Affinage

MARCKS

Myristoylated alanine-rich C-kinase substrate · UniProt P29966

Length
332 aa
Mass
31.6 kDa
Annotated
2026-06-10
100 papers in source corpus 39 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MARCKS is a myristoylated, calmodulin- and phospholipid-binding protein that couples the cortical actin cytoskeleton to the inner leaflet of the plasma membrane and acts as a reversible, PKC-controlled relay in motility, secretion, and signaling (PMID:1560845, PMID:9259558, PMID:15316066). It crosslinks F-actin and tethers to acidic phospholipids through two cooperating modules—an N-terminal myristoyl moiety and a basic effector domain—and both actin crosslinking and membrane binding are switched off by PKC phosphorylation of the effector domain and by Ca2+-calmodulin binding (PMID:1560845, PMID:8486722, PMID:2002042, PMID:9804991). This 'myristoyl-electrostatic switch' drives bi-directional cycling between membrane and cytosol: phosphorylation (followed by PP1/PP2A dephosphorylation) governs translocation, lysosomal targeting via cathepsin B cleavage, and the membrane-versus-cytosol balance required for cell spreading, adhesion, and stress-fiber maturation (PMID:7720702, PMID:9295331, PMID:8262213, PMID:15316066, PMID:12045217). At the membrane MARCKS sequesters PIP2 and restrains PI3K, so PKC-driven release of PIP2 recruits and activates PI3K to form a leading-edge Ca2+–PKC–MARCKS–PIP2–PI3K amplification module that controls PIP3 signaling and directed migration (PMID:27119641, PMID:29715315). Through this switch MARCKS regulates diverse processes including airway mucin secretion via PKCδ, neutrophil and macrophage migration, megakaryocyte proplatelet formation, and ENaC channel activity through PIP2 availability (PMID:18055557, PMID:19574534, PMID:22791334, PMID:25515270, PMID:26744461, PMID:22623357). MARCKS is also acetylated at Lys165 by Tip60 as a prerequisite for phosphorylation and deacetylated by SIRT2, and it binds LPS through an effector-domain heptapeptide to dampen TLR4 signaling (PMID:22427633, PMID:30655546). MARCKS is required for normal brain development, where membrane association mediated by its myristoylation domain governs radial glial progenitor placement (PMID:7862670, PMID:19666823).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1991 High

    Established that PKC phosphorylation of the effector domain is a molecular switch controlling calmodulin affinity, explaining how MARCKS could gate calmodulin-dependent enzyme activation.

    Evidence Synthetic effector-domain peptide phosphorylated by PKC in vitro with calmodulin binding and CaM-enzyme activity assays

    PMID:2002042

    Open questions at the time
    • Done with a 25-mer peptide, not full-length protein in cells
    • Numbering (Ser8/Ser12) of the peptide not yet mapped to physiological residues
  2. 1992 High

    Identified MARCKS as a regulated F-actin crosslinker, linking it physically to the cortical cytoskeleton and showing both PKC and calmodulin inhibit this activity.

    Evidence In vitro F-actin crosslinking assay with PKC phosphorylation and calmodulin binding

    PMID:1560845

    Open questions at the time
    • Crosslinking shown in vitro; cellular consequences not yet established
    • No structural model of the actin-binding interface
  3. 1993 High

    Defined the bipartite membrane-anchoring mechanism (myristoyl plus basic domain) and showed phosphorylation lowers phospholipid affinity, giving a physical basis for membrane release.

    Evidence Purified MARCKS and effector peptide binding to defined liposomes with PKC phosphorylation; mapping of PKC sites to Ser152/156/163 by tryptic analysis

    PMID:8422248 PMID:8486722

    Open questions at the time
    • Phospho-site mapping from a single laboratory
    • Lipid binding measured on planar/vesicle systems, not native membranes
  4. 1993 Medium

    Identified PP1/PP2A as the phosphatases that reverse PKC phosphorylation, completing the reversible cycle that returns MARCKS to the membrane.

    Evidence Cell-free phosphatase assays and okadaic acid treatment in Swiss 3T3 cells

    PMID:8262213

    Open questions at the time
    • Specific phosphatase responsible in vivo not resolved among PP1/PP2A/PP2C
    • No demonstration of physiological membrane re-targeting at this stage
  5. 1995 High

    Demonstrated that phosphorylation is required for MARCKS translocation and lysosomal targeting in cells, and that MARCKS is essential for brain development.

    Evidence Phosphorylation-deficient mutants with immuno-EM/fractionation in fibroblasts; knockout mice with developmental phenotyping

    PMID:7720702 PMID:7862670

    Open questions at the time
    • Cellular targets mediating the developmental phenotype not yet defined
    • Route to lysosomes mechanistically incomplete
  6. 1997 High

    Identified cathepsin B as the MARCKS-cleaving enzyme and showed the myristoyl-electrostatic switch is required for cell spreading and adhesion.

    Evidence Cathepsin B co-purification and cell-free cleavage with CA074-Me; switch-mutant expression in fibroblasts with morphology and adhesion assays

    PMID:9259558 PMID:9295331

    Open questions at the time
    • Functional role of the p40 cleavage product unknown
    • Switch-mutant phenotype from single laboratory
  7. 2003 High

    Refined the calmodulin interaction by showing the myristoyl group itself contributes phosphorylation-independent, ionic-strength-independent calmodulin binding.

