Affinage

ROCK2

Rho-associated protein kinase 2 · UniProt O75116

Length
1388 aa
Mass
160.9 kDa
Annotated
2026-06-10
100 papers in source corpus 43 papers cited in narrative 43 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

ROCK2 is a Rho-activated serine/threonine kinase that couples actomyosin cytoskeletal dynamics to gene expression, immune signaling, and metabolic programs across cardiovascular, neural, immune, and oncogenic contexts (PMID:18718479, PMID:23392171, PMID:32229726). Its canonical cytoskeletal output is phosphorylation of MLC2 and cofilin, which is required to stabilize the actin cytoskeleton and to support cell adhesion, dendritic spine morphology, synaptic transmission, and hippocampal LTP (PMID:18718479, PMID:23392171, PMID:27166169). Beyond the cytoplasm, ROCK2 enters the nucleus to phosphorylate the acetyltransferase p300 and increase its activity, and it directly phosphorylates the transcription factor IRF8 to promote SREBP2-driven cholesterol-biosynthetic gene programs in germinal center B cells while restraining AKT to enhance FOXO1 (PMID:16574662, PMID:32229726). ROCK2 acts as a substrate-specific kinase in additional settings, phosphorylating PKCβ2 at Thr641 to impair GLUT4 translocation in the diabetic heart, phosphorylating p47phox on Ser304/Ser315/Ser320/Ser328 to control monocyte NADPH oxidase activation through a p22phox-anchored complex, and phosphorylating radixin to anchor α5-GABAAR at extrasynaptic sites (PMID:24466133, PMID:36626553, PMID:38825816). A recurring theme is ROCK2-dependent control of protein stability, where ROCK2 prevents ubiquitin-mediated degradation of targets including Cdc25A, while ROCK2 itself is degraded by the APC/C-Cdh1 ligase in neurons and is destabilized by FBXO42, with its accumulation driving dendritic disorganization and neurodegeneration (PMID:22705122, PMID:28396402, PMID:33692332). ROCK2 negatively regulates TGF-β signaling by binding TGF-β type I receptors and accelerating their lysosomal degradation, and many of its disease roles—cardiac hypertrophy and fibrosis, diabetic complications, lymphedema, and tumor invasion—are isoform-specific to ROCK2 rather than ROCK1 (PMID:19509062, PMID:30884801, PMID:28679962, PMID:37782785). Crystallographic work has defined active-site residues (Asp176, Asp218) distinguishing ROCK2 from PKA for inhibitor selectivity (PMID:30384606).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2006 High

    Established that ROCK2 acts in the nucleus, not only the cytoplasm, by binding and phosphorylating p300 to enhance its acetyltransferase activity—extending ROCK2 function from cytoskeletal control to transcriptional regulation.

    Evidence Co-IP, gel filtration, in vitro kinase assay with acetyltransferase readout, and nuclear-restricted constitutively active ROCK2 in cells

    PMID:16574662

    Open questions at the time
    • Phospho-site on p300 not mapped
    • In vivo significance of nuclear ROCK2-p300 axis not established
  2. 2008 High

    Demonstrated that ROCK2 is genetically required for neuronal actin organization and synaptic plasticity, linking the ROCK2/cofilin axis to dendritic spine morphology and LTP.

    Evidence ROCK2 knockout mice with electrophysiology, spine morphometry, and cofilin phosphorylation analysis

    PMID:18718479

    Open questions at the time
    • Does not distinguish direct cofilin phosphorylation from indirect effects
    • Cell-autonomy within neuronal subtypes not resolved
  3. 2009 High

    Identified a non-cytoskeletal role for ROCK2 as a negative regulator of TGF-β signaling by routing TGF-β type I receptors to lysosomal degradation, requiring kinase activity.

    Evidence Co-IP, receptor degradation assays, kinase-dead mutants, and zebrafish epistasis

    PMID:19509062

    Open questions at the time
    • Direct kinase substrate driving receptor degradation not identified
    • Relationship to later pro-fibrotic TGF-β/Smad2 roles unresolved
  4. 2013 High

    Confirmed the isoform-specific requirement of ROCK2 for actin cytoskeleton stability via MLC2 and cofilin phosphorylation and for proper cell adhesion using a clean knockout system.

    Evidence ROCK2 knockout MEFs with actin imaging, MLC2/cofilin western blots, adhesion assays

    PMID:23392171

    Open questions at the time
    • Does not exclude compensatory ROCK1 contributions
    • Adhesion molecule targets not defined
  5. 2014 High

    Showed ROCK2 is a substrate-specific kinase for PKCβ2 (Thr641), connecting ROCK2 over-activation to impaired GLUT4 translocation and metabolic dysfunction in the diabetic heart.

    Evidence In vitro kinase assay, reciprocal co-IP, siRNA knockdown, GLUT4 confocal imaging in diabetic rat hearts

    PMID:24466133

    Open questions at the time
    • Stoichiometry and dynamics of PKCβ2 phosphorylation in vivo not quantified
  6. 2014 High

    Established that ROCK2 activity and isoform-specific splicing are integrated into myogenic differentiation, with KAP activating ROCK2 and Rbfox2-controlled splicing required for myoblast fusion.

    Evidence Isoform-specific siRNA, iCLIP, RNA-seq, KAP co-IP and activity assays, myoblast fusion rescue

    PMID:17606625 PMID:24704824 PMID:25087874

    Open questions at the time
    • Functional distinction of the ROCK2m muscle isoform at the substrate level unclear
    • How KAP activates ROCK2 mechanistically not defined
  7. 2017 High

    Identified ROCK2 as an APC/C-Cdh1 ubiquitin ligase substrate in neurons whose accumulation drives dendritic disorganization, memory loss, and neurodegeneration reversible by ROCK inhibition.

    Evidence Cdh1 conditional knockout mice, ROCK2 protein measurement, in vivo fasudil rescue, behavioral testing

    PMID:28396402

    Open questions at the time
    • Degron/recognition motif on ROCK2 not mapped
    • Substrates downstream of accumulated ROCK2 in neurons not enumerated
  8. 2017 High

    Demonstrated a cell-type-specific paracrine fibrotic role: fibroblast ROCK2 drives CTGF expression and FGF2 secretion that elicit cardiomyocyte hypertrophy.

