Affinage

MELK

Maternal embryonic leucine zipper kinase · UniProt Q14680

Length
651 aa
Mass
74.6 kDa
Annotated
2026-04-28
100 papers in source corpus 44 papers cited in narrative 44 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MELK is a cell-cycle-regulated Snf1/AMPK-family serine/threonine kinase that promotes mitotic progression, cell proliferation, and survival through phosphorylation of diverse substrates. Activated by autophosphorylation at Thr167/Ser171 and by mitotic kinases MPF and MAPK, MELK phosphorylates FOXM1 to drive mitotic gene expression, eIF4B at Ser406 to sustain MCL1 translation during mitosis, EZH2 at S220 to prevent its ubiquitin-mediated degradation, Bcl-GL to suppress apoptosis, p21 at Thr55 to regulate nuclear translocation, and Smad proteins to modulate TGF-β/p53 signaling (PMID:16216881, PMID:23404835, PMID:27528663, PMID:31434700, PMID:17280616, PMID:31097688, PMID:29700281). MELK also inhibits spliceosome assembly through phosphorylation-dependent binding to NIPP1, participates in cytokinesis via association with anillin and regulation of RhoA at the cleavage furrow, and reduces replication stress in cancer cells (PMID:14699119, PMID:21378312, PMID:23836907). CRISPR knockout studies across multiple cancer cell lines reveal that MELK is dispensable for basal proliferation under standard conditions, indicating context-dependent essentiality despite its prominent expression in aggressive cancers (PMID:28926338, PMID:29417930).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1997 Medium

    Identification of MELK as a novel Snf1/AMPK-family kinase with a leucine zipper motif established a new kinase gene expressed in early embryonic development, opening the question of its substrate specificity and biological function.

    Evidence Differential display cloning from mouse egg/preimplantation embryo cDNA libraries with sequence analysis

    PMID:9136115

    Open questions at the time
    • No substrates or cellular function identified
    • Expression pattern limited to mouse early embryo
  2. 2005 High

    Biochemical dissection revealed that MELK activation requires autophosphorylation at Thr167/Ser171, that a UBA domain is part of the minimal active fragment, and that a C-terminal domain is autoinhibitory — establishing the enzymological framework for understanding MELK regulation.

    Evidence In vitro kinase assay, mass spectrometry phosphorylation mapping, site-directed mutagenesis, domain truncation analysis

    PMID:16216881

    Open questions at the time
    • Upstream activating kinase not yet identified in mammalian cells
    • Structural basis of autoinhibition unresolved
  3. 2003 High

    Discovery that MELK inhibits spliceosome assembly through phosphorylation-dependent interaction with NIPP1's FHA domain revealed a non-canonical role for MELK in RNA processing, linking MELK to mitotic translational regulation.

    Evidence Recombinant protein interaction assays, in vitro spliceosome reconstitution, T478A mutagenesis, mitotic cell fractionation

    PMID:14699119

    Open questions at the time
    • Physiological relevance of splicing inhibition during mitosis not demonstrated in vivo
    • Whether MELK kinase activity targets other spliceosome components unknown
  4. 2005 High

    Identification of MELK as an E2F transcriptional target and its requirement for neural progenitor proliferation established MELK as a cell-cycle-coupled proliferative kinase in stem/progenitor cells, with B-myb as a downstream mediator.

    Evidence E2F site mutagenesis in Melk promoter, p107/p130 knockout cell analysis, siRNA knockdown and overexpression in neurosphere assays

    PMID:16061694 PMID:16144839

    Open questions at the time
    • Direct phosphorylation targets mediating progenitor proliferation not identified
    • Relationship between MELK and B-myb not biochemically defined
  5. 2006 High

    Mapping of mitosis-specific phosphorylation sites on Xenopus MELK by MPF and MAPK, and identification of PIG-1 (C. elegans ortholog) as a regulator of asymmetric cell division, expanded MELK's role beyond proliferation to mitotic regulation and cell fate determination.

    Evidence Xenopus M-phase extract phosphorylation mapping with in vitro kinase assays; C. elegans pig-1 mutant lineage tracing

    PMID:16628004 PMID:16774992

    Open questions at the time
    • Mammalian equivalents of MPF/MAPK-mediated activation sites not confirmed
    • How PIG-1 mechanistically controls cell size asymmetry unknown
  6. 2007 High

    Demonstration that MELK phosphorylates the pro-apoptotic Bcl-GL protein and that kinase activity is required to suppress Bcl-GL-induced apoptosis established MELK as a direct anti-apoptotic kinase.

    Evidence Recombinant pull-down, immunocomplex kinase assay with kinase-dead D150A mutant, TUNEL/FACS apoptosis assays

    PMID:17280616

    Open questions at the time
    • Bcl-GL phosphorylation site not mapped
    • In vivo relevance of MELK-Bcl-GL axis not tested
  7. 2011 High

    Localization of Xenopus MELK to the cleavage furrow and its interaction with anillin, combined with overexpression-induced loss of RhoA accumulation, established a direct role for MELK in cytokinesis.

    Evidence Morpholino knockdown, live imaging, co-immunoprecipitation with anillin, RhoA localization in Xenopus embryo

    PMID:21378312

    Open questions at the time
    • Whether MELK directly phosphorylates anillin or RhoA regulators unknown
    • Mammalian cytokinesis role not confirmed
  8. 2012 High

    Genetic epistasis in C. elegans placed PIG-1/MELK downstream of PAR-4/LKB1 in asymmetric neuroblast division, with activation loop T169 phosphorylation essential, establishing a conserved LKB1-MELK kinase cascade controlling cell polarity.

    Evidence Genetic epistasis with par-4/strd-1/mop-25.2, T169A mutagenesis, GFP localization in C. elegans

    PMID:23267054

    Open questions at the time
    • Direct phosphorylation of PIG-1 by PAR-4 not biochemically demonstrated
    • Whether mammalian LKB1 activates MELK in vivo not shown
  9. 2013 High

    Multiple studies converged to identify FOXM1 as a direct MELK substrate in glioma stem cells, established that MELK loss causes replication stress and p53-dependent cell cycle arrest, and resolved the MELK crystal structure — collectively defining MELK as a mitotic kinase hub linking DNA integrity, transcription, and structural drug design.

