocyte lineage markers with increased oligodendrocyte progenitor cells (OPCs) and decreased oligodendrocyte differentiation markers, and increased GFAP astrocyte marker expression. Foxg1-Cre conditional Lztr1 knockout mice, immunohistochemistry for oligodendrocyte lineage markers, GFAP staining, MAPK pathway activation assays (phospho-ERK), quantitative analysis of OPC and mature oligodendrocyte markers Frontiers in cell and developmental biology Medium 34222248

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 231 24362817
2015 Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome. Journal of medical genetics 196 25795793
2018 LZTR1 is a regulator of RAS ubiquitination and signaling. Science (New York, N.Y.) 182 30442766
2018 Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination. Science (New York, N.Y.) 171 30442762
2018 Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants. Genetics in medicine : official journal of the American College of Medical Genetics 163 29469822
2016 Revisiting neurofibromatosis type 2 diagnostic criteria to exclude LZTR1-related schwannomatosis. Neurology 102 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 92 31337872
2019 RIT1 oncoproteins escape LZTR1-mediated proteolysis. Science (New York, N.Y.) 90 30872527
2019 Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the Kelch domain substrate-recognition surface and enhance RAS-MAPK signaling. Human molecular genetics 74 30481304
2014 Expanding the mutational spectrum of LZTR1 in schwannomatosis. European journal of human genetics : EJHG 65 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 51 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 30 32339168
2019 Providing more evidence on LZTR1 variants in Noonan syndrome patients. American journal of medical genetics. Part A 28 31825158
2021 LZTR1: A promising adaptor of the CUL3 family. Oncology letters 24 34113392
2016 Multifocal nerve lesions and LZTR1 germline mutations in segmental schwannomatosis. Annals of neurology 24 27472264
2022 Cross-species analysis of LZTR1 loss-of-function mutants demonstrates dependency to RIT1 orthologs. eLife 21 35467524
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 deficiency exerts high metastatic potential by enhancing sensitivity to EMT induction and controlling KLHL12-mediated collagen secretion. Cell death & disease 19 37626065
2023 LZTR1 Mutation Mediates Oncogenesis through Stabilization of EGFR and AXL. Cancer discovery 18 36445254
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 18 31533111
2024 Mutation-induced LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome. Cell reports 13 39003740
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
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 10 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
2024 Preclinical evaluation of CRISPR-based therapies for Noonan syndrome caused by deep-intronic LZTR1 variants. Molecular therapy. Nucleic acids 5 38333672
2024 Phenotypic Expansion of Autosomal Dominant LZTR1-Related Disorders with Special Emphasis on Adult-Onset Features. Genes 5 39062695
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
2025 Pathogenic Variants and Allele Loss of the NF2 and LZTR1 Gene in Sporadic Vestibular Schwannoma. In vivo (Athens, Greece) 4 40295009
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 4 39140257
2024 Identification and Characterization of Novel Small-Molecule Enhancers of the CUL3LZTR1 E3 Ligase KRAS Complex. ACS chemical biology 4 39194017
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
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 LZTR1 is a melanoma oncogene that promotes invasion and suppresses apoptosis. Oncogene 2 40885854
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 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

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