Affinage

MARK2

Serine/threonine-protein kinase MARK2 · UniProt Q7KZI7

Length
788 aa
Mass
87.9 kDa
Annotated
2026-04-28
100 papers in source corpus 26 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MARK2 (Par-1b/EMK1) is a serine/threonine kinase that serves as a master regulator of cell polarity, coordinating microtubule dynamics, actomyosin contractility, and vesicle trafficking in epithelia, neurons, and migrating cells. It is activated by LKB1-mediated T-loop phosphorylation and GSK-3β phosphorylation at Ser-212, and negatively regulated by aPKC phosphorylation at T595, which promotes 14-3-3 binding and cytoplasmic retention away from the plasma membrane; an intramolecular auto-inhibitory mechanism through the C-terminal KA1 domain further restricts its activity (PMID:14976552, PMID:15084291, PMID:16257959, PMID:30814118). MARK2 phosphorylates a diverse set of substrates—including MAPs (tau, MAP2), Rab11-FIP2, GEF-H1, IRSp53, myosin II RLC, and the kinesin KIF13B—to control epithelial apicobasal polarity, lumen positioning, E-cadherin-based adhesion, directed cell migration, axon specification, and Hippo pathway signaling (PMID:14981097, PMID:16775013, PMID:22072711, PMID:35594862, PMID:20194617, PMID:23940457). MARK2 knockout mice exhibit impaired spatial learning and microglial priming, and the bacterial oncoprotein H. pylori CagA directly binds and inhibits MARK2 to disrupt epithelial junctions (PMID:17196307, PMID:30654821, PMID:18005242).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1997 Medium

    Establishing that MARK2 localizes asymmetrically to the lateral membrane of polarized epithelia and that its kinase activity is required for epithelial polarity answered the foundational question of whether this kinase participates in cell polarization.

    Evidence Immunofluorescence of endogenous MARK2 and dominant-negative overexpression with E-cadherin localization readout in epithelial cells

    PMID:9259552

    Open questions at the time
    • Dominant-negative approach without kinase-dead rescue or loss-of-function genetics
    • Direct substrates mediating polarity were unknown
    • Upstream activating signals undefined
  2. 2004 High

    Identifying LKB1-STRAD-MO25 as the activating kinase that phosphorylates the MARK2 T-loop (>50-fold activation) and aPKC as the inhibitory kinase (T595 phosphorylation promoting 14-3-3 binding and membrane exclusion) established the dual upstream regulatory logic that positions MARK2 activity in space.

    Evidence In vitro kinase reconstitution, T-loop mutagenesis, activity in LKB1-null cells; aPKC phosphorylation assay, 14-3-3 binding, T595A mutagenesis in polarized MDCK cells

    PMID:14976552 PMID:15084291 PMID:15324659

    Open questions at the time
    • Relative contributions of LKB1 vs. GSK-3β activation in different tissues were unclear
    • Whether additional kinases phosphorylate the T-loop in vivo was unknown
  3. 2004 High

    Demonstrating that MARK2 overexpression switches MDCK cells to a hepatic-type lumen phenotype while its depletion prevents nonradial MT networks established MARK2 as a determinant of epithelial lumen position and microtubule organization.

    Evidence Knockdown and overexpression in MDCK and WIFB9 cells with immunofluorescence-based lumen and MT organization analysis

    PMID:14981097

    Open questions at the time
    • Downstream substrates linking MARK2 to lumen position were not identified
    • Whether this applies to in vivo organogenesis was untested
  4. 2005 High

    Showing that GSK-3β phosphorylates MARK2 at Ser-212 to activate it, creating a GSK-3β→MARK2→tau(Ser262) signaling axis, revealed a second upstream activation route with implications for Alzheimer's disease tau hyperphosphorylation.

    Evidence In vitro kinase assay with recombinant proteins, GSK-3β inhibitor (LiCl) and siRNA knockdown of GSK-3β or MARK2 with phospho-tau readout

    PMID:16257959

    Open questions at the time
    • In vivo relevance of GSK-3β→MARK2 axis in neurodegeneration not demonstrated
    • Crosstalk between LKB1 and GSK-3β activation was unexplored
  5. 2006 High

    Systematic mutagenesis of 17 phosphorylation sites on MARK2/3 showed that 14-3-3 binding uses multiple phosphosites (not just aPKC or LKB1 sites) and that 14-3-3 dissociation unmasks a KA1-domain-dependent membrane association, explaining how phosphorylation tunes the cytoplasm-to-membrane distribution without altering catalytic activity.

    Evidence Mass spectrometry phospho-mapping, 17-site alanine mutagenesis, subcellular fractionation and imaging

    PMID:16968750

    Open questions at the time
    • Kinases responsible for all 17 sites were not fully identified
    • Structural basis of KA1-membrane interaction was not resolved
  6. 2006 High

    Identifying Rab11-FIP2 Ser227 as a direct MARK2 substrate linked MARK2 to recycling endosome-mediated junction assembly, revealing a vesicle trafficking mechanism underlying its role in epithelial polarity establishment.