    Evidence Co-IP/kinase assay for FOXM1; DNA fiber assay and γH2AX for replication stress; X-ray crystallography of MELK-AMP-PNP and inhibitor complexes

    PMID:23339114 PMID:23404835 PMID:23836907 PMID:23914841

    Open questions at the time
    • FOXM1 phosphorylation sites by MELK not mapped
    • How MELK prevents replication stress mechanistically unclear
    • Whether MELK-JUN complex is direct or scaffolded unknown
  10. 2014 High

    A kinome-wide screen identified MELK as an oncogenic kinase selectively required in basal-like breast cancer (BBC), with FOXM1 driving its transcription, suggesting a FOXM1-MELK positive feedback loop in aggressive breast cancer subtypes.

    Evidence ORF kinome screen, shRNA knockdown, xenograft proliferation, conditional Melk knockout mice

    PMID:24844244

    Open questions at the time
    • Mechanism of basal-like selectivity not defined
    • Direct evidence for positive feedback loop incomplete
  11. 2016 High

    Identification of eIF4B Ser406 as a direct mitotic MELK substrate controlling MCL1 protein synthesis revealed how MELK sustains anti-apoptotic protein levels specifically during mitosis, linking MELK to translational control.

    Evidence IP/MS substrate identification, peptide library profiling, in vitro kinase assay, protein synthesis measurement

    PMID:27528663

    Open questions at the time
    • Whether other mRNAs are translationally regulated by MELK-eIF4B unknown
    • In vivo validation of eIF4B-MCL1 axis not performed
  12. 2017 High

    CRISPR knockout, chemical degradation, and highly selective inhibitors revealed that MELK is dispensable for basal proliferation of breast cancer cells under standard conditions, challenging prior RNAi-based essentiality claims and demonstrating off-target effects of OTSSP167.

    Evidence CRISPR/Cas9 knockout, selective inhibitor HTH-01-091, dTAG chemical degradation, proliferation assays in multiple BBC lines

    PMID:28926338

    Open questions at the time
    • Context-specific conditions under which MELK becomes essential not systematically defined
    • Whether MELK is essential in vivo under stress or immune challenge not addressed
  13. 2017 High

    Phosphoproteomic analysis in melanoma linked MELK to MAPK/E2F1 transcriptional control and NF-κB activation via SQSTM1/p62, while studies of Smad phosphorylation and ZPR9 activation expanded MELK's signaling network to TGF-β and ASK1 pathways.

    Evidence SILAC phosphoproteomics; Co-IP and in vitro kinase assays with Smad and ZPR9 phosphorylation-defective mutants; CRISPR knockin of ZPR9 T252A

    PMID:28195154 PMID:29212029 PMID:29700281

    Open questions at the time
    • How MELK activates NF-κB via p62 mechanistically unresolved
    • Smad-MELK axis validated primarily in adipogenesis context
  14. 2018 High

    Confirmation that CRISPR-null MELK cancer cells grow normally across multiple cancer types and conditions, combined with evidence that selective MELK inhibition delays mitotic entry via delayed Aurora A/B and CDK1 activation, refined the view that MELK is not a general cancer dependency but does regulate G2/M timing.

    Evidence CRISPR knockout in multiple cancer lines with xenograft; selective inhibitor NVS-MELK8a with live-cell PCNA imaging and synchronization

    PMID:29417930 PMID:31896573

    Open questions at the time
    • Mechanism by which MELK regulates Aurora/CDK1 activation not biochemically defined
    • Whether genetic compensation masks MELK loss in knockouts not tested
  15. 2019 High

    Direct phosphorylation of EZH2 at S220 by MELK was shown to prevent K222 ubiquitination and proteasomal degradation (with USP36 as the deubiquitinase), establishing a site-specific mechanism for MELK-dependent EZH2 stabilization distinct from FOXM1-mediated effects.

    Evidence Quantitative mass spectrometry, ubiquitination assays, MELK chemical and genetic inhibition in NK/T-cell lymphoma

    PMID:31434700

    Open questions at the time
    • Whether MELK directly phosphorylates EZH2 or acts through an intermediate kinase not fully excluded
    • Generalizability beyond NK/T-cell lymphoma not established
  16. 2019 High

    MELK was shown to phosphorylate p21 at Thr55, promoting nuclear translocation, CDK complex formation, and association with PPARγ to inhibit adipogenesis, revealing a metabolic regulatory function for MELK beyond cancer.

    Evidence In vitro kinase assay, T55A mutagenesis, CRISPR knockin, adenoviral delivery in obese mice

    PMID:31097688

    Open questions at the time
    • Whether Thr55 phosphorylation of p21 by MELK occurs in cancer contexts not shown
    • Relative contribution of MELK vs. other Thr55 kinases in vivo unknown
  17. 2020 High

    C. elegans studies established that PIG-1/MELK promotes apoptotic fate by phosphorylating nonmuscle myosin II to partition CES-1 Snail asymmetrically, within an autoregulatory circuit where CES-1 represses pig-1 transcription, providing a complete mechanistic model for MELK-driven asymmetric cell fate.

    Evidence ChIP-seq for CES-1, genetic epistasis, phosphorylation assay, live imaging in C. elegans

    PMID:28652378 PMID:32946434

    Open questions at the time
    • Whether mammalian MELK phosphorylates myosin II or controls asymmetric division similarly is unknown
    • Structural basis of PIG-1-myosin II interaction not determined
  18. 2024 Medium

    MELK was linked to tumor immune evasion through STAT3 phosphorylation driving CCL2 expression and M2 macrophage polarization, and to FABP5 stabilization activating AKT/mTOR, expanding MELK's roles to immunomodulation in hepatocellular carcinoma.