    Evidence Calmodulin-agarose chromatography and dansyl-calmodulin assays with myristoylated vs non-myristoylated MARCKS and N-terminal peptides

    PMID:14506265

    Open questions at the time
    • Physiological relevance of N-terminal CaM binding versus effector-domain binding unresolved
  8. 2009 High

    Separated MARCKS's developmental functions by domain, showing membrane association via myristoylation (not phosphorylation) drives radial glial progenitor placement.

    Evidence Knockout mice rescued with phosphorylation-deficient and myristoylation-deficient mutants

    PMID:19666823

    Open questions at the time
    • Downstream effectors in radial glia not identified
  9. 2012 Medium

    Defined MARCKS as a PIP2-sequestering regulator of ion channels and a lipid/curvature sensor, and as an LPS-binding modulator of TLR4 signaling.

    Evidence FRET/patch-clamp on ENaC; curvature-defined vesicle binding; NMR of the LPS-binding heptapeptide with KO MEFs

    PMID:22427633 PMID:22791334 PMID:23075500

    Open questions at the time
    • ENaC and lipid-sensing data each from single laboratories
    • Whether LPS binding occurs at physiological concentrations in vivo unresolved
  10. 2016 High

    Reconstituted the PKC–MARCKS–PIP2–PI3K leading-edge amplification module at single-molecule resolution and confirmed it as a positive-feedback loop in live macrophages.

    Evidence Single-molecule fluorescence on lipid bilayers; live-cell biosensors with activators/inhibitors in macrophages

    PMID:27119641 PMID:29715315

    Open questions at the time
    • Quantitative contribution relative to other PIP2 effectors in vivo not established
  11. 2019 High

    Identified an acetylation layer upstream of phosphorylation, with Tip60 acetylating Lys165 as a prerequisite for PKC phosphorylation and SIRT2 reversing it.

    Evidence Tip60 acetyltransferase and SIRT2 deacetylation assays with phosphorylation-dead mutant and genetic rescue

    PMID:30655546

    Open questions at the time
    • Generality of acetylation control beyond high-glucose neuroepithelium not established
  12. 2024 Low

    Extended the calmodulin-translocation axis to disease, implicating a circRNA-encoded peptide in enhancing MARCKS-calmodulin binding and PI3K/AKT/mTOR activation.

    Evidence Co-IP of MARCKS-calmodulin with/without TRIM1-269aa and pathway readouts in TNBC cells

    PMID:38755678

    Open questions at the time
    • Single Co-IP with limited validation of the MARCKS-specific step
    • Direct effect on MARCKS translocation not biochemically isolated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the membrane/cytosol cycle, acetylation-priming, calmodulin extraction, and protease cleavage are integrated and spatially coordinated to produce tissue-specific outputs remains unresolved.
  • No integrated structural model of full-length MARCKS at membranes
  • Relative in vivo contributions of cathepsin B and calpain-2 cleavage unknown
  • Cause of opposite migration/proliferation outcomes across cell types unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0098772 molecular function regulator activity 3 GO:0005198 structural molecule activity 2 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005829 cytosol 3 GO:0005886 plasma membrane 3 GO:0005764 lysosome 2 GO:0005856 cytoskeleton 2 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-1266738 Developmental Biology 2 R-HSA-168256 Immune System 2
Partners
CALM1CAPN2CTSBNKAPPI3KPRKCDPRKCE