    Evidence In vitro kinase assay, FIP2-S227A phospho-mutant expression in MDCK cells, calcium switch junctional reassembly assay

    PMID:16775013

    Open questions at the time
    • Whether other Rab11 effectors are MARK2 substrates was unknown
    • Cargo specificity of FIP2-dependent trafficking downstream of MARK2 was not defined
  7. 2006 Medium

    MARK2 knockout mice displayed selective hippocampal-dependent spatial learning deficits, providing the first in vivo evidence that MARK2-mediated MAP phosphorylation is functionally relevant to cognitive processes.

    Evidence MARK2/EMK1 knockout mice tested in radial water maze, elevated plus maze, and activity cages

    PMID:17196307

    Open questions at the time
    • No molecular rescue was performed
    • Whether tau or MAP2 phosphorylation mediates the learning defect was not distinguished
    • Compensation by other MARK isoforms was not assessed
  8. 2007 High

    Discovery that H. pylori CagA directly binds and inhibits MARK2 via the CM sequence to disrupt epithelial junctions provided a pathogen-hijacking paradigm validating MARK2 as a gatekeeper of epithelial integrity.

    Evidence Co-immunoprecipitation, kinase activity assay, MDCK 3D culture polarity readout with CagA CM mutants

    PMID:18005242

    Open questions at the time
    • Whether CagA targets other MARK family members equally was unclear
    • In vivo gastric tissue validation was not provided
  9. 2009 High

    Identification of IRSp53 as a MARK2 substrate (S366) whose phosphorylation-deficient mutant rescued lumen polarity defects connected MARK2 to cell-ECM signaling and SH3-domain-dependent actin regulation in 3D epithelial morphogenesis.

    Evidence In vitro kinase assay, phospho-mutant rescue in 3D MDCK cultures, 14-3-3 binding assay

    PMID:21282462

    Open questions at the time
    • Downstream targets of IRSp53 affected by MARK2 phosphorylation were not identified
    • Whether IRSp53 phosphorylation operates in non-epithelial contexts was untested
  10. 2010 High

    Showing that MARK2 phosphorylates the kinesin KIF13B/GAKIN to suppress its axon-inducing activity, with epistasis placing KIF13B downstream of MARK2 and PI3K, established a polarity kinase–motor protein axis controlling axon specification.

    Evidence Co-immunoprecipitation, in vitro kinase assay, siRNA double-knockdown epistasis in hippocampal neurons

    PMID:20194617

    Open questions at the time
    • Phosphorylation sites on KIF13B were not mapped
    • Whether this pathway operates in non-neuronal polarity was not tested
  11. 2011 High

    Demonstrating that MARK2 phosphorylates GEF-H1 at multiple serines to inhibit its RhoA-GEF activity, release it from microtubules, and suppress stress fiber formation unified MARK2's MT-regulatory and Rho-signaling functions through a single substrate.

    Evidence In vitro kinase assay, phospho-site mapping, RhoA activity assay, live-cell GFP-GEF-H1 imaging, phospho-mutant analysis

    PMID:21513698 PMID:22072711

    Open questions at the time
    • Whether GEF-H1 phosphorylation mediates lumen polarity was not tested
    • Interplay between GEF-H1 regulation and MARK2's direct myosin regulation was unexplored
  12. 2011 High

    Discovery that MARK2 directly phosphorylates myosin II RLC and targets myosin phosphatase (MYPT1) to synergistically drive actomyosin contractility, and that membrane association via the KA1/membrane-binding domain directs MARK2 to focal adhesions to promote FAK phosphorylation and directional migration, revealed a second effector arm controlling cell contractility.

    Evidence In vitro kinase assay on isolated myosin RLC, MARK2 deletion mutants, siRNA depletion, phospho-western blot, focal adhesion and migration assays

    PMID:35594862

    Open questions at the time
    • MYPT1 phosphorylation was indirect—the intervening kinase was not identified
    • In vivo validation of focal adhesion targeting was lacking
  13. 2012 High

    An RNAi screen with automated EB3 tracking established that MARK2 is required for Rac1-dependent polarized microtubule growth at the leading edge, centrosome orientation, and directional cell migration, placing MARK2 downstream of Rac1 in the migration signaling hierarchy.

    Evidence RNAi screen, automated EB3 tracking of MT dynamics, GFP-MARK2 rescue, wound-healing migration assay

    PMID:22848487

    Open questions at the time
    • How Rac1 activates or recruits MARK2 was not mechanistically defined
    • Whether this involves GEF-H1 or another substrate was not determined
  14. 2013 High

    Genetic and biochemical studies in Drosophila and mammalian cells showed Par-1/MARK2 phosphorylates Hippo (Hpo/MST) at Ser30, disrupting Hpo-Salvador association and restricting Hippo signaling; combined with the finding that HMW-HA/CD44 disrupts a PAR1b-MST complex to activate Hippo, this established MARK2 as a signaling node integrating polarity with growth control via the Hippo pathway.

    Evidence EP screen in Drosophila, Co-IP of Par-1 with Hpo and Sav, genetic epistasis with Yorkie targets; Co-IP of PAR1b-MST, HMW-HA stimulation, Hippo reporter assay in mammalian cells

    PMID:23940457 PMID:31080060

    Open questions at the time
    • Whether MARK2 phosphorylation of MST occurs in epithelial polarity contexts was not shown
    • Quantitative contribution relative to other Hippo regulators was not measured
  15. 2013 Medium

    Identification of MTCL1 as a MARK2-binding protein that recruits MARK2 to apicobasal MT bundles provided a mechanism for spatial targeting of MARK2 to specific MT populations in polarizing epithelial cells.