    Evidence IP-MS and Co-IP for STAT3; Co-IP and ubiquitination assay for FABP5; xenograft models with immune profiling

    PMID:38970074 PMID:39871325

    Open questions at the time
    • Whether MELK directly phosphorylates STAT3 or FABP5 not shown by in vitro kinase assay
    • Immunomodulatory role not validated in immunocompetent genetic models
    • Single-lab findings for each axis

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved under which physiological or pathological conditions MELK becomes essential, given that CRISPR knockouts show no proliferative defect; whether genetic compensation or context-dependent stress unmasks MELK dependence is a central open question.
  • Conditions conferring MELK essentiality not systematically identified
  • No comprehensive interactome under stress conditions
  • In vivo immune-competent models of MELK loss largely absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0016740 transferase activity 8 GO:0098772 molecular function regulator activity 3
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 2 GO:0005634 nucleus 1 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-1640170 Cell Cycle 6 R-HSA-162582 Signal Transduction 5 R-HSA-5357801 Programmed Cell Death 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-8953854 Metabolism of RNA 1
Partners
ANLNEIF4BEZH2FOXM1MLST8NIPP1STAT3ZPR9
Complex memberships
MELK-FOXM1 complexMELK-NIPP1 complex

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 MELK encodes a protein with a kinase catalytic domain and a leucine zipper motif, identified as a new member of the Snf1/AMPK family of kinases, expressed in mouse eggs and preimplantation embryos. Differential display analysis of cDNA libraries, sequence analysis Molecular reproduction and development Medium 9136115
2003 MELK inhibits spliceosome assembly through interaction with the phosphothreonine-binding FHA domain of NIPP1; this interaction requires phosphorylation of Thr-478 of MELK and is increased in mitotically arrested cells. The splicing inhibition is independent of MELK kinase activity but requires the NIPP1-binding site (T478). Recombinant protein interaction assays, in vitro spliceosome assembly assays, kinase-dead mutant and T478A mutation analysis, cell fractionation from mitotic arrest The Journal of biological chemistry High 14699119
2005 MELK has broad substrate specificity with 16 autophosphorylation sites (including serines, threonines, and a tyrosine); phosphorylation of Thr167 and Ser171 is required for MELK activation. MELK activity also requires reducing agents and is inhibited by physiological Ca2+ concentrations. The N-terminal catalytic domain plus flanking ubiquitin-associated (UBA) domain is the minimal active fragment, and a C-terminal fragment functions as an autoinhibitory domain. In vitro kinase assay, mass spectrometry mapping of phosphorylation sites, site-directed mutagenesis, domain truncation analysis The Journal of biological chemistry High 16216881
2005 MELK (Melk) is a direct transcriptional target of E2F; its expression is repressed by 1,25-dihydroxyvitamin D3 in a p107/p130-dependent (but not pRb-dependent) manner. Transfection studies and site-directed mutagenesis of E2F binding sites confirmed Melk as a bona fide E2F target gene. Transfection studies, site-directed mutagenesis of E2F binding sites, cDNA microarrays, p107/p130/pRb knockout cell analysis The Journal of biological chemistry High 16144839
2005 MELK is required for proliferation of multipotent neural progenitors (MNPs); overexpression enhances neurosphere formation while knockdown diminishes it. MELK expression is cell cycle-regulated in MNPs, and MELK knockdown downregulates B-myb expression, which also mediates MNP proliferation. Overexpression, siRNA knockdown, neurosphere formation assay, transgenic mice, in vitro culture The Journal of cell biology High 16061694
2006 The C. elegans MELK ortholog PIG-1 (a PAR-1/Kin1/SAD-1 family member) regulates cell size asymmetry in neuroblast divisions; pig-1 mutants produce daughters more equal in size with transformed apoptotic fate, indicating a role in cell polarity rather than solely cell cycle control. Genetic mutant analysis in C. elegans, lineage tracing Development (Cambridge, England) High 16774992
2006 During M-phase, Xenopus MELK (xMELK) is phosphorylated at T414, T449, T451, T481, and S498; phosphorylations at T449, T451, T481 are mitosis-specific. MPF and MAPK directly phosphorylate xMELK (MPF phosphorylates T481), and these phosphorylations enhance xMELK kinase activity in vitro. M-phase egg extract phosphorylation mapping, in vitro kinase assays with MPF and MAPK, in vivo phosphorylation analysis Cell cycle (Georgetown, Tex.) High 16628004
2007 MELK physically interacts with and phosphorylates the long isoform of Bcl-G (Bcl-GL), a pro-apoptotic Bcl-2 family member, in vitro; overexpression of wild-type but not kinase-dead (D150A) MELK suppresses Bcl-GL-induced apoptosis, indicating MELK kinase activity is required for this anti-apoptotic function. Pull-down assay with recombinant wild-type and kinase-dead MELK, immunocomplex kinase assay, TUNEL assay, FACS analysis, siRNA knockdown Breast cancer research : BCR High 17280616
2011 Xenopus MELK (xMELK) is required for cytokinesis completion; endogenous xMELK accumulates at the equatorial cortex of anaphase blastomeres and associates/colocalizes with the cytokinesis organizer anillin. Overexpression of xMELK impairs cytokinesis and abrogates accumulation of activated RhoA at the division furrow. Morpholino knockdown, live imaging, immunofluorescence, co-immunoprecipitation with anillin, RhoA localization assay in Xenopus embryo Journal of cell science High 21378312
2012 C. elegans PAR-4 (LKB1) and its partners STRD-1 (STRAD) and MOP-25.2 (MO25) act in the same genetic pathway as PIG-1 (MELK ortholog) to promote asymmetric neuroblast divisions. A conserved threonine (T169) in the PIG-1 activation loop is essential for PIG-1 activity, consistent with PAR-4-mediated phosphorylation and activation of PIG-1. PIG-1 localizes to centrosomes during Q lineage divisions. Genetic epistasis analysis, site-directed mutagenesis (T169A), GFP localization, C. elegans genetics Genetics High 23267054
2013 MELK forms a protein complex with FOXM1 in glioma stem cells, leading to MELK kinase-dependent phosphorylation and activation of FOXM1, which increases mitotic regulatory gene expression. PLK1 additionally trans-phosphorylates FOXM1 in this complex. Co-immunoprecipitation, kinase assay, siRNA knockdown, transgenic mouse NPCs, neurosphere formation Stem cells (Dayton, Ohio) High 23404835
2013 MELK loss in glioblastoma cells causes G1/S cell cycle arrest via increased p21 expression, which is mediated by consecutive activation of ATM, Chk2, and p53. The p53 activation results not from p53 stabilization but from loss of MDMX (an inhibitor of p53 transactivation). MELK depletion leads to accumulation of DNA double-strand breaks during replication (γH2AX foci), increased stalled replication forks, and reduced fork progression speed, indicating MELK reduces replication stress. siRNA knockdown, cell cycle analysis, γH2AX foci, DNA fiber assay for fork progression, Western blotting, rescue with siRNA-resistant MELK The Journal of biological chemistry High 23836907
