Hyaluronan-mediated motility receptor (HMMR), also known asRHAMM (Receptor for Hyaluronan Mediated Motility) is aprotein which in humans is encoded by theHMMRgene.[5] RHAMM recently has been also designatedCD168 (cluster of differentiation 168).
RHAMM was originally discovered as a soluble protein that altered migratory cell behavior and bound tohyaluronan.[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 theendoplasmic 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 withmicrotubules and, working withBRCA1 andBARD1, 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 tohyaluronan, activates intracellular signaling pathways, mainly the MAPK pathway via ERK1,2 activation[13] Variants of RHAMM caused byalternative splicing have been observed, and alternative start codon usage has been proposed in mice and directly observed in humans.[5]
RHAMM is over expressed inbreast cancer and its expression intriple negative andHER2 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 lineMDA-MB-231.[17]
Elevated levels of RHAMM andhyaluronan are associated with the likelihood of undergoing biochemical failure in intermediate risk prostate cancer patients.[18] RHAMM is also one of 3biomarkers associated with aggressiveness in a multivariate analysis of human prostate tumors[19] and elevated levels of RHAMM are associated with bothandrogen deprivation therapy andcastration resistant disease.[20] RHAMM has also been identified as one of 4 gene products identified in circulating tumor cells in patients withlung adenocarcinoma.[21]
While RHAMM has been less studied than CD44 in the process ofcancer 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 promotefocal adhesion turnover by controllingfocal adhesion kinase (FAK)phosphorylation and cooperating with the α4β1 and α5β1integrins.[23] RHAMM also activates a number of downstream kinases including enhancing the intensity and sustaining the duration ofERK1 /ERK2 activation through themap kinase (MAPK) pathway, pp60 (c-src), and the downstream targets ofrho kinase (ROK).[24] Finally, once a metastatic lesion has been established, RHAMM can cooperate with CD44 to promoteangiogenesis by promoting migration of neighboringendothelial cells towards the tumor.[25]
^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.PMID11024216.
Dawson SJ, White LA (May 1992). "Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin".The Journal of Infection.24 (3):317–320.doi:10.1016/S0163-4453(05)80037-4.PMID1602151.
Spicer AP, Roller ML, Camper SA, McPherson JD, Wasmuth JJ, Hakim S, Wang C, Turley EA, McDonald JA (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):115–117.doi:10.1006/geno.1995.0022.PMID8595891.
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.PMID8890751.
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 (12):1685–1694.doi:10.1242/jcs.111.12.1685.PMID9601098.
Pilarski LM, Pruski E, Wizniak J, Paine D, Seeberger K, Mant MJ, Brown CB, Belch AR (May 1999). "Potential role for hyaluronan and the hyaluronan receptor RHAMM in mobilization and trafficking of hematopoietic progenitor cells".Blood.93 (9):2918–2927.doi:10.1182/blood.V93.9.2918.PMID10216086.
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.PMID10547355.
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.PMID11403955.S2CID38778150.
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.PMID11433424.S2CID23843138.
Akiyama Y, Jung S, Salhia B, Lee S, Hubbard S, Taylor M, Mainprize T, Akaishi K, van Furth W, Rutka JT (Jun 2001). "Hyaluronate receptors mediating glioma cell migration and proliferation".Journal of Neuro-Oncology.53 (2):115–127.doi:10.1023/A:1012297132047.PMID11716065.S2CID33691799.