    Evidence Fibroblast-specific ROCK2 conditional knockout mice, Ang II, echocardiography, conditioned media hypertrophy assay

    PMID:28679962

    Open questions at the time
    • Direct ROCK2 substrate controlling CTGF/FGF2 not identified
  9. 2018 High

    Defined the structural basis for ROCK2 inhibitor selectivity, identifying Asp176 and Asp218 as active-site residues distinguishing ROCK2 from PKA.

    Evidence X-ray cocrystal structures of inhibitor-bound ROCK1 and ROCK2

    PMID:30384606

    Open questions at the time
    • Does not address ROCK2 vs ROCK1 selectivity at these residues
    • No regulatory/full-length conformational information
  10. 2019 High

    Resolved isoform-specific ROCK2 control of cardiac homeostasis, showing single ROCK2 loss triggers compensatory ROCK1 overactivation and autophagy suppression via mTOR, while RyR/CaMKII phosphorylation links ROCK2 to arrhythmic calcium handling.

    Evidence Cardiomyocyte-specific inducible single/double ROCK knockouts and ROCK2+/- diabetic mice with phosphorylation and Ca2+ imaging readouts

    PMID:30728103 PMID:30848941

    Open questions at the time
    • Whether ROCK2 phosphorylates CaMKII/RyR directly not established
    • Mechanism of ROCK1 compensation unresolved
  11. 2019 High

    Showed ROCK2 inhibition reprograms collective tumor invasion and adipocyte fate, revealing FARP2/myosin-II-dependent leader-cell formation and actin-dependent suppression of thermogenic gene programs.

    Evidence siRNA screens with 3D organotypic cultures, myosin-II inhibition; ROCK2+/- and kinase-dead knock-in mice with KD025

    PMID:31304629 PMID:31914704

    Open questions at the time
    • Direct ROCK2 substrate governing the beige/thermogenic switch unidentified
    • Generalizability of leader/follower polarization beyond colorectal models untested
  12. 2020 High

    Identified direct ROCK2 phosphorylation of IRF8 to drive SREBP2-dependent cholesterol-biosynthetic gene programs and germinal center polarization, with parallel AKT restraint enhancing FOXO1.

    Evidence B cell-specific ROCK2 deletion, RNA-seq, ATAC-seq, IRF8 phosphorylation assays, SREBP2 ChIP

    PMID:32229726

    Open questions at the time
    • IRF8 phospho-residues not specified here
    • Connection between AKT restraint and IRF8 axis not integrated
  13. 2022 High

    Established a transcriptional metabolic role in podocytes where ROCK2 suppresses PPARα and fatty acid oxidation genes, contributing to diabetic podocyte apoptosis.

    Evidence Podocyte-specific ROCK2 knockout mice with RNA-seq across multiple diabetic models

    PMID:35396346

    Open questions at the time
    • Whether PPARα suppression is direct or via an intermediate transcription factor unclear
    • Kinase substrate linking ROCK2 to PPARα regulation unknown
  14. 2023 High

    Mapped a ROCK2-p22phox complex and four p47phox phosphorylation sites controlling monocyte NADPH oxidase, and a cytokine-induced ROCK2/JAM-A complex driving lymphatic junction zippering, defining context-specific ROCK2 protein complexes with disease consequences.

    Evidence Reciprocal co-IP with domain mapping and in vitro kinase assays; microfluidic lymphatic models with lymphatic-specific ROCK2 knockout mice

    PMID:36626553 PMID:37782785

    Open questions at the time
    • JAM-A as a direct ROCK2 substrate not established
    • Cell-type restriction of p22phox-ROCK2 binding (monocytes vs neutrophils) mechanistically unexplained
  15. 2024 Medium

    Demonstrated that ROCK2 phosphorylates radixin to anchor α5-GABAAR extrasynaptically, linking ROCK2 activity to anesthesia-associated cognitive impairment in aged brain.

    Evidence Aged-mouse sevoflurane model with p-radixin western blot, receptor fractionation, AAV ROCK2 knockdown, and fasudil rescue with behavioral testing

    PMID:38825816

    Open questions at the time
    • Direct radixin phospho-site not mapped here
    • Whether radixin is a direct ROCK2 substrate in this context not biochemically isolated

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how ROCK2 mechanistically achieves substrate-stability control (preventing ubiquitination of Cdc25A, β-catenin, MMP2, PFKFB3, OGT) versus direct phosphorylation, and whether these stabilizations reflect a common kinase-dependent mechanism.
  • No direct kinase-substrate reconstitution for the stability targets
  • Distinction between ROCK2 catalytic vs scaffolding contributions unclear
  • Whether stability effects are direct or pathway-mediated unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016740 transferase activity 3 GO:0140110 transcription regulator activity 3
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1430728 Metabolism 2 R-HSA-1640170 Cell Cycle 2
Partners
CDC25AIRF8JAM-AKAPP22PHOXP300P47PHOXPKCB2
Complex memberships
ROCK2/JAM-AROCK2/KAPROCK2/LOX-1ROCK2/p22phox-NADPH oxidase

