{"Affiliation":[{"label":"Affiliation","value":"Medicine, Faculty of","attrs":{"lang":"en","ns":"http:\/\/vivoweb.org\/ontology\/core#departmentOrSchool","classmap":"vivo:EducationalProcess","property":"vivo:departmentOrSchool"},"iri":"http:\/\/vivoweb.org\/ontology\/core#departmentOrSchool","explain":"VIVO-ISF Ontology V1.6 Property; The department or school name within institution; Not intended to be an institution name."},{"label":"Affiliation","value":"Other UBC","attrs":{"lang":"en","ns":"http:\/\/vivoweb.org\/ontology\/core#departmentOrSchool","classmap":"vivo:EducationalProcess","property":"vivo:departmentOrSchool"},"iri":"http:\/\/vivoweb.org\/ontology\/core#departmentOrSchool","explain":"VIVO-ISF Ontology V1.6 Property; The department or school name within institution; Not intended to be an institution name."},{"label":"Affiliation","value":"Pediatrics, Department of","attrs":{"lang":"en","ns":"http:\/\/vivoweb.org\/ontology\/core#departmentOrSchool","classmap":"vivo:EducationalProcess","property":"vivo:departmentOrSchool"},"iri":"http:\/\/vivoweb.org\/ontology\/core#departmentOrSchool","explain":"VIVO-ISF Ontology V1.6 Property; The department or school name within institution; Not intended to be an institution name."}],"AggregatedSourceRepository":[{"label":"Aggregated Source Repository","value":"DSpace","attrs":{"lang":"en","ns":"http:\/\/www.europeana.eu\/schemas\/edm\/dataProvider","classmap":"ore:Aggregation","property":"edm:dataProvider"},"iri":"http:\/\/www.europeana.eu\/schemas\/edm\/dataProvider","explain":"A Europeana Data Model Property; The name or identifier of the organization who contributes data indirectly to an aggregation service (e.g. Europeana)"}],"Citation":[{"label":"Citation","value":"Cells 9 (4): 819 (2020)","attrs":{"lang":"en","ns":"https:\/\/open.library.ubc.ca\/terms#identifierCitation","classmap":"oc:PublicationDescription","property":"oc:identifierCitation"},"iri":"https:\/\/open.library.ubc.ca\/terms#identifierCitation","explain":"UBC Open Collections Metadata Components; Local Field; Indicates a bibliographic reference for the resource if it has been previously published."}],"Contributor":[{"label":"Contributor","value":"Children's Hospital (Vancouver, B.C.)","attrs":{"lang":"en","ns":"http:\/\/purl.org\/dc\/terms\/contributor","classmap":"dpla:SourceResource","property":"dcterms:contributor"},"iri":"http:\/\/purl.org\/dc\/terms\/contributor","explain":"A Dublin Core Terms Property; An entity responsible for making contributions to the resource.; Examples of a Contributor include a person, an organization, or a service."}],"Creator":[{"label":"Creator","value":"He, Zhengcheng","attrs":{"lang":"","ns":"http:\/\/purl.org\/dc\/terms\/creator","classmap":"dpla:SourceResource","property":"dcterms:creator"},"iri":"http:\/\/purl.org\/dc\/terms\/creator","explain":"A Dublin Core Terms Property; An entity primarily responsible for making the resource.; Examples of a Contributor include a person, an organization, or a service."},{"label":"Creator","value":"Mei, Lin","attrs":{"lang":"","ns":"http:\/\/purl.org\/dc\/terms\/creator","classmap":"dpla:SourceResource","property":"dcterms:creator"},"iri":"http:\/\/purl.org\/dc\/terms\/creator","explain":"A Dublin Core Terms Property; An entity primarily responsible for making the resource.; Examples of a Contributor include a person, an organization, or a service."},{"label":"Creator","value":"Connell, Marisa","attrs":{"lang":"","ns":"http:\/\/purl.org\/dc\/terms\/creator","classmap":"dpla:SourceResource","property":"dcterms:creator"},"iri":"http:\/\/purl.org\/dc\/terms\/creator","explain":"A Dublin Core Terms Property; An entity primarily responsible for making the resource.; Examples of a Contributor include a person, an organization, or a service."},{"label":"Creator","value":"Maxwell, Chris","attrs":{"lang":"","ns":"http:\/\/purl.org\/dc\/terms\/creator","classmap":"dpla:SourceResource","property":"dcterms:creator"},"iri":"http:\/\/purl.org\/dc\/terms\/creator","explain":"A Dublin Core Terms Property; An entity primarily responsible for making the resource.; Examples of a Contributor include a person, an organization, or a service."}],"DateAvailable":[{"label":"Date Available","value":"2020-04-28T17:11:50Z","attrs":{"lang":"","ns":"http:\/\/purl.org\/dc\/terms\/issued","classmap":"edm:WebResource","property":"dcterms:issued"},"iri":"http:\/\/purl.org\/dc\/terms\/issued","explain":"A Dublin Core Terms Property; Date of formal issuance (e.g., publication) of the resource."}],"DateIssued":[{"label":"Date Issued","value":"2020-03-28","attrs":{"lang":"","ns":"http:\/\/purl.org\/dc\/terms\/issued","classmap":"oc:SourceResource","property":"dcterms:issued"},"iri":"http:\/\/purl.org\/dc\/terms\/issued","explain":"A Dublin Core Terms Property; Date of formal issuance (e.g., publication) of the resource."