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 MARCKS is a filamentous (F)-actin crosslinking protein; this crosslinking activity is inhibited by PKC-mediated phosphorylation and by binding to calcium-calmodulin, establishing MARCKS as a regulated crossbridge between actin and the plasma membrane. In vitro F-actin crosslinking assay, PKC phosphorylation, calmodulin binding assay Nature High 1560845
1993 MARCKS binds to phospholipid membranes through two sites: the N-terminal myristoyl moiety and the basic phosphorylation domain; phosphorylation of the basic domain by PKC lowers its affinity for negatively charged phospholipids (phosphatidylserine), causing dissociation from membranes. Purified MARCKS binding to liposomes (phosphatidylcholine and phosphatidylserine), synthetic phosphorylation domain peptide assays, PKC phosphorylation The Journal of biological chemistry High 8486722
1991 PKC phosphorylation of the MARCKS effector domain peptide at Ser8 and Ser12 (with Ser12 being key) produces a ~200-fold decrease in calmodulin affinity, causing rapid release of bound calmodulin and enabling subsequent calmodulin-dependent enzyme activation. Synthetic MARCKS effector domain peptide (25-mer), PKC phosphorylation in vitro, calmodulin binding assay, calmodulin-dependent enzyme activity assays (phosphodiesterase, calcineurin, myosin light chain kinase) The Journal of biological chemistry High 2002042
1993 In rat brain, PKC isoforms I, II, and III phosphorylate MARCKS at Ser152, Ser156, and Ser163, but not at Ser160 as previously reported; Ser152 and Ser156 are phosphorylated at twice the initial rate of Ser163, with no isoform preference. Tryptic peptide analysis of PKC-phosphorylated MARCKS and synthetic peptide, alpha-chymotrypsin digestion, 32P incorporation mapping Biochemical and biophysical research communications Medium 8422248
1995 PKC-dependent phosphorylation regulates cycling of MARCKS between the plasma membrane and Lamp-1-positive lysosomes in fibroblasts; mutating PKC phosphorylation sites prevents both membrane release and lysosomal targeting, indicating phosphorylation is required for translocation. Immunofluorescence, immunoelectron microscopy, subcellular fractionation, PKC mutant MARCKS (phosphorylation-deficient), lysosomotropic agents, nocodazole The EMBO journal High 7720702
1995 MARCKS is required for normal mouse brain development; MARCKS-deficient mice exhibit exencephaly, agenesis of corpus callosum, failure of cerebral hemisphere fusion, and cortical/retinal lamination abnormalities, with all pups dying perinatally. Homologous recombination gene disruption (knockout mice), histological analysis of embryos and pups Proceedings of the National Academy of Sciences of the United States of America High 7862670
1997 Expression of a MARCKS mutant that abrogates the myristoyl-electrostatic switch prevents cell spreading in fibroblasts, arresting cells at an early stage with membrane blebbing and preventing membrane ruffle and lamellae formation, accompanied by decreased cell-substratum adhesion. Transfection of myristoyl-electrostatic switch mutant MARCKS in fibroblasts, cell morphology analysis, cell adhesion assay Current biology : CB Medium 9259558
1997 Cathepsin B is the cellular MARCKS-cleaving enzyme (MCE); it cleaves MARCKS at the lysosomal compartment to generate a carboxyl-terminal fragment (p40), and specific cathepsin B inhibitor CA074-Me blocks this cleavage in fibroblasts. Co-purification of MCE activity with cathepsin B immunoreactivity, cell-free cathepsin B cleavage assay, cell-permeable cathepsin B inhibitor (CA074-Me), subcellular fractionation, NH4Cl treatment The Journal of biological chemistry High 9295331
1998 The kinetics of MARCKS effector domain peptide binding to phospholipid vesicles is diffusion-limited; Ca2+-calmodulin (5 µM) accelerates removal of the peptide from membranes by ~10-fold (reducing membrane lifetime from 0.1 s to 0.01 s), via a proposed diffusion-limited calmodulin extraction mechanism. Stopped-flow fluorescence measurements, spin-labeled EPR structure determination of membrane-bound effector peptide Biochimica et biophysica acta High 9804991
1993 Okadaic acid-sensitive phosphatases (PP1/PP2A) dephosphorylate MARCKS in intact Swiss 3T3 cells following PKC-mediated phosphorylation; PP1, PP2A, and PP2C can all dephosphorylate MARCKS in cell-free assays. Cell-free phosphatase assays with PP1, PP2A, PP2C; okadaic acid treatment in intact cells; bombesin-stimulated receptor blockade FEBS letters Medium 8262213
2003 The myristoyl moiety at the MARCKS N-terminus directly participates in calmodulin binding, providing ionic-strength-independent binding that is absent in non-myristoylated MARCKS; phosphorylation-independent calmodulin binding occurs through the N-terminal domain. Calmodulin-agarose chromatography with myristoylated vs. non-myristoylated recombinant MARCKS, quantitative dansyl-calmodulin binding assay, synthetic myristoylated N-terminal peptide, mutation analysis The Journal of biological chemistry High 14506265
2004 MARCKS bi-directional translocation between membrane and cytosol regulated by alpha5beta1 integrin-activated PKC is required for actin stress fiber formation during muscle cell spreading; PKC-dependent phosphorylation/membrane dissociation enables initial cell adhesion, while subsequent dephosphorylation/membrane return enables actin crosslinking and cytoskeletal maturation. MARCKS mutants (membrane association-deficient; PKC phosphorylation-deficient) in muscle cells, integrin-fibronectin binding assays, actin staining, cell spreading assays Journal of cell science Medium 15316066
2007 PKC-delta (not PKC-epsilon) specifically phosphorylates MARCKS to regulate airway mucin secretion; dominant-negative PKC-delta blocks both MARCKS phosphorylation and mucin hypersecretion, while wild-type PKC-delta overexpression enhances both. Dominant-negative and wild-type PKC-delta/epsilon constructs transfected into bronchial epithelial cells, PKC-delta selective inhibitor rottlerin, MARCKS phosphorylation assay, mucin secretion assay The American journal of pathology Medium 18055557
