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Gene Review

HMMR  -  hyaluronan-mediated motility receptor (RHAMM)

Homo sapiens

Synonyms: CD168, Hyaluronan mediated motility receptor, IHABP, Intracellular hyaluronic acid-binding protein, RHAMM, ...
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Disease relevance of HMMR


High impact information on HMMR

  • HMMR/RHAMM is an in vitro substrate for BRCA1-BARD1–mediated polyubiquitination and BRCA1 and HMMR genetically interact to control centrosome number in breast tumor– and mammary epithelium–derived cell lines [3]

  • BRCA1/BARD1 modulate spindle assembly through a pathway which attenuates RHAMM function [6]
  • Overexpression of the RHAMM gene by transfection into fibroblasts is transforming and causes spontaneous metastases in the lung [7].
  • H-ras-transformed fibrosarcomas transfected with a dominant suppressor mutant of RHAMM exhibit a so-called revertant phenotype and are completely nontumorigenic and nonmetastatic [7].
  • The loss of functional RHAMM ablates signaling within focal adhesions, in particular changes in focal adhesion kinase phosphorylation, and as a result these focal adhesions are unable to turn over in response to hyaluronan [7].
  • Recombinant techniques were used to generate chimeric proteins containing either the B(X7)B motifs present in CD44 or link protein, with the amino-terminus of RHAMM (amino acids 1-238) that does not bind HA [8].
  • 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 [9].

Chemical compound and disease context of HMMR


Biological context of HMMR

  • Like TPX2, RHAMM expression is up-regulated during mitosis [1].
  • We postulate that augmentation of RHAMM expression within human cancers, including myeloma, can directly affect centrosomal structure and spindle integrity and potentially modulate apoptotic and cell cycle progression pathways [1].
  • A receptor for hyaluronan-mediated motility (RHAMM) has been shown to promote cell locomotion [13].
  • Here we describe the expression of two human RHAMM isoforms, which are generated by alternative splicing of the primary gene transcript, by a series of human breast carcinoma cell lines [2].
  • This interaction domain is composed of two distinct subdomains, one of which is sufficient to mediate binding to the mitotic spindle while both domains are required for binding of RHAMM/IHABP proteins to interphase microtubules [14].

Anatomical context of HMMR

  • Potential role for hyaluronan and the hyaluronan receptor RHAMM in mobilization and trafficking of hematopoietic progenitor cells [15].
  • CD34(+)45(lo/med)Scatterlo/med HPCs from granulocyte colony-stimulating factor (G-CSF)-mobilized blood and mobilized BM were compared with steady-state BM for their ability to bind hyaluronan (HA), their expression of the HA receptors RHAMM and CD44, and their motogenic behavior [15].
  • Elevated expression of receptor for hyaluronan-mediated motility (RHAMM) within ex vivo diagnostic multiple myeloma plasma cells predicts for aggressive disease and patient survival [1].
  • We confirm a previous study showing that the amino terminus of RHAMM interacts with microtubules and further demonstrate that a separate carboxy-terminal domain is required for centrosomal targeting [16].
  • The apparently strong negative regulatory control over RHAMM expression by microenvironmental factors and by known thymic and T cell signaling molecules supports this view [13].

Associations of HMMR with chemical compounds

  • These observations are consistent with the view that cyclosporin A inactivates a RHAMM-directed inhibitory mechanism [13].
  • RHAMM proteins were capable of binding to hyaluronan, but not to heparin or chondroitin sulphate, in an vitro binding assay [2].
  • PURPOSE: Interactions of hyaluronic acid (HA) with its binding protein RHAMM (receptor for HA-mediated motility) have been proposed as being important in promoting tumour progression and dissemination [17].
  • High-avidity interactions via integrins appear to supercede the motogenicity of RHAMM and HA, suggesting that integrin avidity may regulate RHAMM [18].
  • During short-term tissue culture, Mo upregulated their HA avidity and expression of ICAM-1, CD44s, and epitopes encoded by CD44v, all of which were further augmented by IFN-gamma or lipopolysaccharide, whereas RHAMM was not detectable [19].

Physical interactions of HMMR

  • CD44 binds approximately five times more HA than RHAMM as determined by densitometric analysis of transblots, indicating that this protein is the major HA receptor on fibroblasts [20].

