Biology:Hyaluronan-mediated motility receptor

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Hyaluronan-mediated motility receptor (HMMR), also known as RHAMM (Receptor for Hyaluronan Mediated Motility) is a protein which in humans is encoded by the HMMR gene.[1] RHAMM recently has been also designated CD168 (cluster of differentiation 168).

Function

RHAMM was originally discovered as a soluble protein that altered migratory cell behavior and bound to hyaluronan.[2] RHAMM is less well studied than the main hyaluronan (HA) receptor, CD44. In contrast to CD44 and other cell-surface receptors which contain the classical membrane spanning domain and signal sequence for secretion from the endoplasmic reticulum / Golgi complex, RHAMM does not contain a membrane spanning domain nor does the mRNA transcript contain a signal sequence. RHAMM is localized inside the cell and is unconventionally exported to the cell surface in response to certain defined stimuli such as wounding and cytokines including TGF-β.[3] The precise unconventional export mechanism for transporting RHAMM to the extracellular space is still unclear but may involve transport channels or proteins, flippase activity, or exocytosis, similar to other non-conventionally exported cell surface proteins such as BFGF1,2 and epimorphin.[4]

Intracellularly, RHAMM associates with microtubules and, working with BRCA1 and BARD1, plays a role in the regulation of mitosis,[4][5][6] and in maintaining mitotic spindle integrity.[7] RHAMM also binds directly with ERK1 and forms complexes with ERK1,2 and MEK1,[7] suggesting a role as a scaffold protein that targets these MAP kinases to the nucleus.[8]

Extracellularly, RHAMM associates with CD44, and upon binding to hyaluronan, activates intracellular signaling pathways, mainly the MAPK pathway via ERK1,2 activation[9] Variants of RHAMM caused by alternative splicing have been observed, and alternative start codon usage has been proposed in mice and directly observed in humans.[1]

Clinical significance

RHAMM is over expressed in breast cancer and its expression in triple negative and HER2 subtypes is associated with poor outcome.[10] Alternatively spliced forms of RHAMM may be up regulated in some tumor types, promoting tumor progression.[11] The presence of breast tumor cell subsets with high RHAMM expression is associated with reduced metastasis free survival[12] and mediates migration, transformation, and metastatic spread of the triple negative human BCa cell line MDA-MB-231.[13]

Elevated levels of RHAMM and hyaluronan are associated with the likelihood of undergoing biochemical failure in intermediate risk prostate cancer patients.[14] RHAMM is also one of 3 biomarkers associated with aggressiveness in a multivariate analysis of human prostate tumors[15] and elevated levels of RHAMM are associated with both androgen deprivation therapy and castration resistant disease.[16] RHAMM has also been identified as one of 4 gene products identified in circulating tumor cells in patients with lung adenocarcinoma.[17]

While RHAMM has been less studied than CD44 in the process of cancer metastasis, it is likely just as important in this process and can act in concert with, or independently of CD44 to promote cell motility. Increased RHAMM expression is correlated with metastases in colorectal cancer, among others.[18] Mechanistically, RHAMM has been shown to promote cell motility through a number of different pathways. As with CD44, RHAMM can promote focal adhesion turnover by controlling focal adhesion kinase (FAK) phosphorylation and cooperating with the α4β1 and α5β1 integrins.[19] RHAMM also activates a number of downstream kinases including enhancing the intensity and sustaining the duration of ERK1 / ERK2 activation through the map kinase (MAPK) pathway, pp60 (c-src), and the downstream targets of rho kinase (ROK).[20] Finally, once a metastatic lesion has been established, RHAMM can cooperate with CD44 to promote angiogenesis by promoting migration of neighboring endothelial cells towards the tumor.[21]