2009 MARCKS, via its myristoylated N-terminus, regulates human neutrophil migration and beta2 integrin-dependent adhesion; the MANS peptide (N-terminus mimic) reduces F-actin content after fMLF stimulation without affecting beta2 integrin surface expression. Cell-permeant MANS peptide treatment of human neutrophils, migration assays (fMLF, IL-8, LTB4), beta2 integrin expression by FACS, F-actin quantification American journal of respiratory cell and molecular biology Medium 19574534
2009 MARCKS modulates radial glial progenitor placement and proliferation in the developing cerebral cortex; the myristoylation domain (but not PKC phosphorylation sites) is essential for this function, suggesting membrane association is the key requirement for MARCKS role in radial glia. MARCKS knockout mice, genetic rescue with phosphorylation-deficient and myristoylation-deficient MARCKS mutants, immunostaining for polarity complexes and radial glia markers Development (Cambridge, England) High 19666823
2012 MARCKS is identified as a curvature and lipid sensor; the MARCKS effector domain (25-mer peptide) recognizes phosphatidylserine with preference for highly curved vesicles in a sequence-specific manner. Fluorescence-based lipid binding assays with vesicles of defined curvature and composition, sequence-specific peptide variants ACS chemical biology Medium 23075500
2012 MARCKS mediates H2O2-induced endothelial permeability via a signaling cascade: Rac1 → Abl1 → PLCγ1 → PKCδ → MARCKS phosphorylation and translocation from membrane to cytosol, leading to actin cytoskeleton remodeling. siRNA knockdown of MARCKS and pathway components, pharmacological inhibitors, MARCKS phosphorylation/translocation assay, permeability assay in bovine aortic endothelial cells Proceedings of the National Academy of Sciences of the United States of America Medium 22927426
2012 MARCKS regulates Xenopus ENaC activity through PIP2-dependent mechanism; MARCKS sequesters PIP2 at the apical membrane, and its phosphorylation (PKC) or calmodulin-mediated dissociation from the membrane reduces PIP2 availability and ENaC open probability; FRET shows close proximity between ENaC and MARCKS when PKC activity is low. Lipid binding assay, co-immunoprecipitation, confocal microscopy, FRET, transepithelial current measurements, single-channel patch-clamp American journal of physiology. Renal physiology Medium 22791334
2012 MARCKS specifically binds LPS via a heptapeptide within its effector domain (determined by NMR); after LPS stimulation MARCKS translocates to FYVE-positive endosomes and co-localizes with LPS; MARCKS deficiency increases TLR4-specific (not TLR2/3/5) LPS signaling. NMR spectroscopy, LPS binding assay, confocal microscopy (FYVE endosome co-localization), MARCKS-deficient MEFs, siRNA knockdown, MARCKS overexpression, cytokine measurement Journal of immunology High 22427633
2013 TLC-induced retrieval of MRP2 from the canalicular membrane in hepatocytes involves sequential PKCε activation → MARCKS phosphorylation → MARCKS detachment from membrane; phosphorylation-deficient MARCKS mutant blocks TLC-induced MRP2 retrieval. Dominant-negative PKCε transfection, phosphorylation-deficient MARCKS mutant transfection, subcellular fractionation (PM fractions), MARCKS phosphorylation assay in HuH-NTCP cells and rat hepatocytes Hepatology Medium 23424156
2015 δ-PKC (not α-, β-, or ζ-PKC) is the specific isoform that phosphorylates MARCKS to regulate human neutrophil migration and adhesion in vitro; rottlerin (δ-PKC inhibitor) attenuates fMLF-induced MARCKS phosphorylation, adhesion, and migration. PKC isoform-selective inhibitors (rottlerin, Gö6976, others) on human neutrophils, MARCKS phosphorylation assay, migration and adhesion assays Inflammation Medium 25515270
2015 Calmodulin binding to the MARCKS effector domain and CaMKII-mediated phosphorylation of filamin both promote dissociation of MARCKS from the apical membrane, reducing ENaC open probability; mutations in MARCKS preventing calmodulin association prevent membrane dissociation. Calmidazolium (calmodulin inhibitor), KN93 (CaMKII inhibitor), cytochalasin E (actin disruption), ENaC patch-clamp and transepithelial current, MARCKS calmodulin-binding mutants, co-immunoprecipitation American journal of physiology. Renal physiology Medium 26136560
2016 Ca2+-PKC phosphorylation of MARCKS releases sequestered PIP2, which recruits and activates PI3K on the membrane surface; in the unphosphorylated state MARCKS sequesters PIP2 and inhibits PI3K membrane binding; this Ca2+-PKC-MARCKS-PIP2-PI3K module constitutes a leading-edge amplification circuit. Single-molecule fluorescence reconstitution on lipid bilayers, surface density measurements of PKC, MARCKS peptide, and PI3K; PKC phosphorylation assay Biophysical journal High 27119641
2016 In megakaryocytes, dephosphorylated MARCKS promotes proplatelet formation; PKC-mediated MARCKS phosphorylation inhibits proplatelet formation and correlates with Arp2 phosphorylation; MARCKS KO mice show decreased proplatelet levels, and MARCKS inhibition reduces proplatelet formation by 53%. 2D-DIGE proteomics, polysome profiling, MARCKS KO mice, PMA treatment, MARCKS peptide inhibition, Arp2 inhibitor assay, confocal localization Blood High 26744461
2016 A PKC-MARCKS-PI3K regulatory module links leading-edge Ca2+ and PIP3 signals in live macrophages; PKC and PI3K are both essential for the positive feedback loop; activators stimulate leading-edge PKC activity, MARCKS membrane displacement, and increased PIP3, while inhibitors trigger the opposite. Live-cell biosensors (AKT-PH-mRFP for PIP3, CKAR for PKC activity, MARCKSp-mRFP for MARCKS membrane binding, leading-edge area), pharmacological inhibitors (wortmannin, EGTA, Go6976), PDGF and ATP stimulation PloS one High 29715315
2014 Phosphorylated MARCKS (pMARCKS) functions as an E2F-1 cofactor to regulate SKP2 transcription, thereby facilitating cell-cycle progression by suppressing p27Kip1 and promoting Cyclin E/CDK2 activity in multiple myeloma. iTRAQ mass spectrometry, RNAi knockdown, pharmacological inhibition (enzastaurin), co-factor/transcription assay, cell-cycle analysis, xenograft model Leukemia Medium 25179733
2019 MARCKS is acetylated by the acetyltransferase Tip60 at lysine 165 under high glucose conditions, and this acetylation is a prerequisite for subsequent PKC-mediated phosphorylation; SIRT2 deacetylates MARCKS and reverses this modification; phosphorylated/translocated MARCKS leads to mitochondrial abnormalities and ER stress. Co-IP, acetyltransferase assay with Tip60, SIRT2 deacetylation assay, phosphorylation-dead MARCKS (PD-MARCKS) expression, SIRT2 rescue in neuroepithelium, organelle stress assays Nature communications High 30655546