    Evidence Co-immunoprecipitation, siRNA knockdown of MTCL1, MT regrowth and rescue experiments in epithelial cells

    PMID:23902687

    Open questions at the time
    • Single lab study without independent replication
    • Whether MARK2 phosphorylates MTCL1 was not determined
    • In vivo significance was untested
  16. 2019 High

    Demonstrating that the KA1 domain functions as an auto-inhibitory module that cooperates with aPKC phosphorylation to restrict MARK2/PAR-1 to the posterior cortex resolved how dual inhibitory mechanisms produce sharp spatial boundaries of kinase activity.

    Evidence KA1 domain deletion in C. elegans zygotes, heterologous cell reconstitution, epistasis with PKC-3

    PMID:30814118

    Open questions at the time
    • Structural basis of KA1 auto-inhibition was not determined at atomic resolution
    • Whether KA1 auto-inhibition is regulated by lipid binding was not tested
  17. 2019 Medium

    MARK2 knockout mice showed microglial priming with enhanced phagocytosis and lower activation threshold, extending MARK2's roles beyond epithelial/neuronal polarity to innate immune cell regulation.

    Evidence MARK2 knockout mice, two-photon in vivo imaging, shRNA in primary microglia, controlled cortical impact injury model

    PMID:30654821

    Open questions at the time
    • Substrate(s) mediating microglial priming were not identified
    • Whether this reflects cell-autonomous MARK2 function in microglia was not definitively shown
    • Single lab without independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how MARK2 substrate selectivity is determined in different cell types, the structural basis for KA1-mediated membrane binding and auto-inhibition, and whether MARK2's diverse polarity, migration, and Hippo-regulatory functions operate through integrated or parallel signaling modules in vivo.
  • No high-resolution structure of full-length MARK2 with KA1 auto-inhibition
  • In vivo tissue-specific substrate mapping is lacking
  • Functional redundancy with MARK1/3/4 is poorly defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0008092 cytoskeletal protein binding 4
Localization
GO:0005886 plasma membrane 5 GO:0005829 cytosol 3 GO:0005856 cytoskeleton 2
Pathway
R-HSA-1500931 Cell-Cell communication 6 R-HSA-162582 Signal Transduction 5 R-HSA-1266738 Developmental Biology 3
Partners
14-3-3CAGAGEF-H1IRSP53KIF13BLKB1MST1MTCL1