References

  1. ↑ 1.0 1.1 "Entrez Gene: HMMR hyaluronan-mediated motility receptor (RHAMM)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3161. 
  2. ↑ "Purification of a hyaluronate-binding protein fraction that modifies cell social behavior". Biochemical and Biophysical Research Communications 108 (3): 1016–1024. Oct 1982. doi:10.1016/0006-291X(82)92101-5. PMID 6185115. 
  3. ↑ "Molecular cloning of a novel hyaluronan receptor that mediates tumor cell motility". The Journal of Cell Biology 117 (6): 1343–1350. Jun 1992. doi:10.1083/jcb.117.6.1343. PMID 1376732. 
  4. ↑ 4.0 4.1 "RHAMM is a centrosomal protein that interacts with dynein and maintains spindle pole stability". Molecular Biology of the Cell 14 (6): 2262–2276. June 2003. doi:10.1091/mbc.E02-07-0377. PMID 12808028. 
  5. ↑ "The BRCA1/BARD1 heterodimer modulates ran-dependent mitotic spindle assembly". Cell 127 (3): 539–552. Nov 2006. doi:10.1016/j.cell.2006.08.053. PMID 17081976. 
  6. ↑ "Network modeling links breast cancer susceptibility and centrosome dysfunction". Nature Genetics 39 (11): 1338–1349. Nov 2007. doi:10.1038/ng.2007.2. PMID 17922014. 
  7. ↑ 7.0 7.1 "RHAMM promotes interphase microtubule instability and mitotic spindle integrity through MEK1/ERK1/2 activity". The Journal of Biological Chemistry 285 (34): 26461–26474. Aug 2010. doi:10.1074/jbc.M110.121491. PMID 20558733. 
  8. ↑ "How does a protein with dual mitotic spindle and extracellular matrix receptor functions affect tumor susceptibility and progression?". Communicative & Integrative Biology 4 (2): 182–185. Mar 2011. doi:10.4161/cib.4.2.14270. PMID 21655434. 
  9. ↑ "Hyaluronan and a cell-associated hyaluronan binding protein regulate the locomotion of ras-transformed cells". The Journal of Cell Biology 112 (5): 1041–1047. Mar 1991. doi:10.1083/jcb.112.5.1041. PMID 1705559. 
  10. ↑ "ONCOMINE: a cancer microarray database and integrated data-mining platform". Neoplasia 6 (1): 1–6. 2004. doi:10.1016/S1476-5586(04)80047-2. PMID 15068665. 
  11. ↑ "Overexpression of the receptor for hyaluronan-mediated motility (RHAMM) characterizes the malignant clone in multiple myeloma: identification of three distinct RHAMM variants". Blood 93 (5): 1684–1696. Mar 1999. doi:10.1182/blood.V93.5.1684. PMID 10029598. http://www.bloodjournal.org/content/bloodjournal/93/5/1684.full.pdf. 
  12. ↑ "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". Clinical Cancer Research 4 (3): 567–576. Mar 1998. PMID 9533523. http://clincancerres.aacrjournals.org/content/4/3/567.long. 
  13. ↑ "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 111 (1): E89–E98. Jan 2014. doi:10.1073/pnas.1319190110. PMID 24367099. Bibcode: 2014PNAS..111E..89W. 
  14. ↑ "Elevated hyaluronan and hyaluronan-mediated motility receptor are associated with biochemical failure in patients with intermediate-grade prostate tumors". Cancer 120 (12): 1800–1809. Jun 2014. doi:10.1002/cncr.28646. PMID 24668563. 
  15. ↑ "Evaluation of protein biomarkers of prostate cancer aggressiveness". BMC Cancer 14: 244. Apr 2014. doi:10.1186/1471-2407-14-244. PMID 24708576. 
  16. ↑ "Hyaluronan-mediated motility receptor (RHAMM) immunohistochemical expression and androgen deprivation in normal peritumoral, hyperplasic and neoplastic prostate tissue". BJU International 113 (5): 822–829. May 2014. doi:10.1111/bju.12339. PMID 24053431. 
  17. ↑ "Newly identified biomarkers for detecting circulating tumor cells in lung adenocarcinoma". The Tohoku Journal of Experimental Medicine 234 (1): 29–40. Sep 2014. doi:10.1620/tjem.234.29. PMID 25175030. 
  18. ↑ "Alternative splicing of RHAMM gene in chinese gastric cancers and its in vitro regulation" (in zh). Zhonghua Yi Xue Yi Chuan Xue Za Zhi = Zhonghua Yixue Yichuanxue Zazhi = Chinese Journal of Medical Genetics 17 (5): 343–347. Oct 2000. PMID 11024216. 
  19. ↑ "Hyaluronan and the hyaluronan receptor RHAMM promote focal adhesion turnover and transient tyrosine kinase activity". The Journal of Cell Biology 126 (2): 575–588. Jul 1994. doi:10.1083/jcb.126.2.575. PMID 7518470. 
  20. ↑ "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 282 (22): 16667–16680. Jun 2007. doi:10.1074/jbc.M702078200. PMID 17392272. 
  21. ↑ "Differential involvement of the hyaluronan (HA) receptors CD44 and receptor for HA-mediated motility in endothelial cell function and angiogenesis". The Journal of Biological Chemistry 276 (39): 36770–36778. Sep 2001. doi:10.1074/jbc.M102273200. PMID 11448954. 