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 ROCK2 localizes to the nucleus where it associates with and phosphorylates p300 acetyltransferase both in vitro and in cells; nuclear-restricted constitutively active ROCK2 induces p300 phosphorylation, and p300 phosphorylation by ROCK2 increases its acetyltransferase activity in vitro. Co-immunoprecipitation, gel filtration, immunofluorescence colocalization, in vitro kinase assay, nuclear-restricted constitutively active ROCK2 expression The Journal of biological chemistry High 16574662
2009 ROCK2 acts as a negative regulator of TGF-β signaling by binding to TGF-β type I receptors and accelerating their lysosomal degradation after internalization from the cell surface; this inhibitory effect requires ROCK2 kinase activity. Co-immunoprecipitation, receptor degradation assays, kinase-dead mutant analysis, zebrafish mRNA injection and dominant-negative overexpression Journal of cell science High 19509062
2008 ROCK2 knockout mice show deficits in dendritic spine morphology, synapse density, basal synaptic transmission, and hippocampal LTP, associated with deficits in actin cytoskeleton organization and cofilin phosphorylation, indicating ROCK2/cofilin signaling is required for neuronal actin regulation and synaptic function. Genetic knockout mouse model, electrophysiology (LTP), spine morphometry, cofilin phosphorylation western blot Neuropharmacology High 18718479
2013 In ROCK2-/- MEFs, ROCK2 is required for stabilizing the actin cytoskeleton through regulating cofilin phosphorylation; ROCK2 loss results in reduced phosphorylation of both MLC2 and cofilin, increased peripheral membrane folding, and impaired cell adhesion. ROCK2 knockout MEFs, actin cytoskeleton imaging, MLC2 and cofilin phosphorylation western blot, cell adhesion and detachment assays Cell death & disease High 23392171
2010 During ouabain-induced apoptosis in HUVECs, ROCK2 is cleaved by caspase-2, generating a ~140 kDa fragment corresponding to a novel caspase-2 cleavage site on the carboxy terminus of ROCK2; this cleavage is prevented by the caspase-2 inhibitor z-VDVAD-fmk. Caspase inhibitor treatment (z-DEVD-fmk, z-VDVAD-fmk), western blot for ROCK2 cleavage fragments Apoptosis : an international journal on programmed cell death Medium 20661774
2012 ROCK2 directly binds Cdc25A, regulates cell cycle progression at G1/S by preventing Cdc25A ubiquitination and degradation; knockdown of ROCK2 activates Cdc25A ubiquitination and promotes its degradation in hepatocellular carcinoma cells. Co-immunoprecipitation, immunofluorescence colocalization, siRNA knockdown, ubiquitination assay, flow cytometry cell cycle analysis Experimental cell research Medium 22705122
2014 ROCK2 stabilizes MMP2 by preventing its ubiquitination and degradation in hepatocellular carcinoma, thereby promoting invasion and metastasis. siRNA knockdown, ubiquitination assay, rescue experiments with MMP2 re-expression, invasion/migration assays in vitro and in vivo Biochemical and biophysical research communications Medium 25251472
2014 ROCK2 is a positive regulator of the p42/p44 MAPK–p90RSK–eEF2 signaling pathway in myogenic cells and controls hypertrophic responses to IGF-1 and insulin; an alternatively spliced muscle-specific isoform ROCK2m is preferentially expressed in skeletal muscle and strongly upregulated during differentiation. Specific siRNA knockdown of ROCK2 or ROCK2m in C2C12 cells, western blot for MAPK/RSK/eEF2 pathway components, myogenic differentiation markers Molecular and cellular biology Medium 17606625
2014 KAP (cyclin-dependent kinase-associated phosphatase) binds and activates ROCK2; RNA-mediated downregulation of KAP leads to decreased ROCK2 activity, which in turn increases Rac1-mediated glioblastoma invasion. Co-immunoprecipitation, ROCK2 activity assays, siRNA knockdown, invasion assays Oncogene Medium 24704824
2014 The RNA-binding protein Rbfox2 regulates ROCK2 alternative splicing during myogenesis; the specific ROCK2 splicing isoform generated is required for myoblast fusion, and restored ROCK2 activity rescues myoblast fusion in Rbfox2-depleted cultures. RNA-seq, iCLIP, Rbfox2 knockdown, rescue with ROCK2 re-expression, myoblast fusion assays Molecular cell High 25087874
2014 ROCK2 directly phosphorylates PKCβ2 at Thr641 in vitro, forming a physical complex; over-activation of ROCK2 in the diabetic heart leads to PKCβ2 activation and interferes with PDK-1/AKT-mediated GLUT4 translocation. In vitro kinase assay, reciprocal co-immunoprecipitation, siRNA knockdown, GLUT4 translocation confocal microscopy, western blot from diabetic rat hearts PloS one High 24466133
2015 ROCK2 stabilizes β-catenin by preventing its ubiquitination and degradation in colorectal cancer cells, thereby promoting invasion and metastasis via the β-catenin/TCF4 pathway. siRNA knockdown, ubiquitination assay, β-catenin stability assays, in vitro and in vivo invasion assays Biochemical and biophysical research communications Medium 26505794
2015 ROCK2 promotes HCC cell proliferation through a Rock2–p-GSK3β–β-catenin–CEBPD regulatory axis, in which ROCK2 phosphorylates GSK3β to activate β-catenin signaling and suppress the tumor suppressor CEBPD. ROCK2 knockdown, western blot for p-GSK3β/β-catenin/CEBPD, in vitro and in vivo proliferation assays FEBS letters Low 25771860
2016 ROCK2 (but not ROCK1) specifically drives LPA-induced expression of MCP-1 and E-selectin in human aortic endothelial cells via NF-κB RelA/p65 nuclear translocation, controlling monocyte chemotaxis and monocyte–endothelial adhesion. siRNA isoform-selective knockdown, NF-κB nuclear translocation assay, monocyte migration and adhesion assays, IκBα phosphorylation western blot International journal of molecular sciences Medium 30884801
2016 ROCK2 (but not ROCK1) activates JAK2/STAT3 signaling through increased IL-6 expression and upregulation of IKKβ/NF-κB transcription, forming a positive feedback loop that confers chemoresistance in hepatocellular carcinoma; IKKβ is identified as a direct downstream target of ROCK2. siRNA isoform-specific knockdown, ROCK2 overexpression, western blot for JAK2/STAT3/IKKβ/NF-κB, in vitro and in vivo chemoresistance assays Oncotarget Medium 27213590
