| HMMR | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | HMMR , CD168, IHABP, RHAMM, Hyaluronan-mediated motility receptor, hyaluronan mediated motility receptor | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 600936 MGI: 104667 HomoloGene: 8271 GeneCards: HMMR | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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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).
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]
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]
The epidermal growth factor receptor is a transmembrane protein that is a receptor for members of the epidermal growth factor family of extracellular protein ligands.
The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the CD44 gene on chromosome 11. CD44 has been referred to as HCAM, Pgp-1, Hermes antigen, lymphocyte homing receptor, ECM-III, and HUTCH-1.
Aurora kinase A also known as serine/threonine-protein kinase 6 is an enzyme that in humans is encoded by the AURKA gene.
Hyaluronan synthases (HAS) are membrane-bound enzymes that use UDP-α-N-acetyl-D-glucosamine and UDP-α-D-glucuronate as substrates to produce the glycosaminoglycan hyaluronan at the cell surface and extrude it through the membrane into the extracellular space.
Cyclin D1 is a protein that in humans is encoded by the CCND1 gene.
Insulin receptor substrate 1(IRS-1) is a signaling adapter protein that in humans is encoded by the IRS1 gene. It is a 131 kDa protein with amino acid sequence of 1242 residues. It contains a single pleckstrin homology (PH) domain at the N-terminus and a PTB domain ca. 40 residues downstream of this, followed by a poorly conserved C-terminus tail. Together with IRS2, IRS3 (pseudogene) and IRS4, it is homologous to the Drosophila protein chico, whose disruption extends the median lifespan of flies up to 48%. Similarly, Irs1 mutant mice experience moderate life extension and delayed age-related pathologies.
Serine/threonine-protein kinase PAK 1 is an enzyme that in humans is encoded by the PAK1 gene.
Rac GTPase-activating protein 1 is an enzyme that in humans is encoded by the RACGAP1 gene.
Mitotic checkpoint serine/threonine-protein kinase BUB1 beta is an enzyme that in humans is encoded by the BUB1B gene. Also known as BubR1, this protein is recognized for its mitotic roles in the spindle assembly checkpoint (SAC) and kinetochore-microtubule interactions that facilitate chromosome migration and alignment. BubR1 promotes mitotic fidelity and protects against aneuploidy by ensuring proper chromosome segregation between daughter cells. BubR1 is proposed to prevent tumorigenesis.
RhoC is a small signaling G protein, and is a member of the Rac subfamily of the family Rho family of GTPases. It is encoded by the gene RHOC.
Neural precursor cell expressed developmentally down-regulated protein 9 (NEDD-9) is a protein that in humans is encoded by the NEDD9 gene. NEDD-9 is also known as enhancer of filamentation 1 (EF1), CRK-associated substrate-related protein (CAS-L), and Cas scaffolding protein family member 2 (CASS2). An important paralog of this gene is BCAR1.
Serine/threonine-protein kinase Nek2 is an enzyme that in humans is encoded by the NEK2 gene.
Hyaluronidase-2 is a multifunctional protein, previously thought to only possess acid-active hyaluronan-degrading enzymatic function. In humans it is encoded by the HYAL2 gene.
Targeting protein for Xklp2 is a protein that in humans is encoded by the TPX2 gene. It is one of the many spindle assembly factors that play a key role in inducing microtubule assembly and growth during M phase.
Hyaluronan synthase 2 is an enzyme that in humans is encoded by the HAS2 gene.
Large tumor suppressor kinase 1 (LATS1) is an enzyme that in humans is encoded by the LATS1 gene.
Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), also known as extracellular link domain containing 1 (XLKD1) is a Link domain-containing hyaladherin, a protein capable of binding to hyaluronic acid (HA), homologous to CD44, the main HA receptor. In humans it is encoded by the LYVE1 gene.
Aurora kinase C, also Serine/threonine-protein kinase 13 is an enzyme that in humans is encoded by the AURKC gene.
Serine/threonine-protein kinase Nek3 is an enzyme that in humans is encoded by the NEK3 gene.
Breast cancer is the most prevalent type of cancer among women globally, with 685,000 deaths recorded worldwide in 2020. The most commonly used treatment methods for breast cancer include surgery, radiotherapy and chemotherapy. Some of these treated patients experience disease relapse and metastasis. The aggressive progression and recurrence of this disease has been attributed the presence of a subset of tumor cells known as breast cancer stem cells (BCSCs). These cells possess the abilities of self-renewal and tumor initiation, allowing them to be drivers of metastases and tumor growth. The microenvironment in which these cells reside is filled with residential inflammatory cells that provide the needed signaling cues for BCSC-mediated self-renewal and survival. The production of cytokines allows these cells to escape from the primary tumor and travel through the circulation to distant organs, commencing the process of metastasis. Due to their significant role in driving disease progression, BCSCs represent a new target by which to treat the tumor at the source of metastasis.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