Further reading

  • "Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin". The Journal of Infection 24 (3): 317–320. May 1992. doi:10.1016/S0163-4453(05)80037-4. PMID 1602151. 
  • "Overexpression of the hyaluronan receptor RHAMM is transforming and is also required for H-ras transformation". Cell 82 (1): 19–26. Jul 1995. doi:10.1016/0092-8674(95)90048-9. PMID 7541721. 
  • "Regulated expression of a receptor for hyaluronan-mediated motility on human thymocytes and T cells". Journal of Immunology 150 (10): 4292–4302. May 1993. doi:10.4049/jimmunol.150.10.4292. PMID 7683315. 
  • "The human and mouse receptors for hyaluronan-mediated motility, RHAMM, genes (HMMR) map to human chromosome 5q33.2-qter and mouse chromosome 11". Genomics 30 (1): 115–117. Nov 1995. doi:10.1006/geno.1995.0022. PMID 8595891. 
  • "The characterization of a human RHAMM cDNA: conservation of the hyaluronan-binding domains". Gene 174 (2): 299–306. Oct 1996. doi:10.1016/0378-1119(96)00080-7. PMID 8890751. 
  • "The human hyaluronan receptor RHAMM is expressed as an intracellular protein in breast cancer cells". Journal of Cell Science 111 (12): 1685–1694. Jun 1998. doi:10.1242/jcs.111.12.1685. PMID 9601098. 
  • "Potential role for hyaluronan and the hyaluronan receptor RHAMM in mobilization and trafficking of hematopoietic progenitor cells". Blood 93 (9): 2918–2927. May 1999. doi:10.1182/blood.V93.9.2918. PMID 10216086. 
  • "The intracellular hyaluronan receptor RHAMM/IHABP interacts with microtubules and actin filaments". Journal of Cell Science 112 (22): 3943–3954. Nov 1999. doi:10.1242/jcs.112.22.3943. PMID 10547355. 
  • "Differences in hyaluronic acid-mediated functions and signaling in arterial, microvessel, and vein-derived human endothelial cells". The Journal of Biological Chemistry 275 (36): 27641–27649. Sep 2000. doi:10.1074/jbc.M003084200. PMID 10882722. 
  • "Sequence, protein expression and extracellular-regulated kinase association of the hyaladherin RHAMM (receptor for hyaluronan mediated motility) in PC12 cells". Neuroscience Letters 306 (1–2): 49–52. Jun 2001. doi:10.1016/S0304-3940(01)01870-5. PMID 11403955. 
  • "Subcellular distribution, calmodulin interaction, and mitochondrial association of the hyaluronan-binding protein RHAMM in rat brain". Journal of Neuroscience Research 65 (1): 6–16. Jul 2001. doi:10.1002/jnr.1122. PMID 11433424. 
  • "Differential involvement of the hyaluronan (HA) receptors CD44 and receptor for HA-mediated motility in endothelial cell function and angiogenesis". The Journal of Biological Chemistry 276 (39): 36770–36778. Sep 2001. doi:10.1074/jbc.M102273200. PMID 11448954. 
  • "Hyaluronate receptors mediating glioma cell migration and proliferation". Journal of Neuro-Oncology 53 (2): 115–127. Jun 2001. doi:10.1023/A:1012297132047. PMID 11716065. 
  • "Receptor for hyaluronan acid-mediated motility (RHAMM) is a new immunogenic leukemia-associated antigen in acute and chronic myeloid leukemia". Experimental Hematology 30 (9): 1029–1035. Sep 2002. doi:10.1016/S0301-472X(02)00874-3. PMID 12225794. 
  • "Expression of the hyaluronan receptor RHAMM in endometrial carcinomas suggests a role in tumour progression and metastasis". Journal of Cancer Research and Clinical Oncology 129 (3): 161–164. Mar 2003. doi:10.1007/s00432-003-0415-0. PMID 12712331. 
  • "RHAMM is a centrosomal protein that interacts with dynein and maintains spindle pole stability". Molecular Biology of the Cell 14 (6): 2262–2276. Jun 2003. doi:10.1091/mbc.E02-07-0377. PMID 12808028. 
  • "CD44 mediates polymorphonuclear leukocyte motility on hyaluronan". Saudi Medical Journal 24 (8): 827–831. Aug 2003. PMID 12939665. 
  • "Receptor for hyaluronan-mediated motility correlates with centrosome abnormalities in multiple myeloma and maintains mitotic integrity". Cancer Research 65 (3): 850–860. Feb 2005. doi:10.1158/0008-5472.850.65.3. PMID 15705883. 
  • "Dynamic cytoplasmic anchoring of the transcription factor Bach1 by intracellular hyaluronic acid binding protein IHABP". Journal of Biochemistry 137 (3): 287–296. Mar 2005. doi:10.1093/jb/mvi031. PMID 15809329. 
  • "Network modeling links breast cancer susceptibility and centrosome dysfunction". Nature Genetics 39 (11): 1338–1349. Nov 2007. doi:10.1038/ng.2007.2. PMID 17922014. 
  • "Hyaluronan-mediated motility receptor gene single nucleotide polymorphisms and risk of breast cancer". Cancer Epidemiology, Biomarkers & Prevention 17 (12): 3618–3620. Dec 2008. doi:10.1158/1055-9965.EPI-08-0216. PMID 19064580. 

This article incorporates text from the United States National Library of Medicine, which is in the public domain.



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