Hyaluronan-mediated motility receptor

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Hyaluronan-mediated motility receptor (RHAMM)
Identifiers
Symbols HMMR ; CD168; IHABP; RHAMM
External IDs OMIM600936 MGI104667 HomoloGene8271 GeneCards: HMMR Gene
RNA expression pattern
PBB GE HMMR 209709 s at tn.png
PBB GE HMMR 207165 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 3161 15366
Ensembl ENSG00000072571 ENSMUSG00000020330
UniProt O75330 Q00547
RefSeq (mRNA) NM_001142556 NM_013552
RefSeq (protein) NP_001136028 NP_038580
Location (UCSC) Chr 5:
162.89 – 162.92 Mb
Chr 11:
40.7 – 40.73 Mb
PubMed search [1] [2]

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[edit]

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,[5][6][7] and in maintaining mitotic spindle integrity.[8] RHAMM also binds directly with ERK1 and forms complexes with ERK1,2 and MEK1,[8] suggesting a role as a scaffold protein that targets these MAP kinases to the nucleus.[9]

Extracellularly, RHAMM associates with CD44, and upon binding to hyaluronan, activates intracellular signaling pathways, mainly the MAPK pathway via ERK1,2 activation[10] 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[edit]

RHAMM is over expressed in breast cancer and its expression in triple negative and HER2 subtypes is associated with poor outcome.[11] Alternatively spliced forms of RHAMM may be up regulated in some tumor types, promoting tumor progression.[12] The presence of breast tumor cell subsets with high RHAMM expression is associated with reduced metastasis free survival[13] and mediates migration, transformation, and metastatic spread of the triple negative human BCa cell line MDA-MB-231.[14]

Elevated levels of RHAMM and hyaluronan are associated with the likelihood of undergoing biochemical failure in intermediate risk prostate cancer patients.[15] RHAMM is also one of 3 biomarkers associated with aggressiveness in a multivariate analysis of human prostate tumors[16] and elevated levels of RHAMM are associated with both androgen deprivation therapy and castration resistant disease.[17] RHAMM has also been identified as one of 4 gene products identified in circulating tumor cells in patients with lung adenocarcinoma.[18]

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.[19] 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.[20] 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).[21] 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.[22]

References[edit]

