Affinage

HMMR

Hyaluronan mediated motility receptor · UniProt O75330

Length
724 aa
Mass
84.1 kDa
Annotated
2026-04-28
100 papers in source corpus 37 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HMMR/RHAMM is a multifunctional scaffold protein that operates both as an extracellular hyaluronan receptor driving cell motility and as an intracellular centrosomal/spindle-associated protein essential for mitotic spindle assembly, orientation, and integrity. Extracellularly, HMMR binds hyaluronan through C-terminal B(X7)B motifs and activates ERK1/2, FAK, Src, and PI3K-Rac signaling cascades to promote cell migration, adhesion, and focal adhesion turnover, functioning downstream of H-Ras (PMID:7682552, PMID:7508860, PMID:7541721, PMID:16934786, PMID:21914806). Intracellularly, HMMR associates with microtubules, centrosomes, and dynein via its C-terminal domain, scaffolds an ERK1/2-MEK1-tubulin complex to regulate interphase microtubule dynamics and spindle architecture, localizes TPX2 to activate AURKA, and participates in a PLK1-Ran-NuMA-dynein pathway that orients the mitotic spindle in progenitor cells (PMID:12808028, PMID:20558733, PMID:24875404, PMID:28994651). HMMR transcription is repressed by p53, activated by YAP/TEAD and E2F1, and peaks at S/G2-M; the protein stabilizes AURKA from ubiquitin-mediated degradation and is itself targeted for degradation by TRIM29-mediated ubiquitination under ER stress (PMID:18971636, PMID:24367099, PMID:36750558, PMID:37405956).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1994 High

    Identification of the HA-binding mechanism resolved how HMMR recognizes its principal extracellular ligand: two C-terminal B(X7)B motifs are necessary and sufficient for hyaluronan binding, a motif shared with CD44 and link protein.

    Evidence GST-fusion truncations, site-directed mutagenesis of basic residues, HA-Sepharose binding, chimeric protein construction

    PMID:7508860 PMID:7682552

    Open questions at the time
    • Structural basis of HA-RHAMM interaction unresolved
    • Relative contribution of each B(X7)B motif in vivo unknown
  2. 1995 High

    Establishing HMMR as a Ras-pathway effector that promotes transformation and metastasis answered whether HMMR had oncogenic capacity and placed it genetically downstream of H-Ras, upstream of FAK-dependent focal adhesion turnover.

    Evidence Overexpression/antisense/dominant-negative RHAMM in fibroblasts, ras-transformed fibrosarcoma reversion, in vivo tumorigenesis, FAK phosphorylation

    PMID:7541721

    Open questions at the time
    • Direct binding partner linking Ras to RHAMM not identified
    • Mechanism of cell-surface vs. intracellular RHAMM contribution to transformation unclear
  3. 1998 High

    Discovery that intracellular RHAMM isoforms scaffold MEK1-ERK1/2 complexes revealed a non-receptor signaling role, explaining how RHAMM activates ERK independently of cell-surface ligand engagement.

    Evidence Co-immunoprecipitation of RHAMMv4 with MEK1/ERK, dominant-negative epistasis, constitutive ERK activation upon overexpression

    PMID:9556628

    Open questions at the time
    • Stoichiometry and regulation of the RHAMM-MEK1-ERK complex undetermined
    • Whether intracellular HA binding modulates this scaffolding function unknown
  4. 1999 High

    Demonstrating direct microtubule binding via an N-terminal domain established HMMR as a bona fide microtubule-associated protein, linking its intracellular pool to cytoskeletal regulation beyond signaling scaffold roles.

    Evidence GFP-fusion localization, in vitro microtubule-binding assays, deletion mutagenesis, calmodulin affinity chromatography

    PMID:10547355

    Open questions at the time
    • Whether microtubule binding and HA binding are mutually exclusive or concurrent unknown
    • Role of calmodulin binding in regulating HMMR-microtubule interaction not tested
  5. 2003 High

    Localization of HMMR to centrosomes and identification of its interaction with dynein through a C-terminal Xklp2-like domain established HMMR as a centrosomal protein required for mitotic spindle integrity.

    Evidence Co-IP of dynein IC, deletion mapping of centrosomal targeting domain, HMMR depletion/overexpression spindle phenotypes

    PMID:12808028

    Open questions at the time
    • Whether dynein interaction is direct or bridged by adaptor proteins unresolved
    • Regulation of HMMR centrosomal recruitment mechanism unknown
  6. 2007 High

    Demonstration that cell-surface RHAMM and CD44 form a ternary complex with ERK1/2 in invasive breast cancer cells explained how co-receptor assembly sustains high basal motility signaling in aggressive cancers.

    Evidence Reciprocal co-IP, confocal co-localization, antibody blocking and MEK1 inhibitor in MDA-MB-231 cells

    PMID:17392272

    Open questions at the time
    • Whether the complex requires direct RHAMM-CD44 contact or is bridged by HA uncertain
    • Structural determinants of receptor complex assembly unknown
  7. 2010 High

    Using RHAMM-knockout MEFs to show that RHAMM controls interphase microtubule dynamics and spindle bipolarity through MEK1/ERK1/2, and mapping its direct ERK1 D-site and tubulin leucine-zipper binding domains, unified its scaffolding and cytoskeletal functions into a single mechanistic model.

    Evidence RHAMM−/− MEF rescue with RHAMM or constitutively active MEK1, co-IP/pulldown of RHAMM-ERK1-tubulin complex, D-site mutation

    PMID:20558733

    Open questions at the time
    • Whether RHAMM directly activates MEK1 or merely co-localizes it with substrates undetermined
    • Contribution of intracellular HA to this pathway untested in knockout system
  8. 2013 High

    Identification of YAP/TEAD as a direct transcriptional activator of HMMR downstream of the mevalonate-Rho pathway provided the first link between Hippo pathway output and HMMR-dependent cell invasion, explaining how metabolic cues regulate HMMR levels.

