Affinage

LZTS2

Leucine zipper putative tumor suppressor 2 · UniProt Q9BRK4

Length
669 aa
Mass
72.8 kDa
Annotated
2026-04-28
24 papers in source corpus 18 papers cited in narrative 18 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LZTS2 is a multifunctional tumor suppressor that restrains cell proliferation through convergent regulation of Wnt/β-catenin signaling, PI3K/AKT signaling, and centrosomal microtubule dynamics. LZTS2 directly binds β-catenin and drives its nuclear export via a CRM1-dependent nuclear export signal, thereby repressing Wnt target gene transcription — a function validated in mammalian cells, zebrafish gastrulation, and Lzts2 knockout mice that exhibit renal/ureteral developmental defects and increased spontaneous and carcinogen-induced tumorigenesis (PMID:17000760, PMID:22057270, PMID:21949185, PMID:23275340). LZTS2 also inhibits PI3K/AKT signaling by competing with the p110 catalytic subunit for binding to the p85 regulatory subunit, and localizes to centrosomes and midbodies where it inhibits katanin-mediated microtubule severing, suppresses CEP135-dependent microtubule nucleation, and is required for successful cytokinesis — with force-dependent sequestration by α-catenin at adherens junctions depleting midbody LZTS2 and causing binucleation (PMID:29409973, PMID:18490357, PMID:40521914, PMID:39786338). LZTS2 protein levels are tightly controlled by multiple E3 ubiquitin ligases (β-TrCP primed by CK1δ phosphorylation, SPOP, SH3RF2, CCDC137-recruited β-TrCP targeting K467), counterbalanced by the deubiquitinase HAUSP, while PLK1 phosphorylation at Ser451 disrupts its β-catenin interaction without affecting stability (PMID:33420362, PMID:38918619, PMID:41436424, PMID:40676695, PMID:38740232).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2006 High

    Identification of LZTS2 as a direct β-catenin-interacting protein with a functional CRM1-dependent NES established the first mechanism by which LZTS2 suppresses Wnt signaling — nuclear export of β-catenin.

    Evidence Co-IP, GFP-NES fusion reporter, leptomycin B treatment, NES mutagenesis, and β-catenin reporter assays in SW480 colon cancer cells

    PMID:17000760

    Open questions at the time
    • Upstream signals controlling LZTS2–β-catenin interaction were unknown
    • Whether this export mechanism operates in vivo was untested
    • Structural basis of LZTS2–β-catenin binding unresolved
  2. 2007 High

    Discovery that LZTS2 localizes to centrosomes and midbodies and regulates cytokinesis through p80 katanin revealed a second, Wnt-independent tumor-suppressive function in mitotic fidelity.

    Evidence Immunofluorescence colocalization with γ-tubulin/MKLP1/p80 katanin, RNAi knockdown, and overexpression-induced binucleation in v-Fps-transformed cells

    PMID:17351128

    Open questions at the time
    • Whether LZTS2 directly inhibits katanin enzymatic activity was not demonstrated
    • Mechanism linking LZTS2 to midbody recruitment unclear
  3. 2008 High

    Reconstitution of LZTS2 inhibition of katanin-mediated microtubule severing in vitro provided direct biochemical evidence for how LZTS2 controls microtubule dynamics, central spindle formation, and cell motility.

    Evidence In vitro microtubule severing assay, centrosome fractionation, RNAi, dominant-negative katanin, and migration assays

    PMID:18490357

    Open questions at the time
    • Domain of LZTS2 that contacts katanin catalytic subunit not mapped at residue level
    • Relationship between katanin inhibition and tumor suppression not directly tested
  4. 2009 Medium

    Demonstration that LZTS2 forms a complex with ProSAP2/Shank3 at the postsynaptic density and co-migrates with β-catenin to the nucleus upon NMDA receptor activation extended the β-catenin export function to neuronal signaling.

    Evidence Co-IP, immunofluorescence, NMDA activation experiments, and reporter assays for β-catenin target genes in neurons

    PMID:19703901

    Open questions at the time
    • Physiological significance of LZTS2-regulated β-catenin export for synaptic plasticity not established
    • Whether Shank3 modulates LZTS2 export function was not tested
  5. 2011 High

    Genetic validation in zebrafish and Lzts2 knockout mice confirmed that LZTS2-mediated β-catenin nuclear export is essential for vertebrate development, with null mice displaying renal/ureteral duplication and increased Wnt-responsive transcription.