  1. ^ a b "Entrez Gene: HMMR hyaluronan-mediated motility receptor (RHAMM)". 
  2. ^ Turley EA (Oct 1982). "Purification of a hyaluronate-binding protein fraction that modifies cell social behavior". Biochemical and Biophysical Research Communications 108 (3): 1016–24. doi:10.1016/0006-291X(82)92101-5. PMID 6185115. 
  3. ^ Hardwick C, Hoare K, Owens R, Hohn HP, Hook M, Moore D et al. (Jun 1992). "Molecular cloning of a novel hyaluronan receptor that mediates tumor cell motility". The Journal of Cell Biology 117 (6). PMID 1376732. 
  4. ^ Maxwell CA, Keats JJ, Crainie M, Sun X, Yen T, Shibuya E et al. (Jun 2003). "RHAMM is a centrosomal protein that interacts with dynein and maintains spindle pole stability". Molecular Biology of the Cell 14 (6). doi:10.1091/mbc.E02-07-0377. PMID 12808028. 
  5. ^ Maxwell CA, Keats JJ, Crainie M, Sun X, Yen T, Shibuya E et al. (Jun 2003). "RHAMM is a centrosomal protein that interacts with dynein and maintains spindle pole stability". Molecular Biology of the Cell 14 (6): 2262–76. doi:10.1091/mbc.E02-07-0377. PMC 194876. PMID 12808028. 
  6. ^ Joukov V, Groen AC, Prokhorova T, Gerson R, White E, Rodriguez A et al. (Nov 2006). "The BRCA1/BARD1 heterodimer modulates ran-dependent mitotic spindle assembly". Cell 127 (3): 539–52. doi:10.1016/j.cell.2006.08.053. PMID 17081976. 
  7. ^ Pujana MA, Han JD, Starita LM, Stevens KN, Tewari M, Ahn JS et al. (Nov 2007). "Network modeling links breast cancer susceptibility and centrosome dysfunction". Nature Genetics 39 (11): 1338–49. doi:10.1038/ng.2007.2. PMID 17922014. 
  8. ^ a b Tolg C, Hamilton SR, Morningstar L, Zhang J, Zhang S, Esguerra KV et al. (Aug 2010). "RHAMM promotes interphase microtubule instability and mitotic spindle integrity through MEK1/ERK1/2 activity". The Journal of Biological Chemistry 285 (34). doi:10.1074/jbc.M110.121491. PMID 20558733. 
  9. ^ Telmer PG, Tolg C, McCarthy JB, Turley EA (Mar 2011). "How does a protein with dual mitotic spindle and extracellular matrix receptor functions affect tumor susceptibility and progression?". Communicative & Integrative Biology 4 (2). doi:10.4161/cib.4.2.14270. PMID 21655434. 
  10. ^ Turley EA, Austen L, Vandeligt K, Clary C (Mar 1991). "Hyaluronan and a cell-associated hyaluronan binding protein regulate the locomotion of ras-transformed cells". The Journal of Cell Biology 112 (5): 1041–7. doi:10.1083/jcb.112.5.1041. PMC 2288867. PMID 1705559. 
  11. ^ Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D et al. (2004). "ONCOMINE: a cancer microarray database and integrated data-mining platform". Neoplasia 6 (1): 1–6. doi:10.1016/S1476-5586(04)80047-2. PMC 1635162. PMID 15068665. 
  12. ^ Crainie M, Belch AR, Mant MJ, Pilarski LM (Mar 1999). "Overexpression of the receptor for hyaluronan-mediated motility (RHAMM) characterizes the malignant clone in multiple myeloma: identification of three distinct RHAMM variants" (PDF). Blood 93 (5): 1684–96. PMID 10029598. 
  13. ^ Wang C, Thor AD, Moore DH, Zhao Y, Kerschmann R, Stern R et al. (Mar 1998). "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). PMID 9533523. 
  14. ^ Wang Z, Wu Y, Wang H, Zhang Y, Mei L, Fang X et al. (Jan 2014). "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). doi:10.1073/pnas.1319190110. PMC 3890879. PMID 24367099. 
  15. ^ Rizzardi AE, Vogel RI, Koopmeiners JS, Forster CL, Marston LO, Rosener NK et al. (Jun 2014). "Elevated hyaluronan and hyaluronan-mediated motility receptor are associated with biochemical failure in patients with intermediate-grade prostate tumors". Cancer 120 (12). doi:10.1002/cncr.28646. PMID 24668563. 
  16. ^ Rizzardi AE, Rosener NK, Koopmeiners JS, Isaksson Vogel R, Metzger GJ, Forster CL et al. (Apr 2014). "Evaluation of protein biomarkers of prostate cancer aggressiveness". BMC Cancer 14. doi:10.1186/1471-2407-14-244. PMC 4101830. PMID 24708576. 
  17. ^ Korkes F, de Castro MG, de Cassio Zequi S, Nardi L, Del Giglio A, de Lima Pompeo AC (May 2014). "Hyaluronan-mediated motility receptor (RHAMM) immunohistochemical expression and androgen deprivation in normal peritumoral, hyperplasic and neoplastic prostate tissue". BJU International 113 (5). doi:10.1111/bju.12339. PMID 24053431. 
  18. ^ Man Y, Cao J, Jin S, Xu G, Pan B, Shang L et al. (Sep 2014). "Newly identified biomarkers for detecting circulating tumor cells in lung adenocarcinoma". The Tohoku Journal of Experimental Medicine 234 (1). doi:10.1620/tjem.234.29. PMID 25175030. 
  19. ^ Li H, Guo L, Li J, Liu N, Liu J (Oct 2000). "Alternative splicing of RHAMM gene in chinese gastric cancers and its in vitro regulation". Zhonghua Yi Xue Yi Chuan Xue Za Zhi = Zhonghua Yixue Yichuanxue Zazhi = Chinese Journal of Medical Genetics (in Chinese) 17 (5): 343–7. PMID 11024216. 
  20. ^ Hall CL, Wang C, Lange LA, Turley EA (Jul 1994). "Hyaluronan and the hyaluronan receptor RHAMM promote focal adhesion turnover and transient tyrosine kinase activity". The Journal of Cell Biology 126 (2): 575–88. doi:10.1083/jcb.126.2.575. PMC 2200030. PMID 7518470. 
  21. ^ Hamilton SR, Fard SF, Paiwand FF, Tolg C, Veiseh M, Wang C et al. (Jun 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 282 (22): 16667–80. doi:10.1074/jbc.M702078200. PMC 2949353. PMID 17392272. 
  22. ^ Savani RC, Cao G, Pooler PM, Zaman A, Zhou Z, DeLisser HM (Sep 2001). "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): 36770–8. doi:10.1074/jbc.M102273200. PMID 11448954. 

Further reading[edit]