    Evidence ChIP of TEAD on HMMR promoter, reporter assays, simvastatin and RhoA inhibition, in vivo migration assays

    PMID:24367099

    Open questions at the time
    • Whether p53 and YAP/TEAD compete at the HMMR promoter uncharacterized
    • Chromatin-level regulation of HMMR transcription not defined
  9. 2014 High

    Showing that HMMR forms a complex with TPX2 and is required for spatial activation of AURKA at centrosomal and kinetochore-proximal sites resolved how HMMR contributes to spindle assembly kinetics and length control.

    Evidence Co-IP of RHAMM-TPX2, domain mapping (C-terminal basic leucine zipper), AURKA kinase activity assay, siRNA spindle phenotype

    PMID:24875404

    Open questions at the time
    • Whether HMMR directly activates AURKA or acts solely through TPX2 localization unclear
    • Regulation of HMMR-TPX2 complex formation during cell cycle not mapped
  10. 2017 High

    Generation of Hmmr-knockout mice revealed neonatal lethality with neural defects and established that HMMR operates in a PLK1-dependent pathway controlling Ran activity and cortical NuMA-dynein to orient mitotic spindles in progenitor cells.

    Evidence Hmmr-knockout mouse phenotyping, Ran activity assays, NuMA-dynein cortical localization, spindle orientation measurements

    PMID:28994651

    Open questions at the time
    • How PLK1 regulates HMMR (phosphorylation sites, binding) not biochemically defined
    • Whether spindle orientation defects fully account for neonatal lethality unknown
  11. 2022 High

    Transgenic HMMR overexpression in BRCA1-mutant mammary epithelium demonstrated that excess HMMR drives tumorigenesis through AURKA hyperactivation, ARPC2 mislocalization, micronucleation, and consequent cGAS-STING/NF-κB inflammatory signaling, connecting spindle defects to the tumor microenvironment.

    Evidence HMMR-overexpressing Brca1-mutant transgenic mouse, AURKA activity, ARPC2 immunofluorescence, cGAS-STING pathway and macrophage profiling

    PMID:35393420

    Open questions at the time
    • Whether cGAS-STING activation is a direct consequence of micronuclei or involves additional HMMR-dependent signals untested
    • Therapeutic window for AURKA inhibition in HMMR-high tumors undefined
  12. 2023 Medium

    Two studies expanded HMMR's post-translational regulation: HMMR stabilizes AURKA by inhibiting its ubiquitination (forming an HMMR-AURKA-mTORC2-AKT-E2F1 feedback loop), and HMMR itself is degraded by TRIM29-mediated ubiquitination under ER stress while promoting autophagy-lysosome activity.

    Evidence Co-IP of HMMR-AURKA, ubiquitination assays, mTOR inhibitor in vivo, CHOP ChIP on HMMR promoter, TRIM29 ubiquitination assay

    PMID:36750558 PMID:37405956

    Open questions at the time
    • Identity of the E3 ligase whose activity on AURKA is blocked by HMMR unknown
    • Whether TRIM29-mediated degradation of HMMR operates outside ER stress contexts untested
    • Feedback loop components not validated in non-cancer cell types

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of HMMR's multivalent interactions (HA, tubulin, TPX2, dynein, ERK), how isoform-specific functions are partitioned between extracellular and intracellular pools in vivo, and whether HMMR's spindle and signaling functions are mechanistically coupled or independently regulated.
  • No high-resolution structure of HMMR or its complexes
  • Isoform-specific knockout models not available
  • Relationship between HA-binding and spindle functions not experimentally dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005815 microtubule organizing center 3 GO:0005856 cytoskeleton 3 GO:0005886 plasma membrane 3 GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1640170 Cell Cycle 5 R-HSA-1500931 Cell-Cell communication 3 R-HSA-1474244 Extracellular matrix organization 2 R-HSA-9612973 Autophagy 1
Partners
AURKABACH1CD44DYNC1I2MAP2K1MAPK3SRCTPX2
Complex memberships
RHAMM-CD44-ERK1/2 surface signaling complexRHAMM-MEK1-ERK1/2-tubulin intracellular complexRHAMM-TPX2-AURKA spindle complex