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 LKB1, in complex with STRAD and MO25, directly phosphorylates the T-loop threonine of MARK2 (and 12 other AMPK-related kinases), increasing MARK2 activity >50-fold; mutation of this T-loop Thr to Ala prevents activation, while Glu substitution produces constitutively active kinase; endogenous MARK2 activity is markedly reduced in LKB1-deficient cells. In vitro kinase assay, T-loop mutagenesis, activity measurement in LKB1-deficient cells The EMBO journal High 14976552
2004 Atypical PKC (aPKC) phosphorylates MARK2/Par-1b on threonine 595 (T595), negatively regulating its kinase activity and plasma membrane localization in vivo. In vitro kinase assay, in vivo phosphorylation assay, site-directed mutagenesis, subcellular localization imaging Current biology : CB High 15084291 15324659
2004 aPKC phosphorylation of MARK2/Par-1b at T595 promotes 14-3-3 binding, which dissociates MARK2 from the lateral membrane; T595A mutation causes MARK2 leakage into the apical membrane and abnormal membrane domain development in polarized MDCK cells. Site-directed mutagenesis, 14-3-3 binding assay, immunofluorescence in polarized MDCK cells, okadaic acid treatment Current biology : CB High 15084291 15324659
2006 14-3-3 binding to MARK2/MARK3 is mediated by multiple phosphorylation sites (not solely the LKB1 or aPKC sites); 14-3-3 binding anchors MARK isoforms in the cytoplasm, while a 17-site alanine mutant (17A-MARK3) that cannot bind 14-3-3 is strikingly membrane-localized via the conserved C-terminal KA-1 domain; 14-3-3 dissociation does not affect catalytic activity. Phosphorylation site mapping by mass spectrometry, systematic alanine mutagenesis, subcellular fractionation, immunofluorescence Journal of cell science High 16968750
2005 GSK-3β directly phosphorylates MARK2 on Ser-212 (within the activation loop), activating MARK2 and thereby promoting tau phosphorylation at Ser-262; LiCl (GSK-3β inhibitor) suppresses Ser-262 phosphorylation, and siRNA knockdown of either GSK-3β or MARK2 reduces Ser-262 tau phosphorylation. In vitro kinase assay with recombinant GSK-3β and MARK2, siRNA knockdown, phospho-specific western blot The Journal of biological chemistry High 16257959
2004 MARK2/EMK1 (Par-1) knockdown or inhibition in MDCK and WIFB9 cells prevents development of characteristic epithelial lumen position and nonradial microtubule networks; conversely, EMK1 overexpression in MDCK cells induces intercellular (hepatic-type) lumina and horizontal MT arrays, identifying MARK2 as a regulator of the developmental branching decision between hepatic and columnar epithelial phenotypes. Knockdown, overexpression, immunofluorescence, MT organization analysis in epithelial cell culture models The Journal of cell biology High 14981097
2006 MARK2 directly phosphorylates Rab11-FIP2 on serine 227; MDCK cells expressing non-phosphorylatable FIP2(S227A) show a defect in the timely reestablishment of p120-containing junctional complexes during calcium switch assays, linking MARK2-mediated FIP2 phosphorylation to establishment of epithelial polarity. In vitro kinase assay with recombinant MARK2, stable cell lines expressing phospho-mutant FIP2, calcium switch assay, immunofluorescence Molecular biology of the cell High 16775013
2010 MARK2/Par1b directly phosphorylates the kinesin GAKIN/KIF13B; GAKIN/KIF13B accumulates at axon tips and induces extra axons when overexpressed; Par1b phosphorylation suppresses this activity; siRNA epistasis places GAKIN/KIF13B downstream of Par1b, and Par1b acts downstream of PI3K signaling via GAKIN/KIF13B to regulate axon formation. Co-immunoprecipitation, in vitro kinase assay, siRNA knockdown, epistasis by double knockdown, hippocampal neuron overexpression Molecular and cellular biology High 20194617
2011 PAR1b/MARK2 phosphorylates GEF-H1 on serine 885 and serine 959, inhibiting GEF-H1's RhoA-specific exchange activity and preventing RhoA-dependent stress fiber formation. In vitro kinase assay, phospho-site mapping, RhoA activity assay, stress fiber imaging The Journal of biological chemistry High 22072711
2011 Par1b/MARK2 phosphorylates GEF-H1 at three conserved serine residues, releasing GEF-H1 from microtubules, abolishing GEF-H1-induced MT stabilization/acetylation, and rendering GEF-H1 mobile on microtubules; a non-phosphorylatable 3SA mutant is static and resists Par1b, revealing a MT-regulation mechanism. In vitro kinase assay, live-cell time-lapse imaging of GFP-GEF-H1, MT acetylation assay, phospho-mutant analysis Biochemical and biophysical research communications High 21513698
2011 MARK2/Par1b directly phosphorylates myosin II regulatory light chain (RLC) and phosphorylates MYPT1 (myosin phosphatase targeting subunit) indirectly, synergistically driving myosin II contractility and stress fiber formation; membrane association via the membrane-binding domain is required for MARK2 targeting to focal adhesions, where it enhances FAK phosphorylation and oriented focal adhesion formation to promote directional cell migration. Isolated protein kinase assay, MARK2 deletion mutants, siRNA depletion, phospho-specific western blot, focal adhesion analysis, cell migration assay Current biology : CB High 35594862
2012 MARK2 is required for polarized microtubule growth in the leading edge downstream of Rac1; MARK2-depleted cells fail to polarize centrosomes or orient MT growth at the leading edge and display defects in directional migration; GFP-MARK2 rescues these defects and localizes in lamellipodia in a Rac1-activity-dependent manner. RNAi screen, automated EB3 tracking, rescue with GFP-MARK2, wound-edge motility assay, centrosome polarization assay PloS one High 22848487
2009 PAR-1b/MARK2 regulates cell-ECM signaling and lumen polarity in MDCK cells through direct phosphorylation of IRSp53 on S366 (and indirect phosphorylation on S453/3/5); a phosphorylation-deficient IRSp53 mutant rescues both cell spreading defects and lumen polarity defects caused by Par1b overexpression, acting by promoting 14-3-3 binding near the SH3 domain. In vitro kinase assay, phospho-mutant rescue experiments, 14-3-3 binding assay, 3D MDCK culture lumen polarity assay The Journal of cell biology High 21282462