2016 ROCK2 (but not ROCK1) mediates acid-induced upregulation of NOX5-S expression and H2O2 production in esophageal adenocarcinoma cells; constitutively active ROCK2 enhances NOX5-S expression, and this activation is dependent on intracellular calcium increase. ROCK isoform-specific siRNA knockdown, constitutively active ROCK2/ROCK1 overexpression, ROCK activity assay, calcium chelation experiments PloS one Medium 26901778
2017 Rock2 is an APC/C-Cdh1 ubiquitin ligase substrate in neurons; Cdh1 conditional knockout leads to Rock2 protein accumulation in the cortex and hippocampus, and pharmacological Rock inhibition with fasudil rescues dendritic network disorganization, memory loss, and neurodegeneration in these mice. Cdh1 conditional knockout mouse, Rock2 protein level measurement, in vivo fasudil treatment, dendritic morphometry, memory behavioral tests Proceedings of the National Academy of Sciences of the United States of America High 28396402
2017 Fibroblast-specific ROCK2 deletion reduces angiotensin II-stimulated cardiac hypertrophy and fibrosis; mechanistically, ROCK2 knockdown in cardiac fibroblasts decreases expression of CTGF and secretion of FGF2, and conditioned media from ROCK2-knockdown fibroblasts elicits less cardiomyocyte hypertrophy. Fibroblast-specific ROCK2 conditional knockout mice, Ang II treatment, echocardiography, CTGF/FGF2 expression, conditioned media cardiomyocyte hypertrophy assay JCI insight High 28679962
2018 Cocrystal structures of dual ROCK1 and ROCK2 inhibitors identified Asp176 and Asp218 in ROCK2 (corresponding to Glu residues in PKA) as key residues that can be targeted to drive both potency and kinome selectivity. X-ray cocrystal structures of inhibitor-bound ROCK1 and ROCK2 Journal of medicinal chemistry High 30384606
2019 ROCK2 inhibition triggers collective invasion of colorectal adenocarcinoma cells by inducing leader/follower polarization of cell cohorts; FARP2 (a Rac1 GEF) is necessary downstream of ROCK2 inhibition for invasion, and concomitant inhibition of Myosin-II is required alongside ROCK2 inhibition to trigger leader cell formation. siRNA screens targeting Rho-GTPase effectors and GEFs, 3D organotypic Caco-2 cyst cultures, pharmacological myosin-II inhibition, live ex vivo invasion assays The EMBO journal High 31304629
2019 ROCK2 stabilizes PFKFB3 by modifying its ubiquitination and degradation, thereby promoting glycolysis and osteosarcoma proliferation and metastasis. siRNA knockdown, ubiquitination assay, PFKFB3 rescue experiments, in vitro and in vivo proliferation/invasion assays Experimental cell research Low 31678169
2019 ROCK2 disrupts MKP1 at two levels: it activates ERK1/2-ATF2 signaling to increase MKP1 mRNA expression, while simultaneously promoting ERK1/2-dependent ubiquitin-mediated MKP1 protein degradation, net result being decreased MKP1 protein and promoted HCC metastasis. ROCK2 knockdown, western blot for MKP1 protein and mRNA, ERK1/2 pathway analysis, ubiquitination assay American journal of cancer research Low 32266097
2019 ROCK2 promotes cardiomyocyte arrhythmic calcium release in diabetic hearts by promoting CaMKII-mediated phosphorylation of the ryanodine receptor (RyR); ROCK2+/- diabetic mice show decreased CaMKII and RyR phosphorylation and reduced diastolic Ca2+ leak. ROCK2+/- mice, streptozotocin-diabetic model, Ca2+ transient imaging, CaMKII and RyR phosphorylation western blot, pharmacological ROCK inhibition (Y-27632) International journal of cardiology Medium 30728103
2019 ROCK2 disruption in cardiomyocytes leads to reduced MLC and FAK phosphorylation; ROCK2 single knockout causes compensatory ROCK1 overactivation with increased p-MLC and p-FAK, inhibited autophagy via increased mTOR activity, and increased cardiac fibrosis, whereas double ROCK1/ROCK2 knockout promotes autophagy via reduced AKT/mTOR/ULK1 signaling. Cardiomyocyte-specific tamoxifen-inducible ROCK knockout mice, western blot for MLC/FAK/AKT/mTOR/ULK1 phosphorylation, LC3B autophagy marker, cardiac histology FASEB journal High 30848941
2019 ROCK2 inhibition enhances beige adipogenesis in white adipose tissue; ROCK2 activity-mediated actin cytoskeleton dynamics suppress thermogenic gene expression, and selective ROCK2 inhibition (KD025) or ROCK2 haploinsufficiency in vivo reproduces the pro-beige phenotype. ROCK2+/- and ROCK2 kinase-dead knock-in mice, high-fat diet model, adipose tissue histology, thermogenic gene expression, KD025 treatment of differentiated stromal-vascular cells FASEB journal Medium 31914704
2020 ROCK2 is activated in germinal center (GC) B cells by CD40 and IL-21 signals; ROCK2 regulates GC formation and maintains a transcriptional program for GC polarization and cholesterol biosynthesis by: (1) restraining AKT activation to enhance FOXO1 activity, and (2) directly phosphorylating IRF8 to promote its interaction with SREBP2 at cholesterol biosynthetic gene regulatory regions. B cell-specific ROCK2 deletion, RNA-seq, ATAC-seq, biochemical IRF8 phosphorylation assays, ChIP for SREBP2 recruitment The Journal of clinical investigation High 32229726
2020 ROCK2 affects osteosarcoma progression and TRAIL resistance by modifying O-GlcNAcylation through stabilization of O-GlcNAc transferase (preventing its degradation). ROCK2 silencing, proteomics analysis, O-GlcNAc transferase expression and ubiquitination analysis, apoptosis assays American journal of cancer research Low 32266091
2021 ROCK2 directly inhibits Parkin-dependent mitophagy; ROCK2 inhibition promotes mitophagy through this pathway, providing a mechanism for neuroprotection in neurodegenerative disease models. Pharmacological ROCK2 inhibition, mitophagy pathway analysis (reviewed with supporting experimental citations) Neuroscience and biobehavioral reviews Low 36122738
2021 ROCK2 inhibition in macrophages directly disrupts STAT3/cofilin signaling, inhibiting pro-inflammatory cytokine production and macrophage migration; in vivo ROCK2 inhibition reduces STAT3 phosphorylation and cofilin levels in fibrotic liver. Selective ROCK2 inhibitor KD025 treatment in vitro and in vivo, western blot for STAT3/cofilin phosphorylation, macrophage migration and cytokine assays, thioacetamide liver fibrosis model JHEP reports : innovation in hepatology Medium 34917911