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 Two discrete hyaluronan-binding domains were identified in RHAMM near the carboxyl terminus (amino acids 400-434), each containing clusters of basic amino acids. Synthetic peptides mimicking these domains directly bind HA-Sepharose and inhibit HA-RHAMM interactions; deletion of these domains abolishes HA binding. Recombinant GST-fusion protein truncations, HA-Sepharose binding assays, synthetic peptide competition, transblot assays The Journal of biological chemistry High 7682552
1994 A common HA-binding motif B(X7)B (two basic amino acids flanking a seven amino acid stretch) is required for HA binding in RHAMM, CD44, and link protein. Mutation of K423 and R431 in RHAMM domain II abolished HA binding; mutation of all B(X7)B basic residues to histidine eliminated binding. Chimeric proteins containing B(X7)B motifs from CD44 or link protein acquired HA-binding activity. Site-directed mutagenesis of recombinant RHAMM polypeptides, HA-Sepharose binding, transblot assays, chimeric protein construction The EMBO journal High 7508860
1994 RHAMM also contains heparin-binding sites within the same 35 amino acid C-terminal region as the HA-binding domains. Heparin at physiological concentrations stimulates cell locomotion in a RHAMM-dependent manner (blocked by anti-RHAMM antibodies), while lower concentrations inhibit HA-induced locomotion independently of RHAMM. Ligand blotting with biotin-labeled heparin, GST-RHAMM fusion protein binding, HP-Sepharose affinity, anti-RHAMM antibody blocking of cell locomotion Journal of cellular biochemistry Medium 7534313
1995 Overexpression of RHAMM in fibroblasts is transforming and causes lung metastases. RHAMM acts downstream of H-ras: dominant-suppressor RHAMM mutants revert ras-transformed fibrosarcomas to nontumorigenic, and antisense RHAMM renders fibroblasts resistant to ras transformation. Loss of functional RHAMM ablates focal adhesion kinase phosphorylation changes and prevents focal adhesion turnover in response to hyaluronan. Stable transfection (overexpression and antisense), dominant-negative mutant expression, in vivo tumorigenesis and metastasis assays, FAK phosphorylation western blot, focal adhesion assays Cell High 7541721
1995 RHAMM is required for migration of bovine aortic smooth muscle cells after wounding. Anti-RHAMM antisera that block HA binding abolish post-injury SMC migration. A novel RHAMM protein isoform appears within one hour after injury, and membrane expression increases in cells at the wound edge. Scratch-wound migration assay, polyclonal antibody blocking, FACS, immunoblot, confocal microscopy The Journal of clinical investigation High 7533785
1996 c-Src kinase is required for RHAMM-dependent cell motility and acts downstream of RHAMM in the regulation of locomotion. Src physically associates with RHAMM in ras-transformed cells; dominant-negative src inhibits RHAMM-dependent ras and serum-regulated locomotion; v-Src enhances motility independently of RHAMM but cannot restore focal adhesion turnover in the absence of RHAMM. Src-knockout fibroblasts, kinase-dead and truncated Src expression, dominant-negative src, v-src overexpression, anti-RHAMM blocking antibodies, co-immunoprecipitation Oncogene High 8950989
1996 TGF-β1 stabilizes RHAMM mRNA approximately 3-fold through a specific 30-nucleotide cis-element in the 3'-UTR containing three copies of GCUUGC. This element interacts with multiple cytoplasmic trans-acting protein complexes (~175, 97, 63, 26, and 17 kDa) post-TGF-β1 treatment, and insertion of the 3'-UTR into a reporter gene confers TGF-β1-induced mRNA stability. mRNA half-life measurement, RNA-protein binding assays, deletion analysis of 3'-UTR, stable transfection of CAT reporter The Journal of biological chemistry High 8663000
1998 RHAMM isoforms regulate ERK activity. An intracellular isoform (RHAMMv4, encoding exon 4) co-immunoprecipitates with MEK1 and ERK; a dominant-negative RHAMMv4 inhibits mutant-active Ras activation of ERK; overexpression of RHAMMv4 constitutively activates ERK. Cell-surface RHAMM isoforms participate in PDGF-stimulated ERK activation. Co-immunoprecipitation, dominant-negative expression, ERK kinase assays, flow cytometry, confocal analysis, anti-exon-4 antibody blocking The Journal of biological chemistry High 9556628
1998 In human breast cancer cells, RHAMM is predominantly an intracellular protein localized in the cytoplasm (not the cell surface), as confirmed by subcellular fractionation. The intracellular RHAMM isoforms bind hyaluronan but not heparin or chondroitin sulfate, and a potential N-terminal HA-binding motif is not involved in this interaction. Subcellular fractionation, western blot, immunofluorescence, in vitro HA binding assay Journal of cell science High 9601098
1999 RHAMM/IHABP colocalizes with and directly binds microtubules via an N-terminal domain (comprising two subdomains: one sufficient for mitotic spindle binding, both required for interphase microtubule binding). RHAMM also interacts with actin filaments in vivo and in vitro, and binds calmodulin in a Ca2+-dependent manner via residues 574-602. GFP-fusion protein localization, microtubule-binding assays, deletion mutant transfection, calmodulin affinity chromatography, in vitro F-actin co-sedimentation Journal of cell science High 10547355
2001 In rat brain, RHAMM isoforms show differential subcellular distribution: 66 kDa and 85-90 kDa forms are enriched in soluble fractions, while the 75 kDa form localizes to mitochondria (non-intrinsic membrane association, liberated by alkali carbonate). Brain RHAMM binds calmodulin in a Ca2+-dependent manner via calmodulin affinity chromatography. Subcellular fractionation, western blot, calmodulin affinity chromatography, double immunohistochemistry with cytochrome oxidase Journal of neuroscience research Medium 11433424
2003 RHAMM localizes to centrosomes and is required for mitotic spindle integrity. The C-terminal domain (overlapping the HA-binding domain, bearing 72% identity to the dynein interaction domain of Xklp2) is required for centrosomal targeting, and RHAMM antibodies co-immunoprecipitate dynein IC from Xenopus and HeLa extracts. Deregulation of RHAMM expression inhibits mitotic progression and affects spindle architecture. Co-immunoprecipitation (dynein IC), deletion analysis for centrosomal targeting, immunofluorescence localization, RHAMM overexpression/depletion with spindle phenotype readout Molecular biology of the cell High 12808028
2004 Intracellular hyaluronan co-localizes with RHAMM and tubulin in the mitotic spindle of arterial smooth muscle cells. In permeabilized cells, fluorescein-hyaluronan binds to RHAMM-associated microtubules, suggesting intracellular HA-RHAMM-microtubule complexes in cell division. Immunofluorescence co-localization, permeabilized cell fluorescein-HA binding The journal of histochemistry and cytochemistry Low 15557208