2013 MELK is regulated by the JNK signaling pathway and forms a complex with the oncoprotein c-JUN in glioma stem cells but not in normal progenitors. MELK silencing induces p53 expression and MELK/p53 are mutually exclusive; MELK silencing-mediated apoptosis is partially rescued by p53 inhibition or silencing, placing MELK action upstream of p53. shRNA knockdown, co-immunoprecipitation, p53 inhibitor pharmacological rescue, p53 siRNA rescue, intracranial tumor model Stem cells (Dayton, Ohio) High 23339114
2013 Crystal structure of MELK in complex with AMP-PNP and nanomolar inhibitors was determined, characterizing the kinase active site and the role of the UBA domain in inhibitor binding. X-ray crystallography, structure-based drug design analysis Biochemistry High 23914841
2013 RACK1 (Receptor for Activated protein Kinase C) is an xMELK-interacting partner that co-localizes with xMELK at the tight junction in Xenopus embryo epithelial cells. A truncated RACK1 construct interferes with the localization of interphase MELK at cell-cell contacts, indicating RACK1 mediates MELK recruitment to the apical junctional complex. Co-immunoprecipitation, immunofluorescence, dominant-negative RACK1 construct, live cell imaging in Xenopus Biology open Medium 24167714
2014 MELK is identified as an oncogenic kinase in basal-like breast cancer (BBC) from a kinome-wide in vivo tumorigenesis screen; MELK overexpression in BBC is largely dependent on FoxM1 transcriptional regulation. Ablation of MELK selectively impairs proliferation in basal-like but not luminal breast cancer cells; MELK depletion induces caspase-dependent cell death preceded by defective mitosis. ORF kinome screen, shRNA knockdown, in vitro and xenograft proliferation assays, cell death assays, conditional Melk knockout mice eLife High 24844244
2014 Crystal structure of MPK38/MELK (T167E active mutant) in complex with the MELK-selective inhibitor OTSSP167 was determined, revealing detailed protein-inhibitor interactions at the active site. X-ray crystallography Biochemical and biophysical research communications High 24657156
2015 EZH2 is targeted by the MELK-FOXM1 complex in glioma stem cells, promoting radiation resistance; the MELK-EZH2 axis is evolutionarily conserved in C. elegans. MELK or FOXM1 loss reduces EZH2 activity and sensitizes GSCs to radiation. Gain- and loss-of-function (shRNA, overexpression), C. elegans genetic analysis, correlation in clinical GBM samples Stem cell reports High 25601206
2016 MELK phosphorylates eIF4B at Ser406 during mitosis; this MELK-eIF4B signaling axis regulates protein synthesis specifically during mitosis, including synthesis of the anti-apoptotic protein MCL1. Inactivation of MELK or eIF4B reduces MCL1 protein synthesis and induces apoptotic cell death in cancer cells. Immunoprecipitation/mass spectrometry, peptide library profiling, in vitro kinase assay, protein synthesis measurement, Western blotting, siRNA knockdown Proceedings of the National Academy of Sciences of the United States of America High 27528663
2016 MELK inhibition (genetic and pharmacological) reduces DNA damage repair, sensitizing breast cancer cells to radiation; MELK knockdown was associated with impaired γH2AX clearance after radiation in vitro and delayed tumor growth after irradiation in vivo. shRNA knockdown, γH2AX staining, clonogenic survival assay, xenograft irradiation model Clinical cancer research Medium 27225691
2017 MELK is transcriptionally upregulated by MAPK pathway via transcription factor E2F1 in melanoma cells. MELK promotes melanoma growth by activating NF-κB pathway activity via Sequestosome 1 (SQSTM1/p62); SILAC phosphoproteomic analysis identified 469 proteins with reduced phosphorylation after MELK inhibition, including 139 BRAF/MEK substrates. SILAC phosphoproteomics, shRNA knockdown, pharmacological inhibition, NF-κB reporter assay, Western blotting Cell reports High 29212029
2017 MELK phosphorylates HIV-1 capsid at Ser-149 in the multimerized HIV-1 core, triggering uncoating to promote viral cDNA synthesis. A phosphorylation-mimetic substitution at Ser-149 causes premature capsid disassembly and earlier cDNA synthesis but failure to enter the nucleus. Genetic screen in human T-cells, MELK depletion, in vitro phosphorylation assay, capsid disassembly assay, HIV-1 replication assay, site-directed mutagenesis of capsid Ser-149 PLoS pathogens High 28683086
2017 MELK inhibition induces p21 expression in a p53-independent manner; FOXO1 and FOXO3, known transcriptional regulators of p21, are phosphorylated by MELK and are involved in p21 induction after MELK inhibition. MELK inhibitor (OTS167), siRNA knockdown in p53-deficient cell lines, Western blotting, cell cycle analysis Oncotarget Medium 28938528
2017 MELK inhibition by selective inhibitor HTH-01-091, CRISPR/Cas9 knockout, and chemical-induced protein degradation does not significantly affect cellular growth in common culture conditions of basal-like breast cancer cells, revealing selectivity issues with OTSSP167 and potential off-target effects of MELK-targeting shRNAs. CRISPR/Cas9 knockout, novel selective inhibitor HTH-01-091, chemical protein degradation (dTAG), RNAi, CRISPR interference, proliferation assay eLife High 28926338
2017 MELK bound to and phosphorylated EZH2 in medulloblastoma stem-like cells; EZH2-mediated methylation of MELK was also induced, forming a reciprocal regulatory loop. MELK-induced EZH2 phosphorylation and EZH2-mediated MELK methylation together regulate proliferation of cancer stem-like cells. Co-immunoprecipitation, kinase assay, methylation assay, immunohistochemistry, xenograft Molecular cancer research : MCR Medium 28536141
2018 MELK inhibition by the selective inhibitor NVS-MELK8a delays mitotic entry in cancer cells, associated with delayed activation of Aurora A, Aurora B, and CDK1. Live-cell microscopy confirmed 8a significantly lengthens G2 phase in a dose-dependent manner. MIB/MS selectivity profiling, resazurin/crystal violet growth assays, double-thymidine synchronization, Western blotting, live-cell microscopy with fluorescent PCNA The Journal of biological chemistry High 31896573
2018 CRISPR/Cas9-generated MELK null mutant cancer cells of multiple types exhibit wild-type growth in vitro, under environmental stress, in the presence of cytotoxic chemotherapies, and in vivo; acute inhibition of MELK with a highly specific inhibitor also produces no specific anti-proliferative phenotype. CRISPR/Cas9 knockout in multiple cancer lines, specific MELK inhibitor, xenograft growth assay, chemotherapy combination eLife High 29417930