2021 Fibroblast deletion of ROCK2 specifically reduces TGF-β1/Smad2 signaling and cardiac fibroblast activation; ROCK2 mediates cardiac fibrosis through the TGF-β1/Smad2 pathway. ROCK2 siRNA knockdown, belumosudil treatment, western blot for Smad2 phosphorylation, cardiac fibroblast activation assays, TAC mouse model American journal of physiology. Heart and circulatory physiology Medium 35657612
2022 ROCK2 serves as a suppressor of PPARα transcription in podocytes, rewiring cellular metabolism by negatively controlling transcription of genes involved in fatty acid oxidation, which induces podocyte apoptosis in diabetic conditions. Podocyte-specific ROCK2 knockout mice, RNA-sequencing of ROCK2-null podocytes, multiple diabetic mouse models (STZ, db/db, HFD), albuminuria and fibrosis readouts Communications biology High 35396346
2022 ROCK2 enhances homologous recombination (HR) repair in TMZ-resistant glioma cells by upregulating ATM expression through promoting binding of ZEB1 (converted to transcriptional activator by YAP1) to the ATM promoter. ROCK2 silencing, HR assay, ATM expression analysis, ZEB1/YAP1 interaction studies, ChIP for ZEB1 binding to ATM promoter Cell death & disease Medium 35145081
2023 ROCK2 associates with p22phox in human monocytes (but not neutrophils) via interaction between the cytosolic region of p22phox (aa 132–195) and the coiled-coil region of ROCK2 (aa 400–967); ROCK2 phosphorylates p47phox on Ser304, Ser315, Ser320, and Ser328 in vitro but does not phosphorylate p22phox, p40phox, p67phox, or gp91phox, thereby controlling NADPH oxidase activation in monocytes. Reciprocal co-immunoprecipitation, in vitro kinase assay with defined phosphorylation sites, domain-mapping experiments, ROCK2 siRNA knockdown in THP1 cells, KD025 inhibitor, ROS measurement Proceedings of the National Academy of Sciences of the United States of America High 36626553
2023 A ROCK2/JAM-A complex emerges in lymphatic endothelial cells under cytokine challenge and is responsible for cytokine-induced lymphatic junction zippering and impaired lymphatic drainage; lymphatic-specific ROCK2 knockout reverses lymphedema in vivo. Microfluidic lymphatic vessel model, ROCK2 isoform-specific inhibition, lymphatic-specific ROCK2 genetic knockout mouse, lymphedema assessment, ROCK2/JAM-A complex identification Proceedings of the National Academy of Sciences of the United States of America High 37782785
2019 ROCK2 regulates TGF-β-induced CTGF expression and profibrotic gene expression in mesangial cells via NF-κB nuclear translocation and actin cytoskeleton dynamics through phosphorylation of JNK and ERK; siRNA knockdown showed ROCK2 but not ROCK1 controls this fibrotic signaling machinery. ROCK1 and ROCK2 siRNA isoform-specific knockdown, western blot for JNK/ERK phosphorylation and NF-κB nuclear translocation, CTGF expression assay, db/db mouse model American journal of physiology. Renal physiology Medium 31364374
2010 ROCK2 dynamically associates with the LOX-1 scavenger receptor complex in the presence of OxLDL; OxLDL stimulates ROCK2 catalytic activity, and ROCK2 inhibition attenuates NF-κB activation and IL-8 production downstream of LOX-1. Affinity purification/mass spectrometry of LOX-1 complex, reciprocal co-immunoprecipitation, ROCK2 kinase activity assay, NF-κB luciferase reporter, IL-8 ELISA American journal of physiology. Cell physiology Medium 20181930
2017 Nogo-66 signals through Lingo1/NgR1 to restrict LTP at the Schaffer collateral-CA1 pathway via the ROCK2-cofilin pathway, controlling actin cytoskeleton dynamics; p75NTR is not involved in mediating the Nogo-66 effect on LTP. Electrophysiology in acute hippocampal slices, loss-of-function for Lingo1, p75NTR, and NgR1, cofilin phosphorylation biochemistry Cerebral cortex Medium 27166169
2021 GASC1 histone demethylase maintains ROCK2 protein stability by transcriptionally repressing FBXO42, a ROCK2 E3 ubiquitin ligase that mediates K63-linked poly-ubiquitination of ROCK2; GASC1 demethylase activity is required for this FBXO42 repression. GASC1 knockdown, FBXO42 identification as ROCK2 E3 ligase, ubiquitination type analysis (K63-linked), GASC1 inhibitor SD70, xenograft mouse model Cell death & disease Medium 33692332
2024 TRIM26 E3 ligase ubiquitylates ROCK2 and promotes its degradation; upregulation of TRIM26 in doxorubicin-resistant leukemia cells reduces ROCK2 levels and increases drug sensitivity. TRIM26 identification as ROCK2 E3 ligase, ubiquitination assay, drug sensitivity assays in AML cell lines International immunopharmacology Low 39126734
2009 In keratinocytes, ROCK2 depletion results in increased adhesion to fibronectin and inhibition of terminal differentiation, demonstrating ROCK2 has a distinct role from ROCK1 (which decreases adhesion and promotes differentiation) in regulating keratinocyte adhesion and differentiation. RNAi knockdown of ROCK1 or ROCK2 in human keratinocytes, fibronectin adhesion assays, differentiation marker analysis PloS one Medium 19997641
2019 CD99 wild-type expression in osteosarcoma cells inhibits ROCK2 signaling by maintaining c-Src in an inactive conformation; ROCK2 suppression by CD99 leads to decreased ezrin at the cell membrane and translocation of N-cadherin and β-catenin to the plasma membrane, reducing cell migration. CD99 forced expression, ROCK2 expression and activity analysis, c-Src activity, actin cytoskeleton and adherens junction protein localization, migration assays Oncogene Medium 23644663
2018 YAP transcription co-activator upregulates ROCK2 expression by binding the ROCK2 promoter region in an actomyosin activity-dependent manner; ROCK2 in turn promotes transcriptional activation by YAP, establishing a positive feedback loop modulated by ECM stiffness. YAP knockdown, ROCK2 promoter activity assay with constitutively active YAP, ChIP for YAP binding to ROCK2 promoter, ECM rigidity manipulation Cell adhesion & migration Medium 28686514
2024 ROCK2 mediates sevoflurane-induced cognitive impairment by phosphorylating radixin, which anchors α5-GABAAR to extrasynaptic sites; inhibition of the RhoA/ROCK2 pathway with fasudil or AAV-mediated ROCK2 knockdown decreases extrasynaptic α5-GABAAR distribution and improves cognitive function in aged mice. Aged mouse sevoflurane exposure, ROCK2 and p-radixin western blot, α5-GABAAR membrane fractionation, colocalization immunofluorescence, Morris water maze, AAV ROCK2 knockdown, fasudil treatment Aging cell Medium 38825816