2006 RHAMM (not CD44) mediates hyaluronan-induced vascular smooth muscle cell migration through a PI3K-dependent Rac activation pathway. siRNA knockdown of RHAMM inhibits both HA-induced migration and Rac activation, while CD44 knockdown inhibits RhoA activation but not migration. RHAMM and CD44 independently activate Rac and RhoA, respectively. siRNA knockdown, Rho/Rac pull-down activity assays, PI3K inhibitor (LY294002), migration assays, anti-CD44 antibody blocking Cardiovascular research High 16934786
2007 Cell-surface RHAMM and CD44 form a complex with ERK1/2 in invasive breast cancer cells, sustaining high basal ERK1/2 activation and rapid cell motility. This complex depends on endogenous HA synthesis and co-immunoprecipitates and co-localizes exclusively in highly motile/invasive MDA-MB-231 and Ras-MCF10A cells. Combined anti-CD44, anti-RHAMM, and MEK1 inhibitor treatment showed less-than-additive inhibition, consistent with a common signaling pathway. Co-immunoprecipitation, confocal co-localization, antibody blocking, MEK1 inhibitor (PD098059), motility assays The Journal of biological chemistry High 17392272
2007 RHAMM physically associates with RON (recepteur d'origine nantais, an HGF receptor family member) at the apex of ciliated airway epithelial cells, mediating low-molecular-weight HA fragment-induced increases in ciliary beat frequency. Co-immunoprecipitation confirmed the RHAMM-RON complex; RON inhibitor (beta-MSP) and tyrosine kinase inhibitor (genistein) blocked the HA-induced ciliary response. Co-immunoprecipitation, immunohistochemistry co-localization, function-blocking anti-RHAMM antibody, RON inhibitor, ciliary beat frequency measurement American journal of respiratory cell and molecular biology Medium 17395888
2008 RHAMM expression is regulated during the cell cycle, peaking at S/G2M phase, and is transcriptionally repressed by the tumor suppressor p53. p53-mediated repression acts via the RHAMM promoter (including first exon and first intron) as demonstrated by reporter assays in a p53-inducible system and with nutlin-3, doxorubicin, or paclitaxel treatment. Cell cycle synchronization, qRT-PCR, western blot, luciferase reporter assay, p53-inducible transgenic system, pharmacological p53 activation Cell cycle Medium 18971636
2010 Intracellular RHAMM (RHAMMΔ163) promotes interphase microtubule instability and mitotic spindle integrity through MEK1/ERK1/2 activity. RHAMM knockout MEFs show acetylated interphase microtubules, multipolar spindles, and aberrant cytokinesis, rescued by RHAMM or mutant-active MEK1 expression. RHAMM binds α- and β-tubulin via a C-terminal leucine zipper and directly binds ERK1 via a D-site motif; RHAMM-ERK1/2-MEK1-tubulin complexes were detected by co-IP and pulldown. RHAMM-/- MEF rescue experiments, mutant-active MEK1 expression, co-immunoprecipitation, pulldown assays, in vitro kinase assays, D-site motif mutation, immunofluorescence The Journal of biological chemistry High 20558733
2011 RHAMM mediates low-molecular-weight HA (LMWHA)-induced fibrosarcoma cell adhesion to fibronectin via ERK1/2 and focal adhesion kinase (FAK) phosphorylation. RHAMM-deficient (not CD44-deficient) HT1080 cells fail to adhere in response to LMWHA. ERK1/2 acts upstream of FAK in this pathway; ERK1/2 inhibition abolishes LMWHA-dependent adhesion. siRNA knockdown, western blot for ERK1/2 and FAK phosphorylation, ERK1/2 inhibitor, adhesion assays on fibronectin The Journal of biological chemistry High 21914806
2011 BRCA1 and RHAMM, together with AURKA and TPX2, regulate apicobasal polarity through reorganization of microtubules in MCF10A cells. BRCA1 facilitates microtubule reorganization, AURKA impairs it, and RHAMM and TPX2 regulate AURKA through a negative feedback loop. HMMR genetic variation modifies breast cancer risk in BRCA1 (but not BRCA2) mutation carriers. MCF10A polarization assays, AURKA/RHAMM/TPX2 knockdown, immunofluorescence, genetic association analysis PLoS biology Medium 22110403
2011 Rear polarization of the microtubule-organizing center (MTOC) in neointimal smooth muscle cells requires PKCα-phosphorylated RHAMM and ARPC5. RNA silencing of RHAMM, ARPC5 or PKC inhibition disrupts MTOC rear-polarization and inhibits neointimal SMC migration. RHAMM and ARPC5 were identified as PKC-phosphorylated proteins by phosphoproteomic screening and mass spectrometry. Phosphoproteomic screening, mass spectrometry, siRNA silencing, MTOC orientation assay, PKC inhibition, non-phosphorylatable ARPC5 mutant The American journal of pathology Medium 21281821
2012 HA induces an interaction between RHAMM and TGFβ receptor I (via CD44/PKCδ), and induction of PAI-1 is dependent on this RHAMM-TGFβRI interaction and downstream ERK signaling, promoting angiogenesis. Co-immunoprecipitation of RHAMM and TGFβRI, siRNA knockdown, cytokine arrays, endothelial tube formation assay Molecules and cells Medium 22610405
2012 A RHAMM-mimetic peptide (P15-1) specifically blocks hyaluronan oligosaccharide binding to recombinant RHAMM (but not CD44 or TLR2/4) and reduces wound macrophage number, fibroblast number, blood vessel density, and collagen/TGFβ1/αSMA in rat excisional wounds. The peptide was ineffective in RHAMM-/- mice, confirming RHAMM specificity. Signaling analysis showed P15-1 blocks RHAMM-regulated FAK pathways in fibroblasts. Phage display peptide selection, recombinant protein binding assay (Kd measurement), RHAMM-/- mouse comparison, wound repair histology, microarray/signaling analysis The American journal of pathology High 22889846
2013 RHAMM expression is regulated by YAP/TEAD transcription factor downstream of the Hippo and mevalonate pathways. YAP/TEAD directly binds the RHAMM promoter; simvastatin inhibits YAP nuclear localization, reducing RHAMM transcription and breast cancer cell migration/invasion. This regulation requires geranylgeranylation, Rho GTPase activation, and actin cytoskeleton rearrangement but is largely independent of MST/LATS kinase activity. YAP/TEAD ChIP on RHAMM promoter, reporter assays, siRNA knockdown, simvastatin treatment, RhoA inhibition, in vitro and in vivo migration/invasion assays Proceedings of the National Academy of Sciences High 24367099
2013 RHAMM forms an intracellular complex with β-catenin, protecting β-catenin from degradation and supporting its nuclear translocation, leading to c-Myc activation and enhanced fibrosarcoma cell proliferation. LMWHA-driven fibrosarcoma growth depends on this RHAMM/β-catenin/c-Myc axis. Co-immunoprecipitation, immunofluorescence, siRNA knockdown, western blot, proliferation assays Biochimica et biophysica acta Medium 26825774