    Evidence Morpholino knockdown and mRNA rescue in zebrafish; Lzts2 KO mouse model with histology, immunofluorescence of β-catenin localization, and Wnt reporter assays in null fibroblasts

    PMID:21949185 PMID:22057270

    Open questions at the time
    • Whether LZTS2 controls β-catenin in a tissue-specific manner beyond kidney was unexplored
    • Relative contribution of β-catenin export vs. other LZTS2 functions to developmental phenotypes unclear
  6. 2012 High

    Increased spontaneous and carcinogen-induced tumor development in Lzts2 KO mice formally established LZTS2 as a bona fide tumor suppressor in vivo.

    Evidence Lzts2 KO mouse with BBN carcinogen treatment and MEF proliferation assays

    PMID:23275340

    Open questions at the time
    • Which downstream pathway(s) drive tumorigenesis upon Lzts2 loss was not delineated
  7. 2017 High

    Compound Pten/Lzts2 deletion in mouse prostate demonstrated that LZTS2 and PTEN collaborate to restrain β-catenin-mediated transcription, revealing cooperative tumor suppression.

    Evidence Compound KO mouse prostate model, β-catenin reporter assays, immunohistochemistry

    PMID:28323888

    Open questions at the time
    • Whether LZTS2's PI3K-inhibitory function contributes to this synergy was not separated from its β-catenin export role
  8. 2018 High

    Identification of LZTS2 as a competitive inhibitor of p85–p110 interaction established a Wnt-independent tumor-suppressive mechanism through direct suppression of PI3K/AKT signaling.

    Evidence Unbiased proteomics, Co-IP, competition binding assays, PI3K/AKT pathway readouts, tumor and radioresistance assays

    PMID:29409973

    Open questions at the time
    • Structural basis for LZTS2–p85 competition with p110 not determined
    • Whether PI3K and Wnt-suppressive functions are independent or coupled was unclear
  9. 2021 High

    Discovery that CK1δ phosphorylates LZTS2 to prime it for β-TrCP-mediated K48-linked ubiquitination and proteasomal degradation revealed the first regulated turnover mechanism controlling LZTS2 protein levels.

    Evidence In vitro kinase assay, ubiquitination assay, mutant rescue, in vivo HCC tumor models

    PMID:33420362

    Open questions at the time
    • Specific phosphodegron residues on LZTS2 not fully mapped
    • Whether other kinases substitute for CK1δ in other tissues unknown
  10. 2024 High

    PLK1 phosphorylation of LZTS2 at Ser451 was shown to disrupt the LZTS2–β-catenin interaction without altering LZTS2 stability, revealing a mitotic kinase that selectively uncouples LZTS2 from Wnt suppression. Separately, CCDC137 was identified as a nuclear scaffold that recruits β-TrCP to ubiquitinate LZTS2 specifically at K467.

    Evidence In vitro kinase assay with Ser451 mutagenesis, β-catenin localization/reporter assays (PLK1); Co-IP, K467 mutagenesis, domain mapping, PDX/organoid models (CCDC137)

    PMID:38740232 PMID:38918619

    Open questions at the time
    • Whether PLK1-mediated uncoupling is cell-cycle-phase-restricted was not resolved
    • How CCDC137 expression is itself regulated is unknown
  11. 2025 High

    Three concurrent advances resolved how LZTS2 integrates mechanical and signaling cues: force-induced α-catenin M-domain opening sequesters LZTS2 at junctions causing cytokinesis failure; SPOP and HAUSP compete for LZTS2 binding to control its stability and Wnt output; and LZTS2 suppresses centrosomal microtubule nucleation upstream of CEP135.

    Evidence BioID with α-catenin conformation mutants, siRNA, binucleation assays in MDCK cells (α-catenin); Co-IP, ubiquitination assays, competition binding, Wnt reporters in CRC cells (SPOP/HAUSP); siRNA epistasis and microtubule nucleation assays (CEP135)

    PMID:39786338 PMID:40521914 PMID:41436424

    Open questions at the time
    • Whether junctional sequestration of LZTS2 also affects its PI3K-inhibitory function is untested
    • In vivo relevance of the SPOP-HAUSP balance for tumor suppression not established
    • How LZTS2 reduces centrosomal CEP135 mechanistically is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of LZTS2 interactions with β-catenin and p85, how its centrosomal, junctional, and nuclear pools are coordinately regulated during the cell cycle, and whether its multiple tumor-suppressive outputs (Wnt, PI3K/AKT, microtubule dynamics) are independently or cooperatively engaged in specific cancer types.
  • No crystal or cryo-EM structure of LZTS2 or its complexes
  • Quantitative cell-cycle-resolved measurement of LZTS2 pool distribution lacking
  • Relative contribution of Wnt vs. PI3K vs. microtubule functions to tumor suppression in different tissues untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0008092 cytoskeletal protein binding 3
Localization
GO:0005815 microtubule organizing center 3 GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1640170 Cell Cycle 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3
Partners
BTRCCSNK1DCTNNA1CTNNB1KATNA1PIK3R1PLK1SHANK3