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 The Function of Rho-Associated Kinases ROCK1 and ROCK2 in the Pathogenesis of Cardiovascular Disease. Frontiers in pharmacology 287 26635606
2013 Distinct roles for ROCK1 and ROCK2 in the regulation of cell detachment. Cell death & disease 190 23392171
2021 ROCK2 Inhibition With Belumosudil (KD025) for the Treatment of Chronic Graft-Versus-Host Disease. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 158 33877856
2012 ROCK1 and ROCK2 are required for non-small cell lung cancer anchorage-independent growth and invasion. Cancer research 117 22942252
2014 Rbfox2-coordinated alternative splicing of Mef2d and Rock2 controls myoblast fusion during myogenesis. Molecular cell 103 25087874
2018 The Rho Kinase Isoforms ROCK1 and ROCK2 Each Contribute to the Development of Experimental Pulmonary Fibrosis. American journal of respiratory cell and molecular biology 102 29211497
2014 Androgen-regulated microRNA-135a decreases prostate cancer cell migration and invasion through downregulating ROCK1 and ROCK2. Oncogene 93 25065599
2006 Nuclear Rho kinase, ROCK2, targets p300 acetyltransferase. The Journal of biological chemistry 88 16574662
2009 Distinct roles for ROCK1 and ROCK2 in the regulation of keratinocyte differentiation. PloS one 86 19997641
2008 A critical role of Rho-kinase ROCK2 in the regulation of spine and synaptic function. Neuropharmacology 83 18718479
2015 MicroRNA-144 suppresses osteosarcoma growth and metastasis by targeting ROCK1 and ROCK2. Oncotarget 69 25912304
2017 Fibroblast deletion of ROCK2 attenuates cardiac hypertrophy, fibrosis, and diastolic dysfunction. JCI insight 64 28679962
2016 ROCK1 and ROCK2 inhibition alters dendritic spine morphology in hippocampal neurons. Cellular logistics 62 27054047
2016 Panax notoginseng saponins provide neuroprotection by regulating NgR1/RhoA/ROCK2 pathway expression, in vitro and in vivo. Journal of ethnopharmacology 54 27288754
2019 ROCK2 regulates TGF-β-induced expression of CTGF and profibrotic genes via NF-κB and cytoskeleton dynamics in mesangial cells. American journal of physiology. Renal physiology 53 31364374
2018 Tetrahedral DNA nanostructures facilitate neural stem cell migration via activating RHOA/ROCK2 signalling pathway. Cell proliferation 51 30091500
2021 ROCK2, a critical regulator of immune modulation and fibrosis has emerged as a therapeutic target in chronic graft-versus-host disease. Clinical immunology (Orlando, Fla.) 49 34400321
2019 ROCK2 Regulates Monocyte Migration and Cell to Cell Adhesion in Vascular Endothelial Cells. International journal of molecular sciences 49 30884801
2021 ROCK2 inhibition attenuates profibrogenic immune cell function to reverse thioacetamide-induced liver fibrosis. JHEP reports : innovation in hepatology 48 34917911
2019 Disruption of both ROCK1 and ROCK2 genes in cardiomyocytes promotes autophagy and reduces cardiac fibrosis during aging. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 47 30848941
2019 ROCK2 inhibition triggers the collective invasion of colorectal adenocarcinomas. The EMBO journal 47 31304629
2007 ROCK2 and its alternatively spliced isoform ROCK2m positively control the maturation of the myogenic program. Molecular and cellular biology 47 17606625
2019 miR-185-5p targets ROCK2 and inhibits cell migration and invasion of hepatocellular carcinoma. Oncology letters 46 31105794
2023 The RhoA-ROCK1/ROCK2 Pathway Exacerbates Inflammatory Signaling in Immortalized and Primary Microglia. Cells 44 37408199
2017 APC/CCdh1-Rock2 pathway controls dendritic integrity and memory. Proceedings of the National Academy of Sciences of the United States of America 43 28396402
2015 Low Expression of miR-448 Induces EMT and Promotes Invasion by Regulating ROCK2 in Hepatocellular Carcinoma. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 42 25969175
2014 Rock2 promotes the invasion and metastasis of hepatocellular carcinoma by modifying MMP2 ubiquitination and degradation. Biochemical and biophysical research communications 42 25251472
2013 CD99 suppresses osteosarcoma cell migration through inhibition of ROCK2 activity. Oncogene 42 23644663
2021 Perspectives on ROCK2 as a Therapeutic Target for Alzheimer's Disease. Frontiers in cellular neuroscience 35 33790742
2019 Distinct Roles of ROCK1 and ROCK2 on the Cerebral Ischemia Injury and Subsequently Neurodegenerative Changes. Pharmacology 35 31537002
2021 Activation of GPR55 attenuates cognitive impairment and neurotoxicity in a mouse model of Alzheimer's disease induced by Aβ1-42 through inhibiting RhoA/ROCK2 pathway. Progress in neuro-psychopharmacology & biological psychiatry 34 34363866
2012 Rock2 regulates Cdc25A through ubiquitin proteasome system in hepatocellular carcinoma cells. Experimental cell research 34 22705122
2010 Ouabain-induced apoptosis and Rho kinase: a novel caspase-2 cleavage site and fragment of Rock-2. Apoptosis : an international journal on programmed cell death 34 20661774
2016 RhoE/ROCK2 regulates chemoresistance through NF-κB/IL-6/ STAT3 signaling in hepatocellular carcinoma. Oncotarget 33 27213590