2019 MELK mediates EZH2 stability in extranodal NK/T-cell lymphoma through site-specific phosphorylation: MELK increases EZH2 S220 phosphorylation with concomitant loss of K222 ubiquitination, preventing proteasomal degradation of EZH2. USP36 was identified as the deubiquitinating enzyme that deubiquitinates EZH2 at K222. FOXM1 was not involved in this mechanism. Quantitative mass spectrometry, MELK chemical and genetic inhibition, ubiquitination assays, Western blotting, tissue microarray Blood High 31434700
2019 MELK promotes ccRCC progression by phosphorylating PRAS40 (an inhibitory subunit of mTORC1), disrupting the interaction between PRAS40 and raptor, thereby over-activating mTORC1 signaling. Loss- and gain-of-function assays, co-immunoprecipitation, Western blotting, interaction disruption assay Cell transplantation Medium 31813279
2019 MPK38/MELK acts as an interacting partner and activator of p21; MPK38 phosphorylates p21 at Thr55, stimulating p21 nuclear translocation and association with PPARγ, preventing adipogenesis. MPK38 also stabilizes p21 by promoting CDK2-p21 and CDK4-p21 complex formation and reducing MDM2-p21 interaction. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (T55A), nuclear fractionation, CRISPR knockin, adenoviral delivery in obese mice Cell death & disease High 31097688
2020 CES-1 Snail (C. elegans) represses pig-1 MELK transcription in the NSM neuroblast lineage; PIG-1 MELK acts downstream of CES-1 to promote asymmetric neuroblast division by size and along the correct axis, establishing an auto-regulatory loop through which CES-1 Snail controls its own activity. Genome-wide CES-1 ChIP-seq, genetic epistasis, transcriptional reporter assays in C. elegans Genetics High 28652378
2020 PIG-1 MELK (C. elegans ortholog) promotes apoptosis by phosphorylating nonmuscle myosin II, leading to cortical enrichment of myosin II prior to neuroblast division. This promotes partitioning of CES-1 Snail (an anti-apoptotic factor) away from the apoptotic daughter cell. pig-1 MELK is controlled by both a ces-1 Snail- and par-4 LKB1-dependent pathway. Genetic analysis in C. elegans, phosphorylation assay, live imaging, epistasis analysis PLoS genetics High 32946434
2020 MELK directly interacts with MLST8 (a component of mTOR complexes) and activates mTORC1 and mTORC2 signaling pathways in endometrial carcinoma. E2F1 transcriptionally regulates MELK expression, establishing an E2F1/MELK/mTORC1/2 axis. Co-immunoprecipitation, chromatin immunoprecipitation, luciferase reporter assay, Western blotting, xenograft model EBioMedicine Medium 31915116
2020 MELK inhibition arrests LUAD cells at G2/M phase via the PLK1-CDC25C-CDK1 pathway and triggers apoptosis-mediated pyroptosis. MELK knockdown inhibits migration/invasion potentially through Twist1, Slug, MMP7, and N-catenin. MELK inhibitor OTSSP167, shRNA knockdown, cell cycle analysis, apoptosis assay, Western blotting, invasion assay Signal transduction and targeted therapy Medium 33262323
2017 Smad2, Smad3, and Smad4 increase MPK38/MELK-mediated ASK1/TGF-β/p53 signaling and stabilize MPK38 by attenuating its interaction with the negative regulator thioredoxin (Trx) and enhancing interaction with the positive regulator ZPR9. Smad7 has opposite effects. MPK38 phosphorylates Smads (Smad2 S245, Smad3 S204, Smad4 S343, Smad7 T96), and these phosphorylations are required for Smad effects on MPK38 activity. Co-immunoprecipitation, in vitro kinase assay, phosphorylation-defective mutants, adenoviral delivery in HFD-fed obese mice Cell death & disease High 29700281
2017 ZPR9 is an activator of MPK38/MELK; the MPK38-ZPR9 association is mediated by cysteine residues (Cys269/Cys286 of MPK38; Cys305/Cys308 of ZPR9). MPK38 phosphorylates ZPR9 at Thr252, and wild-type (but not T252A mutant) ZPR9 enhances ASK1, TGF-β, and p53 function by stabilizing MPK38. Co-immunoprecipitation, in vitro kinase assay, CRISPR/Cas9 knockin (ZPR9 T252A), NIH 3T3 inducible knockdown, MPK38 kinase assay Scientific reports High 28195154
2023 MELK activates the PI3K/mTOR signaling pathway and subsequently promotes DLAT (dihydrolipoamide S-acetyltransferase) expression, stabilizing mitochondrial function and respiration in HCC. This reduces intracellular ROS and decreases sensitivity to the copper ionophore elesclomol (cuproptosis), promoting HCC progression. MELK knockdown/overexpression, Western blotting, mitochondrial function assays, ROS measurement, copper ionophore treatment, xenograft Cell death & disease Medium 37949877
2024 MELK binds to STAT3 and induces STAT3 phosphorylation in HCC, increasing expression of CCL2. This MELK-STAT3-CCL2 axis promotes M2 macrophage polarization and inhibits CD8+ T cell recruitment, contributing to an immunosuppressive tumor microenvironment. IP-MS, co-immunoprecipitation, luciferase assay, RNA sequencing, xenograft models, flow cytometry Molecular cancer Medium 38970074
2025 MELK binds to FABP5 and affects its ubiquitination through the K48R pathway to increase FABP5 stability, thereby activating the AKT/mTOR signaling axis and weakening RFA-mediated antitumor immune effects in HCC. RNA sequencing, co-immunoprecipitation, ubiquitination assay, nanoparticle-mediated MELK inhibition, in vivo tumor models Military Medical Research Medium 39871325
2020 Wild-type p53 suppresses MELK expression by inhibiting E2F1-dependent transcription of FOXM1 (which in turn drives MELK expression). Mutation/loss of p53 de-represses FOXM1-driven MELK expression. ChIP assays showed wild-type p53 reduces E2F1 binding to the FOXM1 promoter. Promoter deletion studies, ChIP assay, overexpression of wild-type p53 in p53-null cells, Western blotting, gene expression analysis NPJ breast cancer High 31909186
2012 MELK identified PSMA1 (proteasome subunit alpha type 1) and DBNL (drebrin-like) as novel substrates; MELK phosphorylates these substrates in vitro, and these substrates are important for stem-cell characteristics and invasiveness. OTSSP167 inhibits this phosphorylation. High-throughput screening, in vitro kinase assay with recombinant substrates, structure-activity relationship studies Oncotarget Medium 23283305
2016 MELK enhances DEPDC1 phosphorylation and its stability as a downstream molecule in the MELK signaling pathway; MELK inhibition by OTS167 reduces DEPDC1 expression in treated xenograft tumor tissues. Western blotting, in vitro kinase assay (implied), xenograft pharmacodynamic analysis Oncotarget Low 26918358
2018 MELK inhibition in DIPG reduces inhibitory phosphorylation of PPARγ, resulting in increased nuclear translocation and consequent transcriptional activity of PPARγ, identifying a MELK-PPARγ signaling axis. RNA sequencing of MELK inhibitor-treated cells, Western blotting for PPARγ phosphorylation and localization, patient-derived DIPG cultures Clinical cancer research Medium 30061363
2024 DDX56 enhances MELK expression in HCC, and MELK in turn promotes FOXM1 expression/activity; DDX56 knockdown reduces MELK-mediated FOXM1 signaling, establishing a DDX56-MELK-FOXM1 axis regulating cancer stemness and EMT in HCC. shRNA knockdown, Western blotting, xenograft model with lung metastasis assessment iScience Low 38827395