2007 H. pylori CagA protein binds directly to MARK2/Par-1b via its CM (CagA multimerization) sequence, inhibiting MARK2 kinase activity, causing recruitment of MARK2 to the plasma membrane, and disrupting apical junctions and epithelial polarity; the degree of PAR1b-binding correlates with junctional defects. Co-immunoprecipitation, iTRAQ proteomics of detergent-resistant membranes, MDCK 3D culture model, kinase activity assay Cellular microbiology High 18005242
2019 High-molecular-weight hyaluronan (HMW-HA) causes clustering of CD44, which recruits PAR1b/MARK2 via the CD44 intracellular domain; this disrupts the PAR1b-MST complex, liberating MST to activate Hippo signaling and suppress proliferation. Co-immunoprecipitation, HMW-HA stimulation assay, CD44 domain dissection, Hippo pathway reporter assay Developmental cell High 31080060
2009 Par-1b/MARK2 co-localizes with laminin receptors, interacts with the dystroglycan (DG) complex, and is required for basolateral localization of the DG complex and extracellular laminin assembly on the basal surface of epithelial cells, revealing an inside-out pathway linking intracellular polarity to ECM organization. Co-immunoprecipitation, immunofluorescence, PAR-1 depletion in epithelial cells, laminin assembly assay Genes to cells : devoted to molecular & cellular mechanisms Medium 19549170
2013 Par1b defines epithelial lumen position in concert with the position of the LGN-NuMA astral microtubule anchoring complex; Par1b signaling via the ECM determines RhoA/Rho-kinase activity at cell-cell contacts, which controls LGN-NuMA cortical recruitment, spindle alignment, and the resulting epithelial division phenotype. Par1b overexpression/depletion in MDCK and HepG2 cells, RhoA activity assay, LGN-NuMA localization by immunofluorescence, spindle orientation measurement The Journal of cell biology High 24165937
2009 Par-1b/MARK2, following TCR stimulation, is phosphorylated (resulting in 14-3-3 binding and relocalization from membrane to cytoplasm); a dominant-negative Par1b blocks TCR-induced MTOC polarization toward the immunological synapse, establishing Par1b as a regulator of T cell polarity. Phosphorylation assay following TCR stimulation, 14-3-3 pull-down, dominant-negative expression, MTOC polarization imaging Journal of immunology (Baltimore, Md. : 1950) Medium 19553522
2013 Par-1 (MARK) in Drosophila binds myosin phosphatase and phosphorylates it at a known inactivating site, thereby promoting myosin II regulatory light chain phosphorylation and myosin II activity; Par-1 localizes to the cluster rear to establish spatially restricted active myosin II required for border cell detachment during collective migration. Co-immunoprecipitation, in vivo phosphorylation assay, genetic loss-of-function, live imaging of myosin II localization in Drosophila border cells Current biology : CB High 22326025
2006 Par-1b/MARK2 promotes E-cadherin-dependent cell-cell adhesion and resistance of E-cadherin to non-ionic detergent extraction (a measure of actin cytoskeletal association); Par-1b attenuates Dishevelled (Dvl)-induced transformation of MDCK cells independently of direct Dvl phosphorylation, by antagonistically regulating E-cadherin adhesion complex assembly. Kinase assay (Dvl phosphorylation site mapping), detergent extraction of E-cadherin, transformation/focus assay, overexpression in MDCK cells Molecular biology of the cell Medium 16707567
2019 The C-terminal KA1 (kinase-associated domain 1) of PAR-1/MARK functions as an auto-inhibitory domain suppressing kinase activity in parallel with aPKC/PKC-3-mediated phosphorylation; both mechanisms together restrict PAR-1 activity to the posterior cortex; the KA1 domain also plays an essential role in germ plasm maintenance. KA1 domain deletion analysis in C. elegans zygotes, reconstitution in heterologous cells, epistasis with PKC-3, fertility and germ plasm phenotype assays Development (Cambridge, England) High 30814118
1997 Mammalian PAR-1 (MARK2) localizes asymmetrically to the lateral domain of polarized epithelial cells; expression of a kinase-domain-deleted dominant-negative form disrupts lateral cell adhesion and causes mislocalization of E-cadherin, indicating a functional role of MARK2 kinase activity in epithelial polarity. Immunofluorescence of endogenous protein, dominant-negative overexpression, E-cadherin localization assay Current biology : CB Medium 9259552
2013 Par-1 in Drosophila regulates tissue growth by physically interacting with Hippo (Hpo) and Salvador (Sav), phosphorylating Hpo at Ser30 to restrict its activity, and inhibiting Hpo-Sav association leading to Sav dephosphorylation/destabilization; Par-1 acts downstream of Fat/Expanded and upstream of Hpo/Sav in the Hippo pathway; this regulation is conserved in mammalian cells. EP gain-of-function screen in Drosophila, co-immunoprecipitation, in vivo phosphorylation assay, genetic epistasis, Yorkie target gene expression PLoS biology High 23940457
2006 MARK2 knockout (EMK1-KO) mice display specific impairment in spatial learning acquisition and long-term retention in a radial water maze, without defects in locomotion or anxiety, linking MARK2-mediated MAP2/tau phosphorylation to hippocampal-dependent memory processes. EMK1/MARK2 knockout mice, behavioral testing (radial water maze, elevated plus maze, activity cages) Neurobiology of aging Medium 17196307
2013 MTCL1 (microtubule crosslinking factor 1) is a novel PAR-1b-binding protein; MTCL1 crosslinks MTs along the apicobasal axis in epithelial cells, recruits a subpopulation of PAR-1b/MARK2 to apicobasal MT bundles, and this interaction is required for MTCL1-dependent development of non-centrosomal apicobasal MT bundles. Co-immunoprecipitation of MTCL1 and PAR-1b, siRNA knockdown of MTCL1, MT regrowth assay, rescue experiments in epithelial cells Journal of cell science Medium 23902687
2019 Loss of Par1b/MARK2 in mice leads to microglia priming: increased density, hypertrophic morphology, enhanced phagocytosis of neuronal particles early in development, decreased surveillance of brain parenchyma, and a lower threshold for activation upon cortical injury. MARK2 knockout mice, immunohistochemistry, confocal imaging, two-photon in vivo imaging, shRNA knockdown in primary microglia, controlled cortical impact injury model Journal of neuroinflammation Medium 30654821