2022 Small nucleolar RNA SNORA71A promotes epithelial-mesenchymal transition by maintaining ROCK2 mRNA stability in breast cancer. Molecular oncology 32 35100495
2015 ROCK2 promotes HCC proliferation by CEBPD inhibition through phospho-GSK3β/β-catenin signaling. FEBS letters 32 25771860
2009 Rock2 controls TGFbeta signaling and inhibits mesoderm induction in zebrafish embryos. Journal of cell science 32 19509062
2019 A Brain-Targeted Orally Available ROCK2 Inhibitor Benefits Mild and Aggressive Cavernous Angioma Disease. Translational stroke research 31 31446620
2018 Distinct and complementary functions of rho kinase isoforms ROCK1 and ROCK2 in prefrontal cortex structural plasticity. Brain structure & function 31 30196430
2018 Identification of Selective Dual ROCK1 and ROCK2 Inhibitors Using Structure-Based Drug Design. Journal of medicinal chemistry 31 30384606
2012 ROCK1 and ROCK2 regulate epithelial polarisation and geometric cell shape. Biology of the cell 31 22462535
2004 Expression of Rho-kinase (ROCK-1 and ROCK-2) and its substantial role in the contractile activity of the sheep ureter. British journal of pharmacology 31 15351780
2016 Upregulation of ROCK2 in gastric cancer cell promotes tumor cell proliferation, metastasis and invasion. Clinical and experimental medicine 28 27921230
2017 Nogo-66 Restricts Synaptic Strengthening via Lingo1 and the ROCK2-Cofilin Pathway to Control Actin Dynamics. Cerebral cortex (New York, N.Y. : 1991) 27 27166169
2014 KAP regulates ROCK2 and Cdk2 in an RNA-activated glioblastoma invasion pathway. Oncogene 27 24704824
2020 Serine-threonine kinase ROCK2 regulates germinal center B cell positioning and cholesterol biosynthesis. The Journal of clinical investigation 25 32229726
2020 Chemokine receptor CXCR4 activates the RhoA/ROCK2 pathway in spinal neurons that induces bone cancer pain. Molecular pain 25 32349612
2020 Inhibition of ROCK2 alleviates renal fibrosis and the metabolic disorders in the proximal tubular epithelial cells. Clinical science (London, England : 1979) 25 32490513
2019 RhoC/ROCK2 promotes vasculogenic mimicry formation primarily through ERK/MMPs in hepatocellular carcinoma. Biochimica et biophysica acta. Molecular basis of disease 25 30779947
2019 ROCK2 promotes osteosarcoma growth and metastasis by modifying PFKFB3 ubiquitination and degradation. Experimental cell research 25 31678169
2016 Rock2 promotes RCC proliferation by decreasing SCARA5 expression through β-catenin/TCF4 signaling. Biochemical and biophysical research communications 25 27793664
2014 Distinct roles of ROCK1 and ROCK2 during development of porcine preimplantation embryos. Reproduction (Cambridge, England) 25 24803490
2024 RhoA-ROCK2 signaling possesses complex pathophysiological functions in cancer progression and shows promising therapeutic potential. Cancer cell international 24 39402585
2016 Heterogeneous Impact of ROCK2 on Carotid and Cerebrovascular Function. Hypertension (Dallas, Tex. : 1979) 24 27432870
2015 Overexpression of ROCK1 and ROCK2 inhibits human laryngeal squamous cell carcinoma. International journal of clinical and experimental pathology 24 25755711
2015 Rock2 stabilizes β-catenin to promote tumor invasion and metastasis in colorectal cancer. Biochemical and biophysical research communications 24 26505794
2022 Acrolein, an endogenous aldehyde induces synaptic dysfunction in vitro and in vivo: Involvement of RhoA/ROCK2 pathway. Aging cell 23 35315217
2022 ROCK2 inhibition: A futuristic approach for the management of Alzheimer's disease. Neuroscience and biobehavioral reviews 23 36122738
2020 ROCK2 mediates osteosarcoma progression and TRAIL resistance by modulating O-GlcNAc transferase degradation. American journal of cancer research 22 32266091
2019 Comparative Study of ROCK1 and ROCK2 in Hippocampal Spine Formation and Synaptic Function. Neuroscience bulletin 22 30826947
2022 Tanshinone IIA improves sepsis-induced acute lung injury through the ROCK2/NF-κB axis. Toxicology and applied pharmacology 21 35421429
2014 Complex regulation of PKCβ2 and PDK-1/AKT by ROCK2 in diabetic heart. PloS one 21 24466133
2024 An open-label study of belumosudil, a selective ROCK2 inhibitor, as second or subsequent line of therapy for steroid-dependent/steroid-resistant chronic GVHD. American journal of hematology 20 38934629
2019 ROCK2 inhibition enhances the thermogenic program in white and brown fat tissue in mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20 31914704
2023 IL-22-Activated MUC13 Impacts on Colonic Barrier Function through JAK1/STAT3, SNAI1/ZEB1 and ROCK2/MAPK Signaling. Cells 19 37174625
2023 TIPE2 ameliorates neuroinflammation and cognitive impairment in sepsis-associated encephalopathy through regulating RhoA/ROCK2-NF-κB signaling pathway. Biochemical pharmacology 19 37748665
2021 ROCK2 Promotes Osteosarcoma Growth and Glycolysis by Up-Regulating HKII via Phospho-PI3K/AKT Signalling. Cancer management and research 19 33500659
2019 Sema3A inhibits axonal regeneration of retinal ganglion cells via ROCK2. Brain research 19 31733191