2014 RHAMM is required for spatial regulation of Aurora kinase A (AURKA) activity during mitotic spindle assembly. RHAMM localizes to centrosomes and non-centrosomal kinetochore-proximal sites, is required for AURKA activation, and forms a complex with TPX2 via a C-terminal basic leucine zipper in RHAMM and a domain including the TPX2 NLS. RHAMM silencing delays spindle assembly, mislocalizes TPX2, attenuates AURKA activation, and reduces spindle length. Immunofluorescence localization, siRNA silencing, AURKA kinase activity measurement, co-immunoprecipitation of RHAMM-TPX2 complex, domain mapping Cell cycle High 24875404
2014 E2F1 directly upregulates RHAMM transcription, and RHAMM in turn acts as a co-activator of E2F1 to stimulate fibronectin expression. Enhanced fibronectin secretion links E2F1/RHAMM transcriptional activity to integrin-β1-FAK signaling, cytoskeletal remodeling, and tumor cell motility and extravasation. RHAMM depletion abolishes fibronectin expression and transmigration in E2F1-activated cells. ChIP/promoter analysis (E2F1 on RHAMM promoter), siRNA knockdown, fibronectin ELISA, transendothelial migration assay, in vivo xenograft extravasation model The Journal of pathology Medium 25042645
2015 HA and Hmmr are required for epicardial cell epithelial-mesenchymal transition (EMT) and migration into the regenerating zebrafish ventricle. Hmmr depletion blocks cardiac regeneration; chemical inhibition of FAK or Src (downstream of Hmmr) prevents epicardial cell migration, defining a HA/Hmmr/FAK/Src pathway in heart regeneration. Zebrafish hmmr morpholino knockdown, ventricular resection model, FAK/Src chemical inhibitors, proteomics identification, EMT marker analysis Cardiovascular research Medium 26156497
2016 Spindle-associated RHAMM regulates oriented (planar) division of testicular germ cells. RHAMM loss-of-function (caused by downregulation of CFIm25-mediated polyadenylation) dissociates RHAMM from the spindle, causes defective planar divisions, premature germ cell displacement, hypofertility, and seminoma. RHAMM association with the spindle was abolished in 96% of human seminomas. Mouse models, Hmmr immunostaining at spindle, human seminoma tissue analysis, CFIm25 knockdown, spindle orientation assay Cancer research Medium 27543603
2017 HMMR acts at centrosomes in a PLK1-dependent pathway to locate active Ran and modulate cortical NuMA-dynein complex localization for mitotic spindle positioning. Hmmr-knockout mice show neonatal lethality with defective neural development, and HMMR overexpression induces spindle orientation defects consistent with increased active Ran. This identifies HMMR as an essential regulator of progenitor cell division orientation. Hmmr-knockout mouse generation and analysis, HMMR overexpression in cancer cells, Ran activity assays, NuMA-dynein cortical localization analysis, spindle orientation measurements eLife High 28994651
2018 RHAMM acts as a co-activator in the nuclear transcription complex and also functions intracellularly to regulate ERK1/2 activation and MMP-9 expression in a cell-type-specific manner during wound repair. In fibroblasts, RHAMM promotes ERK1/2 activation and MMP-9 expression; in keratinocytes, RHAMM suppresses these activities. Loss of RHAMM in keratinocytes promotes EGFR-regulated MMP-9 expression via ERK1/2, causing CD44 ectodomain cleavage and increased keratinocyte motility. Rhamm-null mouse excisional wound model, ERK1/2 phosphorylation assays, MMP-9 expression analysis, CD44 ectodomain shedding assay, cell-specific migration assays The Journal of biological chemistry High 32165498
2018 BACH1 phosphorylation during mitosis promotes its interaction with HMMR (and CRM1) to stabilize mitotic spindle orientation. This interaction requires mitosis-specific phosphorylation of BACH1 (identified by SILAC mass spectrometry); mutation of these phosphorylation sites abolishes BACH1-HMMR interaction and spindle orientation rescue activity. SILAC mass spectrometry of BACH1 complexes, co-immunoprecipitation, phosphorylation-site mutagenesis, spindle orientation assay, BACH1 knockdown rescue experiments The Biochemical journal Medium 29459360
2019 The RHAMMB isoform (lacking a 15-amino-acid stretch present in RHAMMA) promotes PNET liver metastasis via EGFR signaling; EGFR knockdown abolishes RHAMMB-driven metastasis. RHAMMA does not promote metastasis. RHAMMB expression correlates with higher EGFR expression in pancreatic ductal adenocarcinoma. RNA-Seq isoform analysis, in vivo spontaneous and experimental metastasis mouse models, EGFR knockdown, tumor growth assays Molecular cancer Medium 31072393
2020 CD44/RHAMM complex formation is upregulated when cells interact with immobilized (but not soluble) hyaluronan, as demonstrated by FRET microscopy and co-immunoprecipitation. Expression of both CD44 and RHAMM is regulated via HA interactions in a cell-specific feedback loop. FRET microscopy, co-immunoprecipitation, immunocytochemistry in breast cancer cell lines with soluble vs. immobilized HA Acta biomaterialia Medium 33091625
2022 HMMR overexpression in mouse mammary epithelium increases BRCA1-mutant tumorigenesis by activating AURKA and reducing ARPC2 localization at the mitotic cell cortex, leading to micronucleation and activation of cGAS-STING and non-canonical NF-κB signaling, with downstream epithelial-to-mesenchymal transition and tumor-associated macrophage infiltration. HMMR-overexpressing transgenic mouse mammary model with Brca1 mutation, AURKA activity assays, ARPC2 cortical localization immunofluorescence, cGAS-STING pathway analysis, tumor microenvironment profiling Nature communications High 35393420
2023 HMMR alleviates ER stress by promoting autophagic lysosomal activity in hepatocellular carcinoma. Under ER stress, HMMR is transcriptionally induced by CHOP and degraded by TRIM29-mediated ubiquitination. Mechanistically, HMMR controls the intensity of ER stress by regulating autophagy. HBV-transgenic mouse model, luciferase reporter (CHOP on HMMR promoter), ChIP, co-immunoprecipitation, immunoprecipitation, ubiquitination assay, autophagy/ER stress marker analysis Cancer communications Medium 37405956
2023 HMMR interacts with AURKA and stabilizes AURKA protein by inhibiting its ubiquitination-mediated degradation, which subsequently activates the mTORC2/AKT pathway in prostate cancer. Activated mTORC2/AKT induces E2F1, which transcriptionally promotes HMMR expression, forming a positive feedback loop. mTOR inhibition partially antagonizes HMMR-mediated tumor progression in vivo. Co-immunoprecipitation (HMMR-AURKA), ubiquitination assay, gain/loss-of-function experiments, mTOR inhibitor in vivo, transcription factor (E2F1) promoter analysis Cell death discovery Medium 36750558