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 LZTS2 directly interacts with β-catenin, contains a functional nuclear export signal (NES) in its C-terminus (amino acids 631–641) that is CRM1/exportin-dependent, and promotes nuclear export of β-catenin, thereby repressing β-catenin-mediated transactivation. Point mutations in leucine residues of the NES abolished nuclear exclusion. Co-immunoprecipitation, GFP-NES fusion reporter assays, leptomycin B (CRM1 inhibitor) treatment, NES point mutagenesis, β-catenin reporter assays in SW480 cells Molecular and cellular biology High 17000760
2007 LAPSER1/LZTS2 colocalizes with γ-tubulin, MKLP1, and p80 katanin at centrosomes and midbodies during mitosis, and RNAi-mediated knockdown causes mislocalization of p80 katanin and malformation of the central spindle, implicating LZTS2 in cytokinesis via interaction with p80 katanin. Overexpression of LZTS2 induces binucleation and abortive cytokinesis in a p80 katanin-dependent manner. Immunofluorescence colocalization, RNAi knockdown, overexpression in v-Fps-transformed cells, Z-VAD-fmk rescue experiments FASEB journal High 17351128
2008 LZTS2 C-terminal domain directly inhibits katanin-mediated microtubule severing in vitro. LZTS2 localizes preferentially to mother centrioles independently of microtubules. LZTS2 inhibits central spindle formation by abrogating microtubule transportation, inhibits centrosomal γ-tubulin accumulation (retarding mitotic entry), and prevents cell motility by increasing acetylated microtubules via katanin inhibition. In vitro microtubule severing assay, immunofluorescence of nucleated/severed/transported microtubules, centrosome fractionation, RNAi knockdown, dominant-negative katanin, cell migration assays Human molecular genetics High 18490357
2009 LAPSER1/LZTS2 localizes to the postsynaptic density and forms a complex with ProSAP2/Shank3, SPAR1, and β-catenin. Upon NMDA receptor activation, LAPSER1 and β-catenin co-migrate from the postsynaptic density to the nucleus, inducing transcription of β-catenin target genes Tcfe2a and c-Myc; LAPSER1 regulates the nuclear export and cytoplasmic redistribution of β-catenin in neurons. Co-immunoprecipitation, immunofluorescence, NMDA receptor activation experiments, reporter gene assays for β-catenin target genes The Journal of biological chemistry Medium 19703901
2011 LZTS2 physically interacts with β-catenin-1 and β-catenin-2 in zebrafish and mediates their nuclear export, thereby limiting Wnt/β-catenin activity and regulating gastrula convergence/extension movements, dorsoventral patterning, and midline convergence of organ progenitors. Morpholino knockdown, mRNA overexpression, co-immunoprecipitation, subcellular fractionation, rescue experiments in zebrafish embryos The Journal of biological chemistry High 22057270
2011 Lzts2 knockout mice display severe kidney and urinary tract developmental defects (renal/ureteral duplication, hydroureter, hydronephrosis), and Lzts2-null fibroblasts show altered β-catenin subcellular localization and increased Wnt-induced β-catenin-mediated transcriptional activity, establishing LZTS2 as a direct regulator of β-catenin in nephrogenesis. Lzts2 knockout mouse model, immunofluorescence of β-catenin localization, Wnt-responsive reporter assays in null fibroblasts, histological analysis The Journal of biological chemistry High 21949185
2011 LAPSER1/LZTS2 interacts with all three ProSAP/Shank family members (Shank1, ProSAP1/Shank2, ProSAP2/Shank3) in Xenopus embryos, as shown by co-localization and interaction assays. Co-immunoprecipitation in Xenopus embryos, cell-based colocalization assay Developmental dynamics Medium 21445960
2012 Homozygous Lzts2 deletion in mice increases spontaneous and carcinogen-induced tumor development, and loss of Lzts2 in mouse embryonic fibroblasts enhances cell growth, establishing a direct tumor-suppressive role for LZTS2. Lzts2 knockout mouse model, carcinogen (BBN) treatment, MEF proliferation assays The Journal of biological chemistry High 23275340
2018 LZTS2 interacts with the PI3K regulatory subunit p85 (identified by unbiased proteomics) and competes with the p110 catalytic subunit for p85 binding, thereby inhibiting PI3K/AKT signaling activation. Unbiased proteomics, co-immunoprecipitation, competition binding assays, functional PI3K/AKT activity assays, in vitro and in vivo tumor/radioresistance assays Cancer letters High 29409973