2022 Nc886 promotes renal cancer cell drug-resistance by enhancing EMT through Rock2 phosphorylation-mediated β-catenin nuclear translocation. Cell cycle (Georgetown, Tex.) 18 34974812
2022 Acquired temozolomide resistance in MGMTlow gliomas is associated with regulation of homologous recombination repair by ROCK2. Cell death & disease 18 35145081
2019 ROCK2 promotes ryanodine receptor phosphorylation and arrhythmic calcium release in diabetic cardiomyocytes. International journal of cardiology 18 30728103
2018 Substrate rigidity-dependent positive feedback regulation between YAP and ROCK2. Cell adhesion & migration 18 28686514
2010 ROCK2 associates with lectin-like oxidized LDL receptor-1 and mediates oxidized LDL-induced IL-8 production. American journal of physiology. Cell physiology 18 20181930
2022 ROCK2-induced metabolic rewiring in diabetic podocytopathy. Communications biology 17 35396346
2021 Diverse effects of pan-ROCK and ROCK2 inhibitors on 2 D and 3D cultured human trabecular meshwork (HTM) cells treated with TGFβ2. Scientific reports 17 34315994
2021 ROCK2-Specific Inhibitor KD025 Suppresses Adipocyte Differentiation by Inhibiting Casein Kinase 2. Molecules (Basel, Switzerland) 17 34443331
2024 Sevoflurane-induced overexpression of extrasynaptic α5-GABAAR via the RhoA/ROCK2 pathway impairs cognitive function in aged mice. Aging cell 16 38825816
2023 Deficiency of endothelial FGFR1 signaling via upregulation of ROCK2 activity aggravated ALI/ARDS. Frontiers in immunology 16 36969192
2019 Targeted regulation by ROCK2 on bladder carcinoma via Wnt signaling under hypoxia. Cancer biomarkers : section A of Disease markers 16 30475758
2019 Fasudil or genetic depletion of ROCK1 or ROCK2 induces anxiety-like behaviors. Behavioural brain research 16 31302146
2016 Rho Kinase ROCK2 Mediates Acid-Induced NADPH Oxidase NOX5-S Expression in Human Esophageal Adenocarcinoma Cells. PloS one 16 26901778
2023 ROCK2 interacts with p22phox to phosphorylate p47phox and to control NADPH oxidase activation in human monocytes. Proceedings of the National Academy of Sciences of the United States of America 15 36626553
2023 A 3D biomimetic model of lymphatics reveals cell-cell junction tightening and lymphedema via a cytokine-induced ROCK2/JAM-A complex. Proceedings of the National Academy of Sciences of the United States of America 15 37782785
2020 ROCK2 disturbs MKP1 expression to promote invasion and metastasis in hepatocellular carcinoma. American journal of cancer research 15 32266097
2020 The Rho kinase 2 (ROCK2)-specific inhibitor KD025 ameliorates the development of pulmonary arterial hypertension. Biochemical and biophysical research communications 15 33160621
2011 Peptide substrates for Rho-associated kinase 2 (Rho-kinase 2/ROCK2). PloS one 15 21818369
2022 Knockdown of circRNA Paralemmin 2 Ameliorates Lipopolysaccharide-induced Murine Lung Epithelial Cell Injury by Sponging miR-330-5p to Reduce ROCK2 Expression. Immunological investigations 14 35171050
2021 GASC1 promotes hepatocellular carcinoma progression by inhibiting the degradation of ROCK2. Cell death & disease 14 33692332
2017 Targeting ROCK2 rather than ROCK1 inhibits Ewing sarcoma malignancy. Oncology reports 14 28112365
2023 ZNF143 inhibits hepatocyte mitophagy and promotes non-alcoholic fatty liver disease by targeting increased lncRNA NEAT1 expression to activate ROCK2 pathway. Epigenetics 13 37566742
2022 Belumosudil, ROCK2-specific inhibitor, alleviates cardiac fibrosis by inhibiting cardiac fibroblasts activation. American journal of physiology. Heart and circulatory physiology 13 35657612
2021 Pan-ROCK and ROCK2 Inhibitors Affect Dexamethasone-Treated 2D- and 3D-Cultured Human Trabecular Meshwork (HTM) Cells in Opposite Manners. Molecules (Basel, Switzerland) 13 34770791
2018 Distinct Roles For ROCK1 and ROCK2 in the Regulation of Oxldl-Mediated Endothelial Dysfunction. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 13 30165352
2024 ROCK2 regulates microglia proliferation and neuronal survival after traumatic brain injury. Brain, behavior, and immunity 12 38211634
2024 CRISPR-CasRx-mediated disruption of Aqp1/Adrb2/Rock1/Rock2 genes reduces intraocular pressure and retinal ganglion cell damage in mice. Nature communications 12 39080269
2024 ROCK2 increases drug resistance in acute myeloid leukemia via metabolic reprogramming and MAPK/PI3K/AKT signaling. International immunopharmacology 12 39126734
2023 Neoprzewaquinone A Inhibits Breast Cancer Cell Migration and Promotes Smooth Muscle Relaxation by Targeting PIM1 to Block ROCK2/STAT3 Pathway. International journal of molecular sciences 12 36982538
2023 CircHECTD1 promoted MIRI-associated inflammation via inhibiting miR-138-5p and upregulating ROCK2. The Kaohsiung journal of medical sciences 12 37096660
2022 CircCHMP5 Contributes to Ox-LDL-induced Endothelial Cell Injury Through the Regulation of MiR-532-5p/ROCK2 axis. Cardiovascular drugs and therapy 12 35084579
2017 Clinicopathologic significance of ROCK2 expression in oral squamous cell carcinomas. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 12 29052912

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