2017 ENaC activity is regulated by calpain-2 proteolysis of MARCKS; calpain-2 cleaves MARCKS (but not ENaC subunits) in a Ca2+-dependent manner; calpain-2 inhibition reduces the association between ENaC and MARCKS and decreases ENaC open probability. In vitro calpain-2 cleavage assay with recombinant fusion proteins, pharmacological calpain-2 inhibition, single-channel patch-clamp, transepithelial current, sucrose gradient fractionation, co-immunoprecipitation American journal of physiology. Cell physiology High 28468944
2000 Platelet secretion (serotonin release) induced by phorbol esters requires MARCKS phosphorylation; a peptide corresponding to the MARCKS phosphorylation site domain (MPSD) blocks MARCKS phosphorylation and serotonin secretion in permeabilized platelets without affecting pleckstrin or myosin light chain phosphorylation. Permeabilized platelet secretion assay, MARCKS phosphorylation assay, specific phosphorylation site domain peptide (MPSD) vs. alanine-substituted control peptide, time-course analysis Blood Medium 10648401
2002 PKCβ-MARCKS signaling is required for angiotensin II-stimulated vesicular trafficking along neurites in neurons; antisense knockdown of PKCβ or MARCKS blocks translocation of dopamine-β-hydroxylase-GFP-labeled vesicles from cell body to neurites. Real-time confocal microscopy of GFP-tagged vesicles, antisense oligonucleotides to PKCβ and MARCKS, PKC activators (PMA, carbachol, angiotensin II) Hypertension Medium 11882609
2002 Protein phosphatase-1 (PP1)-mediated dephosphorylation of MARCKS promotes its translocation to the plasma membrane during myoblast fusion; phosphorylation-preventing MARCKS mutation promotes fusion, while myristoylation-deficient MARCKS (which cannot reach the membrane) impairs myoblast fusion. Okadaic acid and tautomycin (PP inhibitors), PP1 identification by dephosphorylation assay, MARCKS phosphorylation mutants (non-phosphorylatable and myristoylation-deficient), cell fusion assay Journal of cell science Medium 12045217
2006 PKCε specifically phosphorylates MARCKS in cardiomyocytes; constitutively active PKCε increases phospho-MARCKS, dominant-negative PKCε reduces it and prevents co-localization of pMARCKS with F-actin; overexpression of wild-type MARCKS increases FAK phosphorylation and cardiomyocyte spreading, while non-phosphorylatable MARCKS blocks these effects. Adenoviral overexpression of wild-type, constitutively active, dominant-negative PKCε/δ/α, and GFP-tagged MARCKS mutants in neonatal and adult rat ventricular myocytes; immunofluorescence; FAK phosphorylation assay; cell area measurement Journal of molecular and cellular cardiology Medium 17157309
2012 PP2A interacts with MARCKS and is the dominant phosphatase for MARCKS after bradykinin-induced transient phosphorylation; this transient MARCKS phosphorylation (via PKC-RhoA/ROCK cascade) is required for bradykinin-induced neurite outgrowth. PP2A inhibitors (calyculin A, fostriecin), co-immunoprecipitation of PP2A with MARCKS, GST pull-down, SH-SY5Y cells expressing wild-type and unphosphorylatable MARCKS, cell morphology analysis Journal of cellular physiology Medium 21448919
2021 Phosphorylated MARCKS (at Ser159/163) directly binds to NF-κB-activating protein (NKAP); upon MARCKS phosphorylation, the MARCKS-NKAP interaction is inhibited, releasing NKAP and leading to NF-κB activation in lung cancer cells. Functional proteomics (MARCKS interactome), co-immunoprecipitation, genetic knockdown, MPS peptide (phosphorylation inhibitor), phosphorylation site analysis (Ser159/163), cytokine measurement Theranostics Medium 33754052
2015 MARCKS knockdown in VSMCs arrests cell cycle at G0/G1 via p27kip1 nuclear trapping through decreased KIS expression; this is p27kip1-dependent (confirmed in p27kip1-/- mice) and rescued by KIS overexpression; in endothelial cells, MARCKS knockdown paradoxically increases KIS and proliferation. siRNA knockdown in VSMCs and ECs, p27kip1-/- mouse-derived VSMCs, adenoviral KIS overexpression, cell cycle analysis, p27kip1 phosphorylation and localization assays, murine aortic injury model with BrdU PloS one Medium 26528715
2018 Membrane-tethered MARCKS suppresses BCR nanoclustering and tonic/chronic active BCR signaling by disturbing the interaction between cortical F-actin and the inner leaflet of the plasma membrane, thereby increasing BCR lateral mobility; genetically induced MARCKS loss increases AKT signaling and B-cell migratory capacity. Single-molecule tracking in live cells, MARCKS mutants (membrane-tethered and membrane-untethered), MARCKS knockout, BCR nanoclustering analysis, AKT phosphorylation assay, migration assay Leukemia Medium 30209404
2009 MCP-1-induced macrophage migration involves rapid MARCKS phosphorylation and translocation from plasma membrane to cytosol, accompanied by actin redistribution into cell protrusions; transient MARCKS-actin interaction during migration was detected biochemically. MANS peptide inhibition, confocal microscopy with fluorescent anti-MARCKS antibody and phalloidin, MARCKS phosphorylation/translocation assay, J774A.1 and primary mouse macrophage migration assay Journal of leukocyte biology Medium 22623357
2024 TRIM1-269aa (encoded by circTRIM1) enhances the interaction between MARCKS and calmodulin, thereby promoting calmodulin-dependent translocation of MARCKS from the membrane, which further activates the PI3K/AKT/mTOR pathway in TNBC cells. Co-immunoprecipitation of MARCKS-calmodulin complex with/without TRIM1-269aa, MARCKS translocation assay, PI3K/AKT/mTOR pathway readout Molecular cancer Low 38755678
2020 WNT5A-induced PKC activation leads to increased MARCKS expression and phosphorylation; MARCKS phosphorylation at the leading edge is required for WNT5A-mediated melanoma cell invasion, as demonstrated by siRNA-mediated MARCKS knockdown and a MARCKS phosphorylation inhibitor peptide. Recombinant WNT5A treatment, WNT5A siRNA, MARCKS siRNA, MARCKS phosphorylation inhibitor peptide, confocal imaging of pMARCKS at leading edge, invasion assay Cancers Medium 32033033

