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HMMR
Identifiers
Aliases	HMMR, CD168, IHABP, RHAMM, Hyaluronan-mediated motility receptor, hyaluronan mediated motility receptor
External IDs	OMIM: 600936; MGI: 104667; HomoloGene: 8271; GeneCards: HMMR; OMA:HMMR - orthologs
Gene location (Human)
Chr.	Chromosome 5 (human)
End	163,491,941 bp
Gene location (Mouse)
Chr.	Chromosome 11 (mouse)
End	40,624,249 bp
RNA expression pattern
	Top expressed in
	sperm; ; trabecular bone; ; testicle; ; gonad; ; secondary oocyte; ; bone marrow; ; ventricular zone; ; embryo; ; bone marrow cells; ; appendix;
	Top expressed in
	Paneth cell; ; condyle; ; genital tubercle; ; tail of embryo; ; lumbar spinal ganglion; ; fossa; ; atrium; ; maxillary prominence; ; endothelial cell of lymphatic vessel; ; atrioventricular junction;
	More reference expression data
	; ;
	More reference expression data
Gene ontology
Molecular function	protein binding; hyaluronic acid binding;
Cellular component	cytoplasm; cell surface; plasma membrane; membrane; cytosol; centrosome; microtubule cytoskeleton;
Biological process	hyaluronan catabolic process; regulation of G2/M transition of mitotic cell cycle;
	Sources:Amigo / QuickGO
Orthologs
	3161
	15366
	ENSG00000072571
	ENSMUSG00000020330
	O75330
	Q00547
	NM_012485; NM_001142556; NM_001142557; NM_012484
	NM_013552
	NP_001136028; NP_001136029; NP_036616; NP_036617
	NP_038580
	Wikidata
View/Edit Human	View/Edit Mouse

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.^[5] 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.^[6] 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.^[7] 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.^[8]

Intracellularly, RHAMM associates with microtubules and, working with BRCA1 and BARD1, plays a role in the regulation of mitosis,^[8]^[9]^[10] and in maintaining mitotic spindle integrity.^[11] RHAMM also binds directly with ERK1 and forms complexes with ERK1,2 and MEK1,^[11] suggesting a role as a scaffold protein that targets these MAP kinases to the nucleus.^[12]

Extracellularly, RHAMM associates with CD44, and upon binding to hyaluronan, activates intracellular signaling pathways, mainly the MAPK pathway via ERK1,2 activation^[13] 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.^[5]

Clinical significance

RHAMM is over expressed in breast cancer and its expression in triple negative and HER2 subtypes is associated with poor outcome.^[14] Alternatively spliced forms of RHAMM may be up regulated in some tumor types, promoting tumor progression.^[15] The presence of breast tumor cell subsets with high RHAMM expression is associated with reduced metastasis free survival^[16] and mediates migration, transformation, and metastatic spread of the triple negative human BCa cell line MDA-MB-231.^[17]

Elevated levels of RHAMM and hyaluronan are associated with the likelihood of undergoing biochemical failure in intermediate risk prostate cancer patients.^[18] RHAMM is also one of 3 biomarkers associated with aggressiveness in a multivariate analysis of human prostate tumors^[19] and elevated levels of RHAMM are associated with both androgen deprivation therapy and castration resistant disease.^[20] RHAMM has also been identified as one of 4 gene products identified in circulating tumor cells in patients with lung adenocarcinoma.^[21]