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 MELK-dependent FOXM1 phosphorylation is essential for proliferation of glioma stem cells. Stem cells (Dayton, Ohio) 172 23404835
2007 Involvement of maternal embryonic leucine zipper kinase (MELK) in mammary carcinogenesis through interaction with Bcl-G, a pro-apoptotic member of the Bcl-2 family. Breast cancer research : BCR 159 17280616
2015 EZH2 protects glioma stem cells from radiation-induced cell death in a MELK/FOXM1-dependent manner. Stem cell reports 147 25601206
2012 The maternal embryonic leucine zipper kinase (MELK) is upregulated in high-grade prostate cancer. Journal of molecular medicine (Berlin, Germany) 134 22945237
2012 Development of an orally-administrative MELK-targeting inhibitor that suppresses the growth of various types of human cancer. Oncotarget 133 23283305
2005 Maternal embryonic leucine zipper kinase (MELK) regulates multipotent neural progenitor proliferation. The Journal of cell biology 131 16061694
1997 New member of the Snf1/AMPK kinase family, Melk, is expressed in the mouse egg and preimplantation embryo. Molecular reproduction and development 109 9136115
2013 Tumor-specific activation of the C-JUN/MELK pathway regulates glioma stem cell growth in a p53-dependent manner. Stem cells (Dayton, Ohio) 100 23339114
2015 MELK-a conserved kinase: functions, signaling, cancer, and controversy. Clinical and translational medicine 98 25852826
2014 MELK is an oncogenic kinase essential for mitotic progression in basal-like breast cancer cells. eLife 98 24844244
2005 Substrate specificity and activity regulation of protein kinase MELK. The Journal of biological chemistry 94 16216881
2016 Maternal Embryonic Leucine Zipper Kinase (MELK) as a Novel Mediator and Biomarker of Radioresistance in Human Breast Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 91 27225691
2017 MELK is not necessary for the proliferation of basal-like breast cancer cells. eLife 86 28926338
2003 Inhibition of spliceosome assembly by the cell cycle-regulated protein kinase MELK and involvement of splicing factor NIPP1. The Journal of biological chemistry 85 14699119
2019 Long noncoding RNA LINC02418 regulates MELK expression by acting as a ceRNA and may serve as a diagnostic marker for colorectal cancer. Cell death & disease 83 31358735
2023 MELK promotes HCC carcinogenesis through modulating cuproptosis-related gene DLAT-mediated mitochondrial function. Cell death & disease 82 37949877
2006 The C. elegans MELK ortholog PIG-1 regulates cell size asymmetry and daughter cell fate in asymmetric neuroblast divisions. Development (Cambridge, England) 82 16774992
2016 MELK is an oncogenic kinase essential for early hepatocellular carcinoma recurrence. Cancer letters 74 27693640
2020 MELK is an oncogenic kinase essential for metastasis, mitotic progression, and programmed death in lung carcinoma. Signal transduction and targeted therapy 73 33262323
2013 Maternal embryonic leucine zipper kinase (MELK): a novel regulator in cell cycle control, embryonic development, and cancer. International journal of molecular sciences 71 24185907
2021 Pharmacological inhibition of MELK restricts ferroptosis and the inflammatory response in colitis and colitis-propelled carcinogenesis. Free radical biology & medicine 69 34144192
2018 MELK expression correlates with tumor mitotic activity but is not required for cancer growth. eLife 65 29417930
2017 MELK Promotes Melanoma Growth by Stimulating the NF-κB Pathway. Cell reports 64 29212029
2016 Mitotic MELK-eIF4B signaling controls protein synthesis and tumor cell survival. Proceedings of the National Academy of Sciences of the United States of America 60 27528663
2015 MELK-T1, a small-molecule inhibitor of protein kinase MELK, decreases DNA-damage tolerance in proliferating cancer cells. Bioscience reports 60 26431963
2020 MELK promotes Endometrial carcinoma progression via activating mTOR signaling pathway. EBioMedicine 59 31915116
2014 Preclinical efficacy of maternal embryonic leucine-zipper kinase (MELK) inhibition in acute myeloid leukemia. Oncotarget 59 25365263
2011 Resistance of colorectal cancer cells to radiation and 5-FU is associated with MELK expression. Biochemical and biophysical research communications 58 21806965
2003 Topological proteomics, toponomics, MELK-technology. Advances in biochemical engineering/biotechnology 57 12934931
2011 Siomycin A targets brain tumor stem cells partially through a MELK-mediated pathway. Neuro-oncology 53 21558073
2017 MELK expression in ovarian cancer correlates with poor outcome and its inhibition by OTSSP167 abrogates proliferation and viability of ovarian cancer cells. Gynecologic oncology 52 28214016
1999 Expression of Melk, a new protein kinase, during early mouse development. Developmental dynamics : an official publication of the American Association of Anatomists 47 10417823
2016 Effective growth-suppressive activity of maternal embryonic leucine-zipper kinase (MELK) inhibitor against small cell lung cancer. Oncotarget 46 26871945
2016 Oncogenic roles of TOPK and MELK, and effective growth suppression by small molecular inhibitors in kidney cancer cells. Oncotarget 45 26933922