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1990 High gradient magnetic cell separation with MACS. Cytometry 1268 1690625
1992 MARCKS is an actin filament crosslinking protein regulated by protein kinase C and calcium-calmodulin. Nature 683 1560845
2009 MicroRNA-21 directly targets MARCKS and promotes apoptosis resistance and invasion in prostate cancer cells. Biochemical and biophysical research communications 304 19302977
1995 MARCKS deficiency in mice leads to abnormal brain development and perinatal death. Proceedings of the National Academy of Sciences of the United States of America 272 7862670
2002 Cross-talk unfolded: MARCKS proteins. The Biochemical journal 270 11829734
1992 Signal transduction and the actin cytoskeleton: the roles of MARCKS and profilin. Trends in biochemical sciences 198 1455513
1993 Interaction of myristoylated alanine-rich protein kinase C substrate (MARCKS) with membrane phospholipids. The Journal of biological chemistry 143 8486722
1997 MARCKS regulates membrane ruffling and cell spreading. Current biology : CB 142 9259558
1991 Phosphorylation-dependent binding of a synthetic MARCKS peptide to calmodulin. The Journal of biological chemistry 131 2002042
1992 MacMARCKS, a novel member of the MARCKS family of protein kinase C substrates. Cell 117 1516135
1995 Protein kinase C regulates MARCKS cycling between the plasma membrane and lysosomes in fibroblasts. The EMBO journal 112 7720702
2018 MARCKS and MARCKS-like proteins in development and regeneration. Journal of biomedical science 106 29788979
1991 The role of protein kinase C and its neuronal substrates dephosphin, B-50, and MARCKS in neurotransmitter release. Molecular neurobiology 106 1688057
2005 Nerve ending "signal" proteins GAP-43, MARCKS, and BASP1. International review of cytology 99 16125549
1998 MARCKS, membranes, and calmodulin: kinetics of their interaction. Biochimica et biophysica acta 99 9804991
1994 YACs, BACs, PACs and MACs: artificial chromosomes as research tools. Trends in biotechnology 98 7765076
1991 The human myristoylated alanine-rich C kinase substrate (MARCKS) gene (MACS). Analysis of its gene product, promoter, and chromosomal localization. The Journal of biological chemistry 89 1860846
2013 Sperm selection using magnetic activated cell sorting (MACS) in assisted reproduction: a systematic review and meta-analysis. Journal of assisted reproduction and genetics 85 23468098
2004 The MARCKS family of phospholipid binding proteins: regulation of phospholipase D and other cellular components. Biochemistry and cell biology = Biochimie et biologie cellulaire 79 15052337
1997 The motility-associated proteins GAP-43, MARCKS, and CAP-23 share unique targeting and surface activity-inducing properties. Experimental cell research 76 9344590
2020 Methodological comparison of FACS and MACS isolation of enriched microglia and astrocytes from mouse brain. Journal of immunological methods 72 32810482
2016 Maxed out macs: physiologic cell clearance as a function of macrophage phagocytic capacity. The FEBS journal 71 27863012
2009 MARCKS modulates radial progenitor placement, proliferation and organization in the developing cerebral cortex. Development (Cambridge, England) 68 19666823
2016 Regulation of PI3K by PKC and MARCKS: Single-Molecule Analysis of a Reconstituted Signaling Pathway. Biophysical journal 64 27119641
2015 Isolation and characterisation of human gingival margin-derived STRO-1/MACS(+) and MACS(-) cell populations. International journal of oral science 63 25257881
2014 Targeting phospho-MARCKS overcomes drug-resistance and induces antitumor activity in preclinical models of multiple myeloma. Leukemia 63 25179733
2009 Myristoylated alanine-rich C-kinase substrate (MARCKS) protein regulation of human neutrophil migration. American journal of respiratory cell and molecular biology 62 19574534
1993 Protein kinase C phosphorylates Ser152, Ser156 and Ser163 but not Ser160 of MARCKS in rat brain. Biochemical and biophysical research communications 60 8422248
2012 MARCKS-ED peptide as a curvature and lipid sensor. ACS chemical biology 59 23075500
2000 Platelet secretion induced by phorbol esters stimulation is mediated through phosphorylation of MARCKS: a MARCKS-derived peptide blocks MARCKS phosphorylation and serotonin release without affecting pleckstrin phosphorylation. Blood 59 10648401
2012 Phosphatidylinositol phosphate-dependent regulation of Xenopus ENaC by MARCKS protein. American journal of physiology. Renal physiology 57 22791334
2017 Myristoylated alanine-rich C kinase substrate (MARCKS): a multirole signaling protein in cancers. Cancer metastasis reviews 52 29039083
2021 The myristoylated alanine-rich C-kinase substrates (MARCKS): A membrane-anchored mediator of the cell function. Autoimmunity reviews 49 34509657
2015 Calmodulin and CaMKII modulate ENaC activity by regulating the association of MARCKS and the cytoskeleton with the apical membrane. American journal of physiology. Renal physiology 49 26136560