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Interactions between Hyaluronan and Its Receptors (CD44, RHAMM) Regulate the Activities of Inflammation and Cancer. Frontiers in immunology 655 25999946
1994 Identification of a common hyaluronan binding motif in the hyaluronan binding proteins RHAMM, CD44 and link protein. The EMBO journal 353 7508860
2006 Hyaluronan-mediated angiogenesis in vascular disease: uncovering RHAMM and CD44 receptor signaling pathways. Matrix biology : journal of the International Society for Matrix Biology 344 17055233
2013 Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility. Proceedings of the National Academy of Sciences of the United States of America 277 24367099
1995 Overexpression of the hyaluronan receptor RHAMM is transforming and is also required for H-ras transformation. Cell 252 7541721
2007 The hyaluronan receptors CD44 and Rhamm (CD168) form complexes with ERK1,2 that sustain high basal motility in breast cancer cells. The Journal of biological chemistry 216 17392272
2008 Cell-surface and mitotic-spindle RHAMM: moonlighting or dual oncogenic functions? Journal of cell science 190 18354082
1998 The hyaluronan receptor RHAMM regulates extracellular-regulated kinase. The Journal of biological chemistry 185 9556628
2007 RHAMM-R3 peptide vaccination in patients with acute myeloid leukemia, myelodysplastic syndrome, and multiple myeloma elicits immunologic and clinical responses. Blood 177 17978170
1995 Migration of bovine aortic smooth muscle cells after wounding injury. The role of hyaluronan and RHAMM. The Journal of clinical investigation 172 7533785
1999 The intracellular hyaluronan receptor RHAMM/IHABP interacts with microtubules and actin filaments. Journal of cell science 153 10547355
2003 RHAMM is a centrosomal protein that interacts with dynein and maintains spindle pole stability. Molecular biology of the cell 149 12808028
2012 Hyaluronic acid promotes angiogenesis by inducing RHAMM-TGFβ receptor interaction via CD44-PKCδ. Molecules and cells 135 22610405
1993 Identification of two hyaluronan-binding domains in the hyaluronan receptor RHAMM. The Journal of biological chemistry 132 7682552
1996 pp60(c-src) is required for cell locomotion regulated by the hyaluronanreceptor RHAMM. Oncogene 117 8950989
2011 Role of receptor for hyaluronic acid-mediated motility (RHAMM) in low molecular weight hyaluronan (LMWHA)-mediated fibrosarcoma cell adhesion. The Journal of biological chemistry 115 21914806
2014 HMMR maintains the stemness and tumorigenicity of glioblastoma stem-like cells. Cancer research 110 24710409
2002 Receptor for hyaluronan acid-mediated motility (RHAMM) is a new immunogenic leukemia-associated antigen in acute and chronic myeloid leukemia. Experimental hematology 106 12225794
2012 A RHAMM mimetic peptide blocks hyaluronan signaling and reduces inflammation and fibrogenesis in excisional skin wounds. The American journal of pathology 104 22889846
2009 Oligosaccharides of hyaluronan induce angiogenesis through distinct CD44 and RHAMM-mediated signalling pathways involving Cdc2 and gamma-adducin. International journal of oncology 104 19724912
2014 Hyaluronan and RHAMM in wound repair and the "cancerization" of stromal tissues. BioMed research international 102 25157350
1998 The human hyaluronan receptor RHAMM is expressed as an intracellular protein in breast cancer cells. Journal of cell science 101 9601098
2005 Identification and characterization of epitopes of the receptor for hyaluronic acid-mediated motility (RHAMM/CD168) recognized by CD8+ T cells of HLA-A2-positive patients with acute myeloid leukemia. Blood 98 15827130
2005 Expression and role of the hyaluronan receptor RHAMM in inflammation after bleomycin injury. American journal of respiratory cell and molecular biology 94 16037485
2006 Hyaluronan induces vascular smooth muscle cell migration through RHAMM-mediated PI3K-dependent Rac activation. Cardiovascular research 92 16934786
2008 RHAMM is differentially expressed in the cell cycle and downregulated by the tumor suppressor p53. Cell cycle (Georgetown, Tex.) 91 18971636
2007 Apical oxidative hyaluronan degradation stimulates airway ciliary beating via RHAMM and RON. American journal of respiratory cell and molecular biology 91 17395888
2011 Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer. PLoS biology 87 22110403
1999 Overexpression of the receptor for hyaluronan-mediated motility (RHAMM) characterizes the malignant clone in multiple myeloma: identification of three distinct RHAMM variants. Blood 84 10029598
2003 Genetic deletion of receptor for hyaluronan-mediated motility (Rhamm) attenuates the formation of aggressive fibromatosis (desmoid tumor). Oncogene 82 14534534
2010 RHAMM promotes interphase microtubule instability and mitotic spindle integrity through MEK1/ERK1/2 activity. The Journal of biological chemistry 79 20558733
2000 Expression of hyaluronan receptors CD44 and RHAMM in stomach cancers: relevance with tumor progression. International journal of oncology 76 11029494
2015 Extracellular component hyaluronic acid and its receptor Hmmr are required for epicardial EMT during heart regeneration. Cardiovascular research 73 26156497