2011 A functional analysis of MELK in cell division reveals a transition in the mode of cytokinesis during Xenopus development. Journal of cell science 45 21378312
2017 MELK and EZH2 Cooperate to Regulate Medulloblastoma Cancer Stem-like Cell Proliferation and Differentiation. Molecular cancer research : MCR 44 28536141
2017 MELK: a potential novel therapeutic target for TNBC and other aggressive malignancies. Expert opinion on therapeutic targets 44 28764577
2021 MELK expression in breast cancer is associated with infiltration of immune cell and pathological compete response (pCR) after neoadjuvant chemotherapy. American journal of cancer research 41 34659896
2018 Sanguinarine triggers intrinsic apoptosis to suppress colorectal cancer growth through disassociation between STRAP and MELK. BMC cancer 41 29783958
2017 p53-independent p21 induction by MELK inhibition. Oncotarget 41 28938528
2005 Characterization of the condensin component Cnap1 and protein kinase Melk as novel E2F target genes down-regulated by 1,25-dihydroxyvitamin D3. The Journal of biological chemistry 40 16144839
2021 KLF5-induced BBOX1-AS1 contributes to cell malignant phenotypes in non-small cell lung cancer via sponging miR-27a-5p to up-regulate MELK and activate FAK signaling pathway. Journal of experimental & clinical cancer research : CR 39 33931086
2014 Multi-kinase inhibitor C1 triggers mitotic catastrophe of glioma stem cells mainly through MELK kinase inhibition. PloS one 38 24739874
2018 MELK Inhibition in Diffuse Intrinsic Pontine Glioma. Clinical cancer research : an official journal of the American Association for Cancer Research 37 30061363
2018 Smad proteins differentially regulate obesity-induced glucose and lipid abnormalities and inflammation via class-specific control of AMPK-related kinase MPK38/MELK activity. Cell death & disease 36 29700281
2023 miR-21-5p Inhibits Ferroptosis in Hepatocellular Carcinoma Cells by Regulating the AKT/mTOR Signaling Pathway through MELK. Journal of immunology research 35 37008632
2006 M-phase MELK activity is regulated by MPF and MAPK. Cell cycle (Georgetown, Tex.) 35 16628004
2024 Tumor cell-intrinsic MELK enhanced CCL2-dependent immunosuppression to exacerbate hepatocarcinogenesis and confer resistance of HCC to radiotherapy. Molecular cancer 34 38970074
2016 Preclinical evaluation of biomarkers associated with antitumor activity of MELK inhibitor. Oncotarget 34 26918358
2020 Upregulated MELK Leads to Doxorubicin Chemoresistance and M2 Macrophage Polarization via the miR-34a/JAK2/STAT3 Pathway in Uterine Leiomyosarcoma. Frontiers in oncology 33 32391256
2019 MELK mediates the stability of EZH2 through site-specific phosphorylation in extranodal natural killer/T-cell lymphoma. Blood 33 31434700
2013 Maternal embryonic leucine zipper kinase (MELK) reduces replication stress in glioblastoma cells. The Journal of biological chemistry 32 23836907
2020 Enigmatic MELK: The controversy surrounding its complex role in cancer. The Journal of biological chemistry 31 32350113
2019 Inhibition of MELK produces potential anti-tumour effects in bladder cancer by inducing G1/S cell cycle arrest via the ATM/CHK2/p53 pathway. Journal of cellular and molecular medicine 31 31821699
2020 MEK/MELK inhibition and blood-brain barrier deficiencies in atypical teratoid/rhabdoid tumors. Neuro-oncology 28 31504799
2019 Maternal Embryonic Leucine Zipper Kinase (MELK), a Potential Therapeutic Target for Neuroblastoma. Molecular cancer therapeutics 27 30674566
2017 Genome-wide effects of MELK-inhibitor in triple-negative breast cancer cells indicate context-dependent response with p53 as a key determinant. PloS one 27 28235006
2017 Discovery of a potent inhibitor of MELK that inhibits expression of the anti-apoptotic protein Mcl-1 and TNBC cell growth. Bioorganic & medicinal chemistry 27 28351607
2017 Phosphorylation of the HIV-1 capsid by MELK triggers uncoating to promote viral cDNA synthesis. PLoS pathogens 27 28683086
2021 MELK Inhibition Effectively Suppresses Growth of Glioblastoma and Cancer Stem-Like Cells by Blocking AKT and FOXM1 Pathways. Frontiers in oncology 26 33520717
2013 Structural insight into maternal embryonic leucine zipper kinase (MELK) conformation and inhibition toward structure-based drug design. Biochemistry 26 23914841
2012 Caenorhabditis elegans PIG-1/MELK acts in a conserved PAR-4/LKB1 polarity pathway to promote asymmetric neuroblast divisions. Genetics 25 23267054
2022 xCT contributes to colorectal cancer tumorigenesis through upregulation of the MELK oncogene and activation of the AKT/mTOR cascade. Cell death & disease 24 35440604
2020 BUB1B Promotes Proliferation of Prostate Cancer via Transcriptional Regulation of MELK. Anti-cancer agents in medicinal chemistry 24 31893996
2020 MELK Accelerates the Progression of Colorectal Cancer via Activating the FAK/Src Pathway. Biochemical genetics 24 32472210
2017 MELK is a novel therapeutic target in high-risk neuroblastoma. Oncotarget 24 29416794
2021 Up-regulation of MELK by E2F1 promotes the proliferation in cervical cancer cells. International journal of biological sciences 23 34671205
2020 Mutant P53 induces MELK expression by release of wild-type P53-dependent suppression of FOXM1. NPJ breast cancer 23 31909186