2015 X MARCKS the spot: myristoylated alanine-rich C kinase substrate in neuronal function and disease. Frontiers in cellular neuroscience 49 26528135
2004 The bi-directional translocation of MARCKS between membrane and cytosol regulates integrin-mediated muscle cell spreading. Journal of cell science 49 15316066
1992 MARCKS protein is transcriptionally down-regulated in v-Src-transformed BALB/c 3T3 cells. The Journal of biological chemistry 47 1370466
2007 Protein kinase C delta regulates airway mucin secretion via phosphorylation of MARCKS protein. The American journal of pathology 45 18055557
1998 Distribution of the protein kinase C substrates MARCKS and MRP in the postnatal developing rat brain. The Journal of comparative neurology 45 9674561
2017 Upregulation of MARCKS in kidney cancer and its potential as a therapeutic target. Oncogene 42 28166200
2014 Eliminating the heart from the curcumin molecule: monocarbonyl curcumin mimics (MACs). Molecules (Basel, Switzerland) 42 25547726
2012 Directed migration of mouse macrophages in vitro involves myristoylated alanine-rich C-kinase substrate (MARCKS) protein. Journal of leukocyte biology 40 22623357
2003 Direct involvement of protein myristoylation in myristoylated alanine-rich C kinase substrate (MARCKS)-calmodulin interaction. The Journal of biological chemistry 40 14506265
2024 CircTRIM1 encodes TRIM1-269aa to promote chemoresistance and metastasis of TNBC via enhancing CaM-dependent MARCKS translocation and PI3K/AKT/mTOR activation. Molecular cancer 39 38755678
2016 Synthesis and dephosphorylation of MARCKS in the late stages of megakaryocyte maturation drive proplatelet formation. Blood 39 26744461
2014 Functional characterization of the tumor-suppressor MARCKS in colorectal cancer and its association with survival. Oncogene 39 24662837
2000 MARCKS: a case of molecular exaptation? The international journal of biochemistry & cell biology 39 10736562
1993 Okadaic acid-sensitive protein phosphatases dephosphorylate MARCKS, a major protein kinase C substrate. FEBS letters 39 8262213
2011 Regulation of mucin secretion and inflammation in asthma: a role for MARCKS protein? Biochimica et biophysica acta 38 21281703
2021 MARCKS cooperates with NKAP to activate NF-kB signaling in smoke-related lung cancer. Theranostics 36 33754052
1996 Developmental expression of MARCKS and protein kinase C in mice in relation to the exencephaly resulting from MARCKS deficiency. Brain research. Developmental brain research 36 8922669
2015 Myristoylated alanine-rich C kinase substrate (MARCKS) regulates the expression of proinflammatory cytokines in macrophages through activation of p38/JNK MAPK and NF-κB. Cellular immunology 35 25929183
2015 Elevated MARCKS phosphorylation contributes to unresponsiveness of breast cancer to paclitaxel treatment. Oncotarget 35 26015406
2019 Tip60- and sirtuin 2-regulated MARCKS acetylation and phosphorylation are required for diabetic embryopathy. Nature communications 34 30655546
2018 A PKC-MARCKS-PI3K regulatory module links Ca2+ and PIP3 signals at the leading edge of polarized macrophages. PloS one 34 29715315
2012 MARCKS protein mediates hydrogen peroxide regulation of endothelial permeability. Proceedings of the National Academy of Sciences of the United States of America 34 22927426
1999 Phagocytic and macropinocytic activity in MARCKS-deficient macrophages and fibroblasts. The American journal of physiology 34 10409119
1997 Identification and characterization of cathepsin B as the cellular MARCKS cleaving enzyme. The Journal of biological chemistry 34 9295331
2016 MARCKS contributes to stromal cancer-associated fibroblast activation and facilitates ovarian cancer metastasis. Oncotarget 33 27081703
2009 A cell motility screen reveals role for MARCKS-related protein in adherens junction formation and tumorigenesis. PloS one 33 19924305
2015 In Vitro Neutrophil Migration Requires Protein Kinase C-Delta (δ-PKC)-Mediated Myristoylated Alanine-Rich C-Kinase Substrate (MARCKS) Phosphorylation. Inflammation 32 25515270
2009 Dynamic adhesions and MARCKS in melanoma cells. Journal of cell science 31 19509053
2010 Inhibition of myristoylated alanine-rich C kinase substrate (MARCKS) protein inhibits ozone-induced airway neutrophilia and inflammation. Experimental lung research 30 20205598
1998 Promoter sequence, expression, and fine chromosomal mapping of the human gene (MLP) encoding the MARCKS-like protein: identification of neighboring and linked polymorphic loci for MLP and MACS and use in the evaluation of human neural tube defects. Genomics 30 9598313
2020 PICSI vs. MACS for abnormal sperm DNA fragmentation ICSI cases: a prospective randomized trial. Journal of assisted reproduction and genetics 29 32772268
2017 MARCKS protein overexpression in inflammatory breast cancer. Oncotarget 29 28009981