2009 RHAMM (CD168) is overexpressed at the protein level and may constitute an immunogenic antigen in advanced prostate cancer disease. Neoplasia (New York, N.Y.) 69 19724689
2004 Intracellular hyaluronan in arterial smooth muscle cells: association with microtubules, RHAMM, and the mitotic spindle. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 69 15557208
2020 Hyaluronan Mediated Motility Receptor (HMMR) Encodes an Evolutionarily Conserved Homeostasis, Mitosis, and Meiosis Regulator Rather than a Hyaluronan Receptor. Cells 68 32231069
1995 Hyaluronan: RHAMM mediated cell locomotion and signaling in tumorigenesis. Journal of neuro-oncology 68 8750188
2020 HCG18/miR-34a-5p/HMMR axis accelerates the progression of lung adenocarcinoma. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 67 32559619
2018 Hyaluronan-CD44/RHAMM interaction-dependent cell proliferation and survival in lung cancer cells. Molecular carcinogenesis 67 30365189
1993 Ras-transformed cells express both CD44 and RHAMM hyaluronan receptors: only RHAMM is essential for hyaluronan-promoted locomotion. Experimental cell research 67 7688314
2001 The pattern of expression of the microtubule-binding protein RHAMM/IHABP in mammary carcinoma suggests a role in the invasive behaviour of tumour cells. The Journal of pathology 66 11592098
2022 Exosomal lncRNA HMMR-AS1 mediates macrophage polarization through miR-147a/ARID3A axis under hypoxia and affects the progression of hepatocellular carcinoma. Environmental toxicology 65 35179300
2018 Hyaluronic acid, CD44 and RHAMM regulate myoblast behavior during embryogenesis. Matrix biology : journal of the International Society for Matrix Biology 65 30130585
2006 Expression of RHAMM/CD168 and other tumor-associated antigens in patients with B-cell chronic lymphocytic leukemia. International journal of oncology 62 16773189
1996 Differential expression of the hyaluronan receptors CD44 and RHAMM in human pancreatic cancer cells. Clinical cancer research : an official journal of the American Association for Cancer Research 61 9816340
2013 The roles of hyaluronan/RHAMM/CD44 and their respective interactions along the insidious pathways of fibrosarcoma progression. BioMed research international 56 24083250
1996 The characterization of a human RHAMM cDNA: conservation of the hyaluronan-binding domains. Gene 53 8890751
2012 TCR-transgenic lymphocytes specific for HMMR/Rhamm limit tumor outgrowth in vivo. Blood 52 22371883
1995 Characterization of the murine gene encoding the hyaluronan receptor RHAMM. Gene 51 7590272
2017 Triptolide suppresses the in vitro and in vivo growth of lung cancer cells by targeting hyaluronan-CD44/RHAMM signaling. Oncotarget 50 28460475
2017 The hyaluronan-mediated motility receptor RHAMM promotes growth, invasiveness and dissemination of colorectal cancer. Oncotarget 50 29050306
2019 LncRNA HMMR-AS1 promotes proliferation and metastasis of lung adenocarcinoma by regulating MiR-138/sirt6 axis. Aging 49 31128573
2017 HMMR acts in the PLK1-dependent spindle positioning pathway and supports neural development. eLife 49 28994651
2018 Targeting Long Noncoding RNA HMMR-AS1 Suppresses and Radiosensitizes Glioblastoma. Neoplasia (New York, N.Y.) 45 29574252
2018 The Receptor for Hyaluronan-Mediated Motility (CD168) promotes inflammation and fibrosis after acute lung injury. Matrix biology : journal of the International Society for Matrix Biology 45 30098420
1994 Astrocyte and microglial motility in vitro is functionally dependent on the hyaluronan receptor RHAMM. Glia 44 7531178
2014 Spatial regulation of Aurora A activity during mitotic spindle assembly requires RHAMM to correctly localize TPX2. Cell cycle (Georgetown, Tex.) 41 24875404
1996 Transforming growth factor-beta1 stimulates multiple protein interactions at a unique cis-element in the 3'-untranslated region of the hyaluronan receptor RHAMM mRNA. The Journal of biological chemistry 41 8663000
2020 Co-localization and crosstalk between CD44 and RHAMM depend on hyaluronan presentation. Acta biomaterialia 40 33091625
2017 Redox Responsive Hyaluronic Acid Nanogels for Treating RHAMM (CD168) Over-expressive Cancer, both Primary and Metastatic Tumors. Theranostics 40 28529647
2015 Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers. PloS one 40 25830658
2022 Modification of BRCA1-associated breast cancer risk by HMMR overexpression. Nature communications 39 35393420
2023 Resveratrol improves the cytotoxic effect of CD8 +T cells in the tumor microenvironment by regulating HMMR/Ferroptosis in lung squamous cell carcinoma. Journal of pharmaceutical and biomedical analysis 38 37001272
2019 Function and clinical relevance of RHAMM isoforms in pancreatic tumor progression. Molecular cancer 38 31072393
2015 Expression of the hyaluronan-mediated motility receptor RHAMM in tumor budding cells identifies aggressive colorectal cancers. Human pathology 38 26351067
2014 Association of RHAMM with E2F1 promotes tumour cell extravasation by transcriptional up-regulation of fibronectin. The Journal of pathology 38 25042645
1994 Identification of a novel heparin binding domain in RHAMM and evidence that it modifies HA mediated locomotion of ras-transformed cells. Journal of cellular biochemistry 38 7534313