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. The EMBO journal 1147 14976552
2000 The Drosophila homolog of C. elegans PAR-1 organizes the oocyte cytoskeleton and directs oskar mRNA localization to the posterior pole. Cell 255 10830165
2004 aPKC acts upstream of PAR-1b in both the establishment and maintenance of mammalian epithelial polarity. Current biology : CB 251 15324659
2004 Atypical PKC phosphorylates PAR-1 kinases to regulate localization and activity. Current biology : CB 228 15084291
2003 Common signaling pathways link activation of murine PAR-1, LPA, and S1P receptors to proliferation of astrocytes. Molecular pharmacology 180 14573770
2002 Thrombin (PAR-1)-induced proliferation in astrocytes via MAPK involves multiple signaling pathways. American journal of physiology. Cell physiology 172 12372796
2004 Mammalian PAR-1 determines epithelial lumen polarity by organizing the microtubule cytoskeleton. The Journal of cell biology 161 14981097
1997 Mammalian homologues of C. elegans PAR-1 are asymmetrically localized in epithelial cells and may influence their polarity. Current biology : CB 146 9259552
2003 The role of PAR-1 in regulating the polarised microtubule cytoskeleton in the Drosophila follicular epithelium. Development (Cambridge, England) 138 12874119
2001 Drosophila par-1 is required for oocyte differentiation and microtubule organization. Current biology : CB 122 11231123
2002 Drosophila 14-3-3/PAR-5 is an essential mediator of PAR-1 function in axis formation. Developmental cell 121 12431373
2012 Loss of axonal mitochondria promotes tau-mediated neurodegeneration and Alzheimer's disease-related tau phosphorylation via PAR-1. PLoS genetics 112 22952452
2005 PAR-1 activation on human late endothelial progenitor cells enhances angiogenesis in vitro with upregulation of the SDF-1/CXCR4 system. Arteriosclerosis, thrombosis, and vascular biology 107 16141404
2001 The thrombin receptor, PAR-1, causes transformation by activation of Rho-mediated signaling pathways. Oncogene 104 11360179
2005 Distinct PAR-1 proteins function in different branches of Wnt signaling during vertebrate development. Developmental cell 94 15935773
2011 A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines. Human molecular genetics 91 22156579
2016 Stabilization of Microtubule-Unbound Tau via Tau Phosphorylation at Ser262/356 by Par-1/MARK Contributes to Augmentation of AD-Related Phosphorylation and Aβ42-Induced Tau Toxicity. PLoS genetics 86 27023670
2004 An overview of the KIN1/PAR-1/MARK kinase family. Biology of the cell 85 15182702
2011 Pharmacodynamics and pharmacokinetics of the novel PAR-1 antagonist vorapaxar (formerly SCH 530348) in healthy subjects. European journal of clinical pharmacology 83 21935705
2019 High-Molecular-Weight Hyaluronan Is a Hippo Pathway Ligand Directing Cell Density-Dependent Growth Inhibition via PAR1b. Developmental cell 76 31080060
2007 Analysis of detergent-resistant membranes of Helicobacter pylori infected gastric adenocarcinoma cells reveals a role for MARK2/Par1b in CagA-mediated disruption of cellular polarity. Cellular microbiology 72 18005242
2006 Tissue factor deficiency and PAR-1 deficiency are protective against renal ischemia reperfusion injury. Blood 72 16990608
2017 Protease-activated receptor-1 (PAR-1): a promising molecular target for cancer. Oncotarget 70 29291033
2019 Thrombin Signaling Promotes Pancreatic Adenocarcinoma through PAR-1-Dependent Immune Evasion. Cancer research 68 31048498
2012 Par-1 controls myosin-II activity through myosin phosphatase to regulate border cell migration. Current biology : CB 66 22326025
2009 PP2A antagonizes phosphorylation of Bazooka by PAR-1 to control apical-basal polarity in dividing embryonic neuroblasts. Developmental cell 62 19531360
2010 Par1b/MARK2 phosphorylates kinesin-like motor protein GAKIN/KIF13B to regulate axon formation. Molecular and cellular biology 60 20194617
2004 Proteinase-activated receptor 1 (PAR-1) and cell apoptosis. Apoptosis : an international journal on programmed cell death 59 15505415
2007 The Par-1/MARK family of protein kinases: from polarity to metabolism. Cell cycle (Georgetown, Tex.) 58 17721078
2006 Drosophila anterior-posterior polarity requires actin-dependent PAR-1 recruitment to the oocyte posterior. Current biology : CB 58 16753562
2006 Regulation of the polarity kinases PAR-1/MARK by 14-3-3 interaction and phosphorylation. Journal of cell science 58 16968750
2013 Par-1 regulates tissue growth by influencing hippo phosphorylation status and hippo-salvador association. PLoS biology 56 23940457
2011 Drosophila tao controls mushroom body development and ethanol-stimulated behavior through par-1. The Journal of neuroscience : the official journal of the Society for Neuroscience 54 21248138
2011 Polarity-regulating kinase partitioning-defective 1b (PAR1b) phosphorylates guanine nucleotide exchange factor H1 (GEF-H1) to regulate RhoA-dependent actin cytoskeletal reorganization. The Journal of biological chemistry 52 22072711