  • Dawson SJ, White LA (May 1992). "Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin". The Journal of Infection 24 (3): 317–20. doi:10.1016/S0163-4453(05)80037-4. PMID 1602151. 
  • Hall CL, Yang B, Yang X, Zhang S, Turley M, Samuel S et al. (Jul 1995). "Overexpression of the hyaluronan receptor RHAMM is transforming and is also required for H-ras transformation". Cell 82 (1): 19–26. doi:10.1016/0092-8674(95)90048-9. PMID 7541721. 
  • Pilarski LM, Miszta H, Turley EA (May 1993). "Regulated expression of a receptor for hyaluronan-mediated motility on human thymocytes and T cells". Journal of Immunology 150 (10): 4292–302. PMID 7683315. 
  • Spicer AP, Roller ML, Camper SA, McPherson JD, Wasmuth JJ, Hakim S et al. (Nov 1995). "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): 115–7. doi:10.1006/geno.1995.0022. PMID 8595891. 
  • Wang C, Entwistle J, Hou G, Li Q, Turley EA (Oct 1996). "The characterization of a human RHAMM cDNA: conservation of the hyaluronan-binding domains". Gene 174 (2): 299–306. doi:10.1016/0378-1119(96)00080-7. PMID 8890751. 
  • Assmann V, Marshall JF, Fieber C, Hofmann M, Hart IR (Jun 1998). "The human hyaluronan receptor RHAMM is expressed as an intracellular protein in breast cancer cells". Journal of Cell Science. 111 ( Pt 12) (12): 1685–94. PMID 9601098. 
  • Pilarski LM, Pruski E, Wizniak J, Paine D, Seeberger K, Mant MJ et al. (May 1999). "Potential role for hyaluronan and the hyaluronan receptor RHAMM in mobilization and trafficking of hematopoietic progenitor cells". Blood 93 (9): 2918–27. PMID 10216086. 
  • Assmann V, Jenkinson D, Marshall JF, Hart IR (Nov 1999). "The intracellular hyaluronan receptor RHAMM/IHABP interacts with microtubules and actin filaments". Journal of Cell Science. 112 ( Pt 22) (22): 3943–54. PMID 10547355. 
  • Lokeshwar VB, Selzer MG (Sep 2000). "Differences in hyaluronic acid-mediated functions and signaling in arterial, microvessel, and vein-derived human endothelial cells". The Journal of Biological Chemistry 275 (36): 27641–9. doi:10.1074/jbc.M003084200. PMID 10882722. 
  • Lynn BD, Li X, Cattini PA, Nagy JI (Jun 2001). "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. doi:10.1016/S0304-3940(01)01870-5. PMID 11403955. 
  • Lynn BD, Turley EA, Nagy JI (Jul 2001). "Subcellular distribution, calmodulin interaction, and mitochondrial association of the hyaluronan-binding protein RHAMM in rat brain". Journal of Neuroscience Research 65 (1): 6–16. doi:10.1002/jnr.1122. PMID 11433424. 
  • Savani RC, Cao G, Pooler PM, Zaman A, Zhou Z, DeLisser HM (Sep 2001). "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): 36770–8. doi:10.1074/jbc.M102273200. PMID 11448954. 
  • Akiyama Y, Jung S, Salhia B, Lee S, Hubbard S, Taylor M et al. (Jun 2001). "Hyaluronate receptors mediating glioma cell migration and proliferation". Journal of Neuro-Oncology 53 (2): 115–27. doi:10.1023/A:1012297132047. PMID 11716065. 
  • Greiner J, Ringhoffer M, Taniguchi M, Schmitt A, Kirchner D, Krähn G et al. (Sep 2002). "Receptor for hyaluronan acid-mediated motility (RHAMM) is a new immunogenic leukemia-associated antigen in acute and chronic myeloid leukemia". Experimental Hematology 30 (9): 1029–35. doi:10.1016/S0301-472X(02)00874-3. PMID 12225794. 
  • Rein DT, Roehrig K, Schöndorf T, Lazar A, Fleisch M, Niederacher D et al. (Mar 2003). "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): 161–4. doi:10.1007/s00432-003-0415-0. PMID 12712331. 
  • Maxwell CA, Keats JJ, Crainie M, Sun X, Yen T, Shibuya E et al. (Jun 2003). "RHAMM is a centrosomal protein that interacts with dynein and maintains spindle pole stability". Molecular Biology of the Cell 14 (6): 2262–76. doi:10.1091/mbc.E02-07-0377. PMC 194876. PMID 12808028. 
  • Aziz KA (Aug 2003). "CD44 mediates polymorphonuclear leukocyte motility on hyaluronan". Saudi Medical Journal 24 (8): 827–31. PMID 12939665. 
  • Maxwell CA, Keats JJ, Belch AR, Pilarski LM, Reiman T (Feb 2005). "Receptor for hyaluronan-mediated motility correlates with centrosome abnormalities in multiple myeloma and maintains mitotic integrity". Cancer Research 65 (3): 850–60. PMID 15705883. 
  • Yamasaki C, Tashiro S, Nishito Y, Sueda T, Igarashi K (Mar 2005). "Dynamic cytoplasmic anchoring of the transcription factor Bach1 by intracellular hyaluronic acid binding protein IHABP". Journal of Biochemistry 137 (3): 287–96. doi:10.1093/jb/mvi031. PMID 15809329. 
  • Pujana MA, Han JD, Starita LM, Stevens KN, Tewari M, Ahn JS et al. (Nov 2007). "Network modeling links breast cancer susceptibility and centrosome dysfunction". Nature Genetics 39 (11): 1338–49. doi:10.1038/ng.2007.2. PMID 17922014. 
  • Kalmyrzaev B, Pharoah PD, Easton DF, Ponder BA, Dunning AM (Dec 2008). "Hyaluronan-mediated motility receptor gene single nucleotide polymorphisms and risk of breast cancer". Cancer Epidemiology, Biomarkers & Prevention 17 (12): 3618–20. 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.