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.^[22] 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.^[23] 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).^[24] 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.^[25]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000072571 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000020330 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ ^a ^b "Entrez Gene: HMMR hyaluronan-mediated motility receptor (RHAMM)".
^ Turley EA (Oct 1982). "Purification of a hyaluronate-binding protein fraction that modifies cell social behavior". Biochemical and Biophysical Research Communications. 108 (3): 1016–1024. doi:10.1016/0006-291X(82)92101-5. PMID 6185115.
^ Hardwick C, Hoare K, Owens R, Hohn HP, Hook M, Moore D, Cripps V, Austen L, Nance DM, Turley EA (Jun 1992). "Molecular cloning of a novel hyaluronan receptor that mediates tumor cell motility". The Journal of Cell Biology. 117 (6): 1343–1350. doi:10.1083/jcb.117.6.1343. PMC 2289508. PMID 1376732.
^ ^a ^b Maxwell CA, Keats JJ, Crainie M, Sun X, Yen T, Shibuya E, Hendzel M, Chan G, Pilarski LM (June 2003). "RHAMM is a centrosomal protein that interacts with dynein and maintains spindle pole stability". Molecular Biology of the Cell. 14 (6): 2262–2276. doi:10.1091/mbc.E02-07-0377. PMC 194876. PMID 12808028.
^ Joukov V, Groen AC, Prokhorova T, Gerson R, White E, Rodriguez A, Walter JC, Livingston DM (Nov 2006). "The BRCA1/BARD1 heterodimer modulates ran-dependent mitotic spindle assembly". Cell. 127 (3): 539–552. doi:10.1016/j.cell.2006.08.053. PMID 17081976. S2CID 17769149.
^ Pujana MA, Han JD, Starita LM, Stevens KN, Tewari M, Ahn JS, Rennert G, Moreno V, Kirchhoff T, Gold B, Assmann V, Elshamy WM, Rual JF, Levine D, Rozek LS, Gelman RS, Gunsalus KC, Greenberg RA, Sobhian B, Bertin N, Venkatesan K, Ayivi-Guedehoussou N, Solé X, Hernández P, Lázaro C, Nathanson KL, Weber BL, Cusick ME, Hill DE, Offit K, Livingston DM, Gruber SB, Parvin JD, Vidal M (Nov 2007). "Network modeling links breast cancer susceptibility and centrosome dysfunction". Nature Genetics. 39 (11): 1338–1349. doi:10.1038/ng.2007.2. PMID 17922014.
^ ^a ^b Tolg C, Hamilton SR, Morningstar L, Zhang J, Zhang S, Esguerra KV, Telmer PG, Luyt LG, Harrison R, McCarthy JB, Turley EA (Aug 2010). "RHAMM promotes interphase microtubule instability and mitotic spindle integrity through MEK1/ERK1/2 activity". The Journal of Biological Chemistry. 285 (34): 26461–26474. doi:10.1074/jbc.M110.121491. PMC 2924079. PMID 20558733.
^ 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): 182–185. doi:10.4161/cib.4.2.14270. PMC 3104573. PMID 21655434.
^ 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): 1041–1047. doi:10.1083/jcb.112.5.1041. PMC 2288867. PMID 1705559.
^ Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A, Chinnaiyan AM (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.
^ 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): 1684–1696. doi:10.1182/blood.V93.5.1684. PMID 10029598.
^ Wang C, Thor AD, Moore DH, Zhao Y, Kerschmann R, Stern R, Watson PH, Turley EA (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): 567–576. PMID 9533523.
^ Wang Z, Wu Y, Wang H, Zhang Y, Mei L, Fang X, Zhang X, Zhang F, Chen H, Liu Y, Jiang Y, Sun S, Zheng Y, Li N, Huang L (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): E89 – E98. Bibcode:2014PNAS..111E..89W. doi:10.1073/pnas.1319190110. PMC 3890879. PMID 24367099.
^ Rizzardi AE, Vogel RI, Koopmeiners JS, Forster CL, Marston LO, Rosener NK, Akentieva N, Price MA, Metzger GJ, Warlick CA, Henriksen JC, Turley EA, McCarthy JB, Schmechel SC (Jun 2014). "Elevated hyaluronan and hyaluronan-mediated motility receptor are associated with biochemical failure in patients with intermediate-grade prostate tumors". Cancer. 120 (12): 1800–1809. doi:10.1002/cncr.28646. PMC 4047165. PMID 24668563.
^ Rizzardi AE, Rosener NK, Koopmeiners JS, Isaksson Vogel R, Metzger GJ, Forster CL, Marston LO, Tiffany JR, McCarthy JB, Turley EA, Warlick CA, Henriksen JC, Schmechel SC (Apr 2014). "Evaluation of protein biomarkers of prostate cancer aggressiveness". BMC Cancer. 14: 244. doi:10.1186/1471-2407-14-244. PMC 4101830. PMID 24708576.
^ 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): 822–829. doi:10.1111/bju.12339. PMID 24053431. S2CID 9302075.
^ Man Y, Cao J, Jin S, Xu G, Pan B, Shang L, Che D, Yu Q, Yu Y (Sep 2014). "Newly identified biomarkers for detecting circulating tumor cells in lung adenocarcinoma". The Tohoku Journal of Experimental Medicine. 234 (1): 29–40. doi:10.1620/tjem.234.29. PMID 25175030.
^ 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): 343–347. PMID 11024216.
^ 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): 575–588. doi:10.1083/jcb.126.2.575. PMC 2200030. PMID 7518470.
^ Hamilton SR, Fard SF, Paiwand FF, Tolg C, Veiseh M, Wang C, McCarthy JB, Bissell MJ, Koropatnick J, Turley EA (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): 16667–16680. doi:10.1074/jbc.M702078200. PMC 2949353. PMID 17392272.
^ 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): 36770–36778. doi:10.1074/jbc.M102273200. PMID 11448954.

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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 (22): 3943–3954. doi:10.1242/jcs.112.22.3943. PMID 10547355.
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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. S2CID 23843138.
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): 36770–36778. doi:10.1074/jbc.M102273200. PMID 11448954.
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Maxwell CA, Keats JJ, Crainie M, Sun X, Yen T, Shibuya E, Hendzel M, Chan G, Pilarski LM (Jun 2003). "RHAMM is a centrosomal protein that interacts with dynein and maintains spindle pole stability". Molecular Biology of the Cell. 14 (6): 2262–2276. 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): 827–831. 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): 850–860. doi:10.1158/0008-5472.850.65.3. PMID 15705883. S2CID 15463595.
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Pujana MA, Han JD, Starita LM, Stevens KN, Tewari M, Ahn JS, Rennert G, Moreno V, Kirchhoff T, Gold B, Assmann V, Elshamy WM, Rual JF, Levine D, Rozek LS, Gelman RS, Gunsalus KC, Greenberg RA, Sobhian B, Bertin N, Venkatesan K, Ayivi-Guedehoussou N, Solé X, Hernández P, Lázaro C, Nathanson KL, Weber BL, Cusick ME, Hill DE, Offit K, Livingston DM, Gruber SB, Parvin JD, Vidal M (Nov 2007). "Network modeling links breast cancer susceptibility and centrosome dysfunction". Nature Genetics. 39 (11): 1338–1349. doi:10.1038/ng.2007.2. PMID 17922014.
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