2017 LZTS2 and PTEN collaborate to suppress β-catenin-mediated transcription; simultaneous deletion of Pten and Lzts2 in the murine prostate causes earlier onset and accelerated tumor progression compared to single deletions, with higher levels of cytoplasmic and nuclear β-catenin. Co-expression in prostate cancer cell lines, β-catenin reporter assays, compound Pten/Lzts2 KO mouse prostate model, immunohistochemistry PloS one High 28323888
2021 LZTS2 is a bona fide substrate of the E3 ubiquitin ligase β-TrCP and the kinase CK1δ; CK1δ phosphorylates LZTS2 to prime it for β-TrCP-mediated K48-linked polyubiquitination and proteasomal degradation. This degradation activates PI3K/AKT signaling to promote hepatocellular carcinoma tumorigenesis and metastasis. Co-immunoprecipitation, ubiquitination assays, in vitro kinase assays, mutant rescue experiments, in vitro and in vivo tumor models Oncogene High 33420362
2024 PLK1 binds to LZTS2 and phosphorylates it at Ser451, which disrupts the interaction between LZTS2 and β-catenin without affecting LZTS2 protein stability, leading to nuclear accumulation of β-catenin and activation of the Wnt pathway in lung adenocarcinoma cells. Co-immunoprecipitation, in vitro kinase assay, phosphorylation site mutagenesis (Ser451), β-catenin localization assay, reporter assays, cell proliferation/migration assays Cellular signalling High 38740232
2024 CCDC137 binds LZTS2 and recruits the E3 ligase β-TrCP to mediate K48-linked polyubiquitination of LZTS2 specifically at lysine 467 in the nucleus, thereby promoting LZTS2 degradation, AKT phosphorylation, and β-catenin pathway activation. The 1–75 domain of CCDC137 is responsible for forming this ternary complex. Co-immunoprecipitation, ubiquitination assays with site-specific mutation (K467), domain mapping, peptide competition experiments in HCC organoids and PDX models Cell death and differentiation High 38918619
2025 α-Catenin in a force-sensitive (M-domain open) conformation recruits and sequesters LZTS2 at apical adherens junctions, depleting LZTS2 from the midbody/intercellular bridge and causing cytokinesis failure and binucleation. LZTS2 knockdown independently elevates binucleation rates. α-Catenin KO/reconstitution in MDCK cells with conformation mutants, proximity biotinylation (BioID), immunofluorescence, siRNA knockdown, binucleation quantification The Journal of cell biology High 39786338
2025 SPOP (E3 ligase) promotes ubiquitination-mediated degradation of LZTS2, whereas HAUSP (deubiquitinase) counteracts SPOP by competing for binding to the same region of LZTS2, thereby stabilizing LZTS2 and enhancing its suppression of the Wnt pathway in colorectal cancer cells. Co-immunoprecipitation, ubiquitination assays, SPOP/HAUSP overexpression and knockdown, Wnt reporter assays, cell proliferation and metastasis assays Cell death & disease Medium 41436424
2025 LZTS2 negatively regulates centrosomal levels of CEP135 and suppresses microtubule nucleation at centrosomes; LZTS2 depletion increases centrosomal microtubule nucleation and partially rescues nucleation defects caused by CEP135 knockdown, placing LZTS2 upstream of CEP135 in centrosomal microtubule organization. siRNA knockdown, fluorescence and electron microscopy, microtubule nucleation assays, CEP135 immunofluorescence quantification Cytoskeleton Medium 40521914
2025 SH3RF2 (E3 ubiquitin ligase) interacts with LZTS2 via its RING domain and promotes LZTS2 ubiquitination and degradation, leading to nuclear translocation of β-catenin in lung squamous cell carcinoma cells. Proteomic analysis, co-immunoprecipitation, ubiquitination assays, overexpression/knockdown functional assays, in vivo tumorigenesis Biology direct Medium 40676695
2026 LZTS2 functionally interacts with DYRK1A during craniofacial development in Xenopus; sub-phenotypic reductions of Lzts2 and Dyrk1a synergize to produce craniofacial defects, and partial reduction of Lzts2 attenuates craniofacial phenotypes caused by Dyrk1a overexpression, supporting a modulatory relationship between LZTS2 and DYRK1A. Morpholino knockdown, mRNA overexpression, genetic epistasis/synergy assays in Xenopus laevis, in situ hybridization for sox9/pax3 bioRxivpreprint Medium 41959346