2006 MARK2/EMK1/Par-1Balpha phosphorylation of Rab11-family interacting protein 2 is necessary for the timely establishment of polarity in Madin-Darby canine kidney cells. Molecular biology of the cell 52 16775013
2006 The angiopoietin pathway is modulated by PAR-1 activation on human endothelial progenitor cells. Journal of thrombosis and haemostasis : JTH 52 16803467
2016 uPA Attenuated LPS-induced Inflammatory Osteoclastogenesis through the Plasmin/PAR-1/Ca(2+)/CaMKK/AMPK Axis. International journal of biological sciences 51 26722218
2008 Structural and functional diversity in the PAR1b/MARK2-binding region of Helicobacter pylori CagA. Cancer science 51 19016760
2004 Par-1 promotes a hepatic mode of apical protein trafficking in MDCK cells. Proceedings of the National Academy of Sciences of the United States of America 50 15365179
2022 Matrix metalloproteinase-2 on activated platelets triggers endothelial PAR-1 initiating atherosclerosis. European heart journal 48 34529782
2005 GSK-3beta directly phosphorylates and activates MARK2/PAR-1. The Journal of biological chemistry 48 16257959
2002 RhoA- and RhoD-dependent regulatory switch of Galpha subunit signaling by PAR-1 receptors in cellular invasion. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 48 11919159
2006 PAR1b promotes cell-cell adhesion and inhibits dishevelled-mediated transformation of Madin-Darby canine kidney cells. Molecular biology of the cell 47 16707567
2019 Genetic Overlap Between Alzheimer's Disease and Bipolar Disorder Implicates the MARK2 and VAC14 Genes. Frontiers in neuroscience 46 30930738
2011 The serine/threonine kinase Par1b regulates epithelial lumen polarity via IRSp53-mediated cell-ECM signaling. The Journal of cell biology 46 21282462
2010 Expression of proteinase-activated receptor 1-4 (PAR 1-4) in human cancer. Journal of molecular histology 46 20563836
2004 PAR-1 deficiency protects against neuronal damage and neurologic deficits after unilateral cerebral hypoxia/ischemia. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 46 15356417
1999 Activation of the protease-activated thrombin receptor (PAR)-1 induces motoneuron degeneration in the developing avian embryo. Journal of neuropathology and experimental neurology 46 10331438
2007 Par1b promotes hepatic-type lumen polarity in Madin Darby canine kidney cells via myosin II- and E-cadherin-dependent signaling. Molecular biology of the cell 43 17409351
2016 Baicalin attenuates DDP (cisplatin) resistance in lung cancer by downregulating MARK2 and p-Akt. International journal of oncology 42 27878245
2011 The emerging role of the thrombin receptor (PAR-1) in melanoma metastasis--a possible therapeutic target. Oncotarget 41 21378407
2006 Thrombin and PAR-1 stimulate differentiation of bone marrow-derived endothelial progenitor cells. Journal of thrombosis and haemostasis : JTH 41 16460448
2016 Regulation of Cell Polarity by PAR-1/MARK Kinase. Current topics in developmental biology 40 28236972
2009 The polarity protein Par1b/EMK/MARK2 regulates T cell receptor-induced microtubule-organizing center polarization. Journal of immunology (Baltimore, Md. : 1950) 39 19553522
2020 Thrombin activation of PAR-1 contributes to microvascular stasis in mouse models of sickle cell disease. Blood 38 31977004
2008 Emerging roles of PAR-1 and PAFR in melanoma metastasis. Cancer microenvironment : official journal of the International Cancer Microenvironment Society 38 19308689
2011 Dynamic regulation of GEF-H1 localization at microtubules by Par1b/MARK2. Biochemical and biophysical research communications 35 21513698
2002 HcSTK, a Caenorhabditis elegans PAR-1 homologue from the parasitic nematode, Haemonchus contortus. International journal for parasitology 35 12062493
2012 Automated screening of microtubule growth dynamics identifies MARK2 as a regulator of leading edge microtubules downstream of Rac1 in migrating cells. PloS one 34 22848487
2009 Intracellular polarity protein PAR-1 regulates extracellular laminin assembly by regulating the dystroglycan complex. Genes to cells : devoted to molecular & cellular mechanisms 33 19549170
2013 Par1b links lumen polarity with LGN-NuMA positioning for distinct epithelial cell division phenotypes. The Journal of cell biology 32 24165937
2006 Impairment of spatial learning and memory in ELKL Motif Kinase1 (EMK1/MARK2) knockout mice. Neurobiology of aging 32 17196307
2002 Hep Par 1 in gastric and bowel carcinomas: an immunohistochemical study. Pathology 32 12408340
1998 Human serine/threonine protein kinase EMK1: genomic structure and cDNA cloning of isoforms produced by alternative splicing. Cytogenetics and cell genetics 32 9730619
2013 A critical role of thrombin/PAR-1 in ADP-induced platelet secretion and the second wave of aggregation. Journal of thrombosis and haemostasis : JTH 30 23406164
2012 Residual platelet activation through protease-activated receptors (PAR)-1 and -4 in patients on P2Y12 inhibitors. International journal of cardiology 30 23041015
2020 The PAR-1 antagonist vorapaxar ameliorates kidney injury and tubulointerstitial fibrosis. Clinical science (London, England : 1979) 29 33078834
2019 HIV-1 Tat promotes astrocytic release of CCL2 through MMP/PAR-1 signaling. Glia 29 31124192