2014 The crystal structure of MPK38 in complex with OTSSP167, an orally administrative MELK selective inhibitor. Biochemical and biophysical research communications 23 24657156
2005 Melk-like kinase plays a role in hematopoiesis in the zebra fish. Molecular and cellular biology 23 16024803
2021 Discovery of a new molecule inducing melanoma cell death: dual AMPK/MELK targeting for novel melanoma therapies. Cell death & disease 22 33431809
2017 Zinc finger protein ZPR9 functions as an activator of AMPK-related serine/threonine kinase MPK38/MELK involved in ASK1/TGF-β/p53 signaling pathways. Scientific reports 22 28195154
2022 Circular RNA MELK Promotes Chondrocyte Apoptosis and Inhibits Autophagy in Osteoarthritis by Regulating MYD88/NF-κB Signaling Axis through MicroRNA-497-5p. Contrast media & molecular imaging 21 35992546
2020 Mass spectrometry-based selectivity profiling identifies a highly selective inhibitor of the kinase MELK that delays mitotic entry in cancer cells. The Journal of biological chemistry 21 31896573
2018 MELK as a potential target to control cell proliferation in triple-negative breast cancer MDA-MB-231 cells. Oncology letters 21 29805690
2020 Maslinic Acid Enhances Docetaxel Response in Human Docetaxel-Resistant Triple Negative Breast Carcinoma MDA-MB-231 Cells via Regulating MELK-FoxM1-ABCB1 Signaling Cascade. Frontiers in pharmacology 20 32581798
2020 MELK/MPK38 in cancer: from mechanistic aspects to therapeutic strategies. Drug discovery today 20 33010478
2019 Thr55 phosphorylation of p21 by MPK38/MELK ameliorates defects in glucose, lipid, and energy metabolism in diet-induced obese mice. Cell death & disease 20 31097688
2019 MELK is Upregulated in Advanced Clear Cell Renal Cell Carcinoma and Promotes Disease Progression by Phosphorylating PRAS40. Cell transplantation 20 31813279
2018 Corosolic acid induces cell cycle arrest and cell apoptosis in human retinoblastoma Y-79 cells via disruption of MELK-FoxM1 signaling. Oncology reports 20 29620242
2025 MELK prevents radiofrequency ablation-induced immunogenic cell death and antitumor immune response by stabilizing FABP5 in hepatocellular malignancies. Military Medical Research 19 39871325
2020 Phillygenin, a MELK Inhibitor, Inhibits Cell Survival and Epithelial-Mesenchymal Transition in Pancreatic Cancer Cells. OncoTargets and therapy 19 32308417
2017 RNA sequencing of esophageal adenocarcinomas identifies novel fusion transcripts, including NPC1-MELK, arising from a complex chromosomal rearrangement. Cancer 18 28640357
2019 MELK inhibition targets cancer stem cells through downregulation of SOX2 expression in head and neck cancer cells. Oncology reports 17 30720113
2016 Identification of IL11RA and MELK amplification in gastric cancer by comprehensive genomic profiling of gastric cancer cell lines. World journal of gastroenterology 17 27920471
2011 Serine/threonine kinase, Melk, regulates proliferation and glial differentiation of retinal progenitor cells. Cancer science 16 21923749
2022 Preclinical assessment of synergistic efficacy of MELK and CDK inhibitors in adrenocortical cancer. Journal of experimental & clinical cancer research : CR 15 36151566
2020 PIG-1 MELK-dependent phosphorylation of nonmuscle myosin II promotes apoptosis through CES-1 Snail partitioning. PLoS genetics 15 32946434
2016 Expression of Maternal Embryonic Leucine Zipper Kinase (MELK) Correlates to Malignant Potentials in Hepatocellular Carcinoma. Anticancer research 14 27798878
2024 DDX56 promotes EMT and cancer stemness via MELK-FOXM1 axis in hepatocellular carcinoma. iScience 13 38827395
2020 High expression of maternal embryonic leucine-zipper kinase (MELK) impacts clinical outcomes in patients with ovarian cancer and its inhibition suppresses ovarian cancer cells growth ex vivo. Journal of gynecologic oncology 13 33078598
2014 Copy number alterations and neoplasia-specific mutations in MELK, PDCD1LG2, TLN1, and PAX5 at 9p in different neoplasias. Genes, chromosomes & cancer 13 24664538
2021 PCDHB17P/miR-145-3p/MELK/NF-κB Feedback Loop Promotes Metastasis and Angiogenesis of Breast Cancer. Frontiers in oncology 12 34350110
2017 Caenorhabditis elegans CES-1 Snail Represses pig-1 MELK Expression To Control Asymmetric Cell Division. Genetics 12 28652378
2013 Cell-cycle dependent localization of MELK and its new partner RACK1 in epithelial versus mesenchyme-like cells in Xenopus embryo. Biology open 12 24167714
2021 Circ_0007031 Silencing Inhibits Cell Proliferation and Induces Cell Apoptosis via Downregulating MELK at a miR-485-3p-Dependent Way in Colorectal Cancer. Biochemical genetics 11 34322757
2020 Suppression of long non-coding RNA PCAT19 inhibits glioma cell proliferation and invasion, and increases cell apoptosis through regulation of MELK targeted by miR-142-5p. Genes & genomics 11 32980991
2018 A Conditional Dependency on MELK for the Proliferation of Triple-Negative Breast Cancer Cells. iScience 11 30391850
2024 The high expression of TOP2A and MELK induces the occurrence of psoriasis. Aging 10 38382096
2024 Upregulation of MELK promotes chemoresistance and induces macrophage M2 polarization via CSF-1/JAK2/STAT3 pathway in gastric cancer. Cancer cell international 10 39135038