2008 A putative role for RHAMM/HMMR as a negative marker of stem cell-containing population of human limbal epithelial cells. Stem cells (Dayton, Ohio) 36 18356573
2013 The impact of the receptor of hyaluronan-mediated motility (RHAMM) on human urothelial transitional cell cancer of the bladder. PloS one 35 24069434
2021 RHAMM Is a Multifunctional Protein That Regulates Cancer Progression. International journal of molecular sciences 32 34638654
2001 Subcellular distribution, calmodulin interaction, and mitochondrial association of the hyaluronan-binding protein RHAMM in rat brain. Journal of neuroscience research 32 11433424
2017 Increased RHAMM expression relates to ovarian cancer progression. Journal of ovarian research 31 28954627
2014 Role of receptor for hyaluronan-mediated motility (RHAMM) in human head and neck cancers. Journal of cancer research and clinical oncology 31 24676428
2014 Hyaluronan/RHAMM interactions in mesenchymal tumor pathogenesis: role of growth factors. Advances in cancer research 31 25081535
2016 Receptor for hyaluronic acid- mediated motility (RHAMM) regulates HT1080 fibrosarcoma cell proliferation via a β-catenin/c-myc signaling axis. Biochimica et biophysica acta 30 26825774
2012 ANKRD26 and its interacting partners TRIO, GPS2, HMMR and DIPA regulate adipogenesis in 3T3-L1 cells. PloS one 30 22666460
2011 Rear polarization of the microtubule-organizing center in neointimal smooth muscle cells depends on PKCα, ARPC5, and RHAMM. The American journal of pathology 30 21281821
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2017 Receptor for hyaluronan mediated motility (RHAMM/HMMR) is a novel target for promoting subcutaneous adipogenesis. Integrative biology : quantitative biosciences from nano to macro 29 28217782
2010 RHAMM mRNA expression in proliferating and migrating cells of the developing central nervous system. Gene expression patterns : GEP 29 20044037
2016 Impaired Planar Germ Cell Division in the Testis, Caused by Dissociation of RHAMM from the Spindle, Results in Hypofertility and Seminoma. Cancer research 28 27543603
2012 RHAMM/HMMR (CD168) is not an ideal target antigen for immunotherapy of acute myeloid leukemia. Haematologica 28 22532518
1998 The hyaluronan receptor RHAMM in noradrenergic fibers contributes to axon growth capacity of locus coeruleus neurons in an intraocular transplant model. Neuroscience 28 9692758
2023 HMMR alleviates endoplasmic reticulum stress by promoting autophagolysosomal activity during endoplasmic reticulum stress-driven hepatocellular carcinoma progression. Cancer communications (London, England) 26 37405956
1999 Characterisation of the murine gene encoding the intracellular hyaluronan receptor IHABP (RHAMM). Gene 26 9889313
2024 FIGNL1 Promotes Hepatocellular Carcinoma Formation via Remodeling ECM-receptor Interaction Pathway Mediated by HMMR. Current gene therapy 25 37929733
2020 Oleate acid-stimulated HMMR expression by CEBPα is associated with nonalcoholic steatohepatitis and hepatocellular carcinoma. International journal of biological sciences 25 33061798
2005 Integrative genomics based identification of potential human hepatocarcinogenesis-associated cell cycle regulators: RHAMM as an example. Biochemical and biophysical research communications 25 15796909
2003 Developmental regulation of hyaluronan-binding protein (RHAMM/IHABP) expression in early bovine embryos. Biology of reproduction 25 12493696
2023 HMMR promotes prostate cancer proliferation and metastasis via AURKA/mTORC2/E2F1 positive feedback loop. Cell death discovery 24 36750558
2016 CD44 and RHAMM are essential for rapid growth of bladder cancer driven by loss of Glycogen Debranching Enzyme (AGL). BMC cancer 24 27595989
2021 High levels of truncated RHAMM cooperate with dysfunctional p53 to accelerate the progression of pancreatic cancer. Cancer letters 23 34044069
2016 HMMR antisense RNA 1, a novel long noncoding RNA, regulates the progression of basal-like breast cancer cells. Breast cancer (Dove Medical Press) 23 27920576
2006 Imatinib impairs CD8+ T lymphocytes specifically directed against the leukemia-associated antigen RHAMM/CD168 in vitro. Cancer immunology, immunotherapy : CII 23 17009043
2018 Phosphorylation of BACH1 switches its function from transcription factor to mitotic chromosome regulator and promotes its interaction with HMMR. The Biochemical journal 22 29459360
2017 Hyaluronic acid enhances cell migration and invasion via the YAP1/TAZ-RHAMM axis in malignant pleural mesothelioma. Oncotarget 22 29212185
2008 Androgen receptor regulates CD168 expression and signaling in prostate cancer. Carcinogenesis 22 18174258
2022 Serum Proteins, HMMR, NXPH4, PITX1 and THBS4; A Panel of Biomarkers for Early Diagnosis of Hepatocellular Carcinoma. Journal of clinical medicine 21 35456219
2020 Cell-specific expression of the transcriptional regulator RHAMM provides a timing mechanism that controls appropriate wound re-epithelialization. The Journal of biological chemistry 21 32165498
2013 The cytoskeletal protein RHAMM and ERK1/2 activity maintain the pluripotency of murine embryonic stem cells. PloS one 21 24019927