2022 MARK2 regulates directed cell migration through modulation of myosin II contractility and focal adhesion organization. Current biology : CB 28 35594862
2020 Sarsasapogenin alleviates diabetic nephropathy through suppression of chronic inflammation by down-regulating PAR-1: In vivo and in vitro study. Phytomedicine : international journal of phytotherapy and phytopharmacology 28 32882582
2018 Overexpression of miR-582-5p Inhibits the Apoptosis of Neuronal Cells after Cerebral Ischemic Stroke Through Regulating PAR-1/Rho/Rho Axis. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 28 30327244
2014 Canonical and noncanonical roles of Par-1/MARK kinases in cell migration. International review of cell and molecular biology 28 25262242
2015 Activation of PAR-1/NADPH oxidase/ROS signaling pathways is crucial for the thrombin-induced sFlt-1 production in extravillous trophoblasts: possible involvement in the pathogenesis of preeclampsia. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 26 25824463
1998 Thrombin receptor (PAR-1) antagonists. Heterocycle-based peptidomimetics of the SFLLR agonist motif. Bioorganic & medicinal chemistry letters 26 9873407
2013 The novel PAR-1-binding protein MTCL1 has crucial roles in organizing microtubules in polarizing epithelial cells. Journal of cell science 25 23902687
2005 The Drosophila PAR-1 spacer domain is required for lateral membrane association and for polarization of follicular epithelial cells. Current biology : CB 25 15694310
2003 Apical surface formation in MDCK cells: regulation by the serine/threonine kinase EMK1. Methods (San Diego, Calif.) 25 12798141
2013 Protease-activated receptors (PAR)-1 and -3 drive epithelial-mesenchymal transition of alveolar epithelial cells - potential role in lung fibrosis. Thrombosis and haemostasis 24 23739922
2013 Thrombin induces epithelial-mesenchymal transition via PAR-1, PKC, and ERK1/2 pathways in A549 cells. Experimental lung research 24 23919450
2011 Neural crest specification by noncanonical Wnt signaling and PAR-1. Development (Cambridge, England) 24 22110058
2020 Thrombin/PAR-1 activation induces endothelial damages via NLRP1 inflammasome in gestational diabetes. Biochemical pharmacology 23 32059841
2018 In-Cell NMR Study of Tau and MARK2 Phosphorylated Tau. International journal of molecular sciences 23 30587819
2006 Thrombin receptor (PAR-1) antagonists as novel antithrombotic agents. Expert opinion on therapeutic patents 23 20144050
2002 Thrombin receptor antagonists; recent advances in PAR-1 antagonist development. Current medicinal chemistry 23 12052165
2019 Direct oral anticoagulants are associated with limited damage of endothelial cells of the blood-brain barrier mediated by the thrombin/PAR-1 pathway. Brain research 22 31121158
2018 Establishment of the PAR-1 cortical gradient by the aPKC-PRBH circuit. Nature chemical biology 22 30177850
2016 Impact of structural polymorphism for the Helicobacter pylori CagA oncoprotein on binding to polarity-regulating kinase PAR1b. Scientific reports 22 27445265
2020 MARK2 enhances cisplatin resistance via PI3K/AKT/NF-κB signaling pathway in osteosarcoma cells. American journal of translational research 21 32509178
2019 Spatial regulation of the polarity kinase PAR-1 by parallel inhibitory mechanisms. Development (Cambridge, England) 21 30814118
2011 PAR-1/MARK: a kinase essential for maintaining the dynamic state of microtubules. Cell structure and function 21 22139392
2022 MARK2 potentiate aerobic glycolysis-mediated cell growth in breast cancer through regulating mTOR/HIF-1α and p53 pathways. Journal of cellular biochemistry 20 35048405
2019 Loss of Par1b/MARK2 primes microglia during brain development and enhances their sensitivity to injury. Journal of neuroinflammation 19 30654821
2013 Streptococcal SpeB cleaved PAR-1 suppresses ERK phosphorylation and blunts thrombin-induced platelet aggregation. PloS one 19 24278414
2010 X-ray imaging of differential vascular density in MMP-9-/-, PAR-1-/+, hyperhomocysteinemic (CBS-/+) and diabetic (Ins2-/+) mice. Archives of physiology and biochemistry 19 20839901
2009 Zyxin is involved in thrombin signaling via interaction with PAR-1 receptor. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19 19690217
2009 MAP kinase signaling antagonizes PAR-1 function during polarization of the early Caenorhabditis elegans embryo. Genetics 19 19720857
2023 The USP7-STAT3-granzyme-Par-1 axis regulates allergic inflammation by promoting differentiation of IL-5-producing Th2 cells. Proceedings of the National Academy of Sciences of the United States of America 18 38015852
2020 The inhibition of MARK2 suppresses cisplatin resistance of osteosarcoma stem cells by regulating DNA damage and repair. Journal of bone oncology 18 32368441
2020 Blockade of PAR-1 Signaling Attenuates Cardiac Hypertrophy and Fibrosis in Renin-Overexpressing Hypertensive Mice. Journal of the American Heart Association 18 32495720
2016 Par-1b is required for morphogenesis and differentiation of myoepithelial cells during salivary gland development. Organogenesis 18 27841695