Regulatory relationships of HMMR


Other interactions of HMMR

  • Our results further demonstrate that both CD44 and receptor for hyaluronan-mediated motility (RHAMM) are involved in binding cell surface associated HA on Hfob cells [23].
  • Culture of MN thymocytes on thymic epithelial layers, with or without IL-2, resulted in a lack of RHAMM expression [13].
  • RHAMM is differentially expressed: significant mRNA expression was not found in normal tissues, except from testis, placenta, and thymus, or in PBMN- and CD34-separated cell samples of healthy volunteers [5].
  • As others have shown that excess pericentriolar material strongly associates with abnormal mitoses, we modeled centrosomal abnormalities with exogenous RHAMM overexpression [1].
  • The receptor for hyaluronan-mediated motility (RHAMM), an acidic coiled coil protein, has previously been characterized as a cell surface receptor for hyaluronan, and a microtubule-associated intracellular hyaluronan binding protein [16].

Analytical, diagnostic and therapeutic context of HMMR

  • A polyclonal antibody, raised against a bacterially expressed RHAMM fusion protein, detected an 85-90 kDa protein by western blot analysis [2].
  • CONCLUSIONS: RHAMM is an immunogenic antigen in leukemias and solid tumors and might be a potential target structure for cellular immunotherapies and antibody therapies [5].
  • METHODS: We examined a series of 89 endometrial carcinomas and 15 normal endometrial tissues by immunohistochemistry, using a RHAMM-specific polyclonal antibody [17].
  • To assess whether this motif predicts HA binding in the intact RHAMM protein, we mutated all basic amino acids in domains I and II that form part of these motifs using site-directed mutagenesis and prepared fusion protein from the mutated cDNA [8].
  • Moreover, confocal microscopy showed a polarized distribution of RHAMM and F-actin, but not CD44, in cells which had become motile on HA in the presence of IL-8 [24].