2009 Enrichment of cell subpopulations applying automated MACS technique: purity, recovery and applicability for PCR-based chimerism analysis. Bone marrow transplantation 29 19421174
2019 Isolation of B-cells using Miltenyi MACS bead isolation kits. PloS one 28 30893384
2017 ENaC activity is regulated by calpain-2 proteolysis of MARCKS proteins. American journal of physiology. Cell physiology 28 28468944
2015 miR-34c-3p inhibits cell proliferation, migration and invasion of hepatocellular carcinoma by targeting MARCKS. International journal of clinical and experimental pathology 28 26722462
2000 Role of MARCKS in regulating endothelial cell proliferation. American journal of physiology. Cell physiology 28 11029309
2013 Taurolithocholate-induced MRP2 retrieval involves MARCKS phosphorylation by protein kinase Cϵ in HUH-NTCP Cells. Hepatology (Baltimore, Md.) 27 23424156
2013 Fibroblast Migration Is Regulated by Myristoylated Alanine-Rich C-Kinase Substrate (MARCKS) Protein. PloS one 27 23840497
2000 Analogous structural motifs in myelin basic protein and in MARCKS. Molecular and cellular biochemistry 27 10942213
2015 Altered prefrontal cortical MARCKS and PPP1R9A mRNA expression in schizophrenia and bipolar disorder. Schizophrenia research 26 25757715
1992 Chromosomal mapping of the human (MACS) and mouse (Macs) genes encoding the MARCKS protein. Genomics 26 1427822
2017 Validating the Manchester Acute Coronary Syndromes (MACS) and Troponin-only Manchester Acute Coronary Syndromes (T-MACS) rules for the prediction of acute myocardial infarction in patients presenting to the emergency department with chest pain. Emergency medicine journal : EMJ 25 28363994
2017 Intramyocardial fate and effect of iron nanoparticles co-injected with MACS® purified stem cell products. Biomaterials 25 28494265
2020 WNT5A-Induced Activation of the Protein Kinase C Substrate MARCKS Is Required for Melanoma Cell Invasion. Cancers 24 32033033
2012 Angiotensin-II and MARCKS: a hydrogen peroxide- and RAC1-dependent signaling pathway in vascular endothelium. The Journal of biological chemistry 24 22773836
2010 MARCKS-related peptide modulates in vivo the secretion of airway Muc5ac. American journal of physiology. Lung cellular and molecular physiology 24 20543006
2000 Phosphorylation of MARCKS in Alzheimer disease brains. Neuroreport 24 10757536
1994 Differential expression of MARCKS and other calmodulin-binding protein kinase C substrates in cultured neuroblastoma and glioma cells. Journal of neurochemistry 24 7964753
1992 Relationship between the major protein kinase C substrates acidic 80-kDa protein-kinase-C substrate (80K) and myristoylated alanine-rich C-kinase substrate (MARCKS). Members of a gene family or equivalent genes in different species. European journal of biochemistry 24 1396720
2019 MARCKS and Lung Disease. American journal of respiratory cell and molecular biology 23 30339463
2017 MARCKS promotes invasion and is associated with biochemical recurrence in prostate cancer. Oncotarget 23 29069765
2012 MARCKS as a negative regulator of lipopolysaccharide signaling. Journal of immunology (Baltimore, Md. : 1950) 22 22427633
1991 Phosphorylation of MARCKS (80-kDa) protein, a major substrate for protein kinase C in oligodendroglial progenitors. Journal of neuroscience research 22 1798060
2021 MARCKS affects cell motility and response to BTK inhibitors in CLL. Blood 21 33735912
2022 The Role of MARCKS in Metastasis and Treatment Resistance of Solid Tumors. Cancers 20 36230850
2002 Involvement of protein phosphatase-1-mediated MARCKS translocation in myogenic differentiation of embryonic muscle cells. Journal of cell science 20 12045217
2019 Tackling MARCKS-PIP3 circuit attenuates fibroblast activation and fibrosis progression. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19 31661644
2018 MARCKS regulates tonic and chronic active B cell receptor signaling. Leukemia 19 30209404
2002 Obligatory role of protein kinase Cbeta and MARCKS in vesicular trafficking in living neurons. Hypertension (Dallas, Tex. : 1979) 19 11882609
2014 Myristoylated Alanine Rich C Kinase Substrate (MARCKS) is essential to β2-integrin dependent responses of equine neutrophils. Veterinary immunology and immunopathology 18 24857637
2012 MARCKS dephosphorylation is involved in bradykinin-induced neurite outgrowth in neuroblastoma SH-SY5Y cells. Journal of cellular physiology 18 21448919
2010 Mesenchymal stem cells require MARCKS protein for directed chemotaxis in vitro. American journal of respiratory cell and molecular biology 18 20224071
2006 Protein kinase Cepsilon-dependent MARCKS phosphorylation in neonatal and adult rat ventricular myocytes. Journal of molecular and cellular cardiology 18 17157309
2016 Mammalian Synthetic Biology: Time for Big MACs. ACS synthetic biology 17 27076218
2015 MARCKS Signaling Differentially Regulates Vascular Smooth Muscle and Endothelial Cell Proliferation through a KIS-, p27kip1- Dependent Mechanism. PloS one 17 26528715

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