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 LZTS2 is a novel beta-catenin-interacting protein and regulates the nuclear export of beta-catenin. Molecular and cellular biology 69 17000760
2018 LZTS2 inhibits PI3K/AKT activation and radioresistance in nasopharyngeal carcinoma by interacting with p85. Cancer letters 52 29409973
2009 Synaptic cross-talk between N-methyl-D-aspartate receptors and LAPSER1-beta-catenin at excitatory synapses. The Journal of biological chemistry 47 19703901
2001 LAPSER1: a novel candidate tumor suppressor gene from 10q24.3. Oncogene 40 11709705
2007 LAPSER1 is a putative cytokinetic tumor suppressor that shows the same centrosome and midbody subcellular localization pattern as p80 katanin. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 39 17351128
2008 LAPSER1/LZTS2: a pluripotent tumor suppressor linked to the inhibition of katanin-mediated microtubule severing. Human molecular genetics 29 18490357
2021 β-Trcp and CK1δ-mediated degradation of LZTS2 activates PI3K/AKT signaling to drive tumorigenesis and metastasis in hepatocellular carcinoma. Oncogene 26 33420362
2012 Deletion of leucine zipper tumor suppressor 2 (Lzts2) increases susceptibility to tumor development. The Journal of biological chemistry 24 23275340
2007 Crossregulation of beta-catenin/Tcf pathway by NF-kappaB is mediated by lzts2 in human adipose tissue-derived mesenchymal stem cells. Biochimica et biophysica acta 23 17950943
2011 Lzts2 regulates embryonic cell movements and dorsoventral patterning through interaction with and export of nuclear β-catenin in zebrafish. The Journal of biological chemistry 19 22057270
2023 RRP15 deficiency induces ribosome stress to inhibit colorectal cancer proliferation and metastasis via LZTS2-mediated β-catenin suppression. Cell death & disease 18 36750557
2011 The leucine zipper putative tumor suppressor 2 protein LZTS2 regulates kidney development. The Journal of biological chemistry 17 21949185
2017 LZTS2 and PTEN collaboratively regulate ß-catenin in prostatic tumorigenesis. PloS one 16 28323888
2011 The spatio-temporal expression of ProSAP/shank family members and their interaction partner LAPSER1 during Xenopus laevis development. Developmental dynamics : an official publication of the American Association of Anatomists 13 21445960
2024 Disrupting CCDC137-mediated LZTS2 and β-TrCP interaction in the nucleus inhibits hepatocellular carcinoma development via β-catenin and AKT. Cell death and differentiation 8 38918619
2024 Phosphorylation of LZTS2 by PLK1 activates the Wnt pathway. Cellular signalling 7 38740232
2022 Long non-coding RNA linc00921 suppresses tumorigenesis and epithelial-to-mesenchymal transition of triple-negative breast cancer via targeting miR-9-5p/LZTS2 axis. Human cell 7 35179718
2025 α-Catenin force-sensitive binding and sequestration of LZTS2 leads to cytokinesis failure. The Journal of cell biology 4 39786338
2023 EBV-encoded miRNAs BHRF1-1 and BART2-5p aggravate post- transplant lymphoproliferative disorder via LZTS2-PI3K-AKT axis. Biochemical pharmacology 1 37419372
2026 LZTS2 Emerges as a Regulator of Craniofacial Development and Modulator of DYRK1A. bioRxiv : the preprint server for biology 0 41959346
2025 LZTS2 Negatively Regulates Centrosomal CEP135 Levels and Microtubule Nucleation. Cytoskeleton (Hoboken, N.J.) 0 40521914
2025 The role of SH3RF2 in lung squamous cell carcinoma and M2 polarization: insights into LZTS2 ubiquitination. Biology direct 0 40676695
2025 SPOP and HAUSP bidirectionally regulate LZTS2 ubiquitination to modulate the Wnt pathway. Cell death & disease 0 41436424
2023 α-catenin mechanosensitivity as a route to cytokinesis failure through sequestration of LZTS2. bioRxiv : the preprint server for biology 0 37662204