  1. Receptor for hyaluronan-mediated motility correlates with centrosome abnormalities in multiple myeloma and maintains mitotic integrity. Maxwell, C.A., Keats, J.J., Belch, A.R., Pilarski, L.M., Reiman, T. Cancer Res. (2005) [Pubmed]
  2. The human hyaluronan receptor RHAMM is expressed as an intracellular protein in breast cancer cells. Assmann, V., Marshall, J.F., Fieber, C., Hofmann, M., Hart, I.R. J. Cell. Sci. (1998) [Pubmed]
  3. Network modeling links breast cancer susceptibility and centrosome dysfunction. Pujana, M.A., Han, J.D., Starita, L.M., Stevens, K.N., Tewari, M., Ahn, J.S., Rennert, G., Moreno, V., Kirchhoff, T., Gold, B., Assmann, V., Elshamy, W.M., Rual, J.F., Levine, D., Rozek, L.S., Gelman, R.S., Gunsalus, K.C., Greenberg, R.A., Sobhian, B., Bertin, N., Venkatesan, K., Ayivi-Guedehoussou, N., Solé, X., Hernández, P., Lázaro, C., Nathanson, K.L., Weber, B.L., Cusick, M.E., Hill, D.E., Offit, K., Livingston, D.M., Gruber, S.B., Parvin, J.D., Vidal, M. Nat. Genet. (2007) [Pubmed]
  4. Hyaluronan-mediated motility receptor gene single nucleotide polymorphisms and risk of breast cancer. Kalmyrzaev, B., Pharoah, P.D., Easton, D.F., Ponder, B.A., Dunning, A.M. Cancer. Epidemiol. Biomarkers. Prev. (2008) [Pubmed]
  5. Receptor for hyaluronan acid-mediated motility (RHAMM) is a new immunogenic leukemia-associated antigen in acute and chronic myeloid leukemia. Greiner, J., Ringhoffer, M., Taniguchi, M., Schmitt, A., Kirchner, D., Krähn, G., Heilmann, V., Gschwend, J., Bergmann, L., Döhner, H., Schmitt, M. Exp. Hematol. (2002) [Pubmed]
  6. The BRCA1/BARD1 heterodimer modulates ran-dependent mitotic spindle assembly. Joukov, V., Groen, A.C., Prokhorova, T., Gerson, R., White, E., Rodriguez, A., Walter, J.C., Livingston, D.M. Cell. (2006) [Pubmed]
  7. Overexpression of the hyaluronan receptor RHAMM is transforming and is also required for H-ras transformation. Hall, C.L., Yang, B., Yang, X., Zhang, S., Turley, M., Samuel, S., Lange, L.A., Wang, C., Curpen, G.D., Savani, R.C., Greenberg, A.H., Turley, E.A. Cell (1995) [Pubmed]
  8. Identification of a common hyaluronan binding motif in the hyaluronan binding proteins RHAMM, CD44 and link protein. Yang, B., Yang, B.L., Savani, R.C., Turley, E.A. EMBO J. (1994) [Pubmed]
  9. 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. Greiner, J., Li, L., Ringhoffer, M., Barth, T.F., Giannopoulos, K., Guillaume, P., Ritter, G., Wiesneth, M., Döhner, H., Schmitt, M. Blood (2005) [Pubmed]
  10. CD44 is the principal mediator of hyaluronic-acid-induced melanoma cell proliferation. Ahrens, T., Assmann, V., Fieber, C., Termeer, C., Herrlich, P., Hofmann, M., Simon, J.C. J. Invest. Dermatol. (2001) [Pubmed]
  11. Hyaluronate receptors mediating glioma cell migration and proliferation. Akiyama, Y., Jung, S., Salhia, B., Lee, S., Hubbard, S., Taylor, M., Mainprize, T., Akaishi, K., van Furth, W., Rutka, J.T. J. Neurooncol. (2001) [Pubmed]
  12. Identification of two hyaluronan-binding domains in the hyaluronan receptor RHAMM. Yang, B., Zhang, L., Turley, E.A. J. Biol. Chem. (1993) [Pubmed]
  13. Regulated expression of a receptor for hyaluronan-mediated motility on human thymocytes and T cells. Pilarski, L.M., Miszta, H., Turley, E.A. J. Immunol. (1993) [Pubmed]
  14. The intracellular hyaluronan receptor RHAMM/IHABP interacts with microtubules and actin filaments. Assmann, V., Jenkinson, D., Marshall, J.F., Hart, I.R. J. Cell. Sci. (1999) [Pubmed]
  15. Potential role for hyaluronan and the hyaluronan receptor RHAMM in mobilization and trafficking of hematopoietic progenitor cells. Pilarski, L.M., Pruski, E., Wizniak, J., Paine, D., Seeberger, K., Mant, M.J., Brown, C.B., Belch, A.R. Blood (1999) [Pubmed]
  16. RHAMM is a centrosomal protein that interacts with dynein and maintains spindle pole stability. Maxwell, C.A., Keats, J.J., Crainie, M., Sun, X., Yen, T., Shibuya, E., Hendzel, M., Chan, G., Pilarski, L.M. Mol. Biol. Cell (2003) [Pubmed]
  17. Expression of the hyaluronan receptor RHAMM in endometrial carcinomas suggests a role in tumour progression and metastasis. Rein, D.T., Roehrig, K., Schöndorf, T., Lazar, A., Fleisch, M., Niederacher, D., Bender, H.G., Dall, P. J. Cancer Res. Clin. Oncol. (2003) [Pubmed]
  18. During human thymic development, beta 1 integrins regulate adhesion, motility, and the outcome of RHAMM/hyaluronan engagement. Gares, S.L., Giannakopoulos, N., MacNeil, D., Faull, R.J., Pilarski, L.M. J. Leukoc. Biol. (1998) [Pubmed]
  19. Activation-dependent modulation of hyaluronate-receptor expression and of hyaluronate-avidity by human monocytes. Weiss, J.M., Renkl, A.C., Ahrens, T., Moll, J., Mai, B.H., Denfeld, R.W., Schöpf, E., Ponta, H., Herrlich, P., Simon, J.C. J. Invest. Dermatol. (1998) [Pubmed]
  20. Ras-transformed cells express both CD44 and RHAMM hyaluronan receptors: only RHAMM is essential for hyaluronan-promoted locomotion. Turley, E.A., Austen, L., Moore, D., Hoare, K. Exp. Cell Res. (1993) [Pubmed]
  21. Differential involvement of the hyaluronan (HA) receptors CD44 and receptor for HA-mediated motility in endothelial cell function and angiogenesis. Savani, R.C., Cao, G., Pooler, P.M., Zaman, A., Zhou, Z., DeLisser, H.M. J. Biol. Chem. (2001) [Pubmed]
  22. The overexpression of RHAMM, a hyaluronan-binding protein that regulates ras signaling, correlates with overexpression of mitogen-activated protein kinase and is a significant parameter in breast cancer progression. Wang, C., Thor, A.D., Moore, D.H., Zhao, Y., Kerschmann, R., Stern, R., Watson, P.H., Turley, E.A. Clin. Cancer Res. (1998) [Pubmed]
  23. Secretory products of breast cancer cells upregulate hyaluronan production in a human osteoblast cell line. Bose, N., Masellis, A.M. Clin. Exp. Metastasis (2005) [Pubmed]
  24. The role of hyaluronan and interleukin 8 in the migration of chronic lymphocytic leukemia cells within lymphoreticular tissues. Till, K.J., Zuzel, M., Cawley, J.C. Cancer Res. (1999) [Pubmed]
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