}],"Description":[{"label":"Description","value":"Hyaluronan is an extracellular matrix component that absorbs water in tissues and engages cell surface receptors, like Cluster of Differentiation 44 (CD44), to promote cellular growth and movement. Consequently, CD44 demarks stem cells in normal tissues and tumor-initiating cells isolated from neoplastic tissues. Hyaluronan mediated motility receptor (HMMR, also known as RHAMM) is another one of few defined hyaluronan receptors. HMMR is also associated with neoplastic processes and its role in cancer progression is often attributed to hyaluronan-mediated signaling. But, HMMR is an intracellular, microtubule-associated, spindle assembly factor that localizes protein complexes to augment the activities of mitotic kinases, like polo-like kinase 1 and Aurora kinase A, and control dynein and kinesin motor activities. Expression of HMMR is elevated in cells prior to and during mitosis and tissues with detectable HMMR expression tend to be highly proliferative, including neoplastic tissues. Moreover, HMMR is a breast cancer susceptibility gene product. Here, we briefly review the associations between HMMR and tumorigenesis as well as the structure and evolution of HMMR, which identifies Hmmr-like gene products in several insect species that do not produce hyaluronan. This review supports the designation of HMMR as a homeostasis, mitosis, and meiosis regulator, and clarifies how its dysfunction may promote the tumorigenic process and cancer progression.","attrs":{"lang":"en","ns":"http:\/\/purl.org\/dc\/terms\/description","classmap":"dpla:SourceResource","property":"dcterms:description"},"iri":"http:\/\/purl.org\/dc\/terms\/description","explain":"A Dublin Core Terms Property; An account of the resource.; Description may include but is not limited to: an abstract, a table of contents, a graphical representation, or a free-text account of the resource."}],"DigitalResourceOriginalRecord":[{"label":"Digital Resource Original Record","value":"https:\/\/circle.library.ubc.ca\/rest\/handle\/2429\/74200?expand=metadata","attrs":{"lang":"en","ns":"http:\/\/www.europeana.eu\/schemas\/edm\/aggregatedCHO","classmap":"ore:Aggregation","property":"edm:aggregatedCHO"},"iri":"http:\/\/www.europeana.eu\/schemas\/edm\/aggregatedCHO","explain":"A Europeana Data Model Property; The identifier of the source object, e.g. the Mona Lisa itself. This could be a full linked open date URI or an internal identifier"}],"FullText":[{"label":"Full Text","value":"cellsReviewHyaluronan Mediated Motility Receptor (HMMR)Encodes an Evolutionarily Conserved Homeostasis,Mitosis, and Meiosis Regulator Rather than aHyaluronan ReceptorZhengcheng He 1, Lin Mei 1, Marisa Connell 1,\u2020 and Christopher A. Maxwell 1,2,*1 Department of Pediatrics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada;zche@bcchr.ca (Z.H.); lmei@bcchr.ca (L.M.); marisa.connell@gmail.com (M.C.)2 Michael Cuccione Childhood Cancer Research Program, BC Children\u2019s Hospital, Vancouver, BC V5Z 4H4,Canada* Correspondence: cmaxwell@bcchr.ubc.ca; Tel.: +1-6048752000 (ext. 4691)\u2020 Current position: Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse,NY 13210, USA.Received: 3 March 2020; Accepted: 25 March 2020; Published: 28 March 2020\u0001\u0002\u0003\u0001\u0004\u0005\u0006\u0007\b\u0001\u0001\u0002\u0003\u0004\u0005\u0006\u0007Abstract: Hyaluronan is an extracellular matrix component that absorbs water in tissues and engagescell surface receptors, like Cluster of Differentiation 44 (CD44), to promote cellular growth andmovement. Consequently, CD44 demarks stem cells in normal tissues and tumor-initiating cellsisolated from neoplastic tissues. Hyaluronan mediated motility receptor (HMMR, also known asRHAMM) is another one of few defined hyaluronan receptors. HMMR is also associated withneoplastic processes and its role in cancer progression is often attributed to hyaluronan-mediatedsignaling. But, HMMR is an intracellular, microtubule-associated, spindle assembly factor thatlocalizes protein complexes to augment the activities of mitotic kinases, like polo-like kinase 1 andAurora kinase A, and control dynein and kinesin motor activities. Expression of HMMR is elevatedin cells prior to and during mitosis and tissues with detectable HMMR expression tend to be highlyproliferative, including neoplastic tissues. Moreover, HMMR is a breast cancer susceptibility geneproduct. Here, we briefly review the associations between HMMR and tumorigenesis as well as thestructure and evolution of HMMR, which identifies Hmmr-like gene products in several insect speciesthat do not produce hyaluronan. This review supports the designation of HMMR as a homeostasis,mitosis, and meiosis regulator, and clarifies how its dysfunction may promote the tumorigenic processand cancer progression.Keywords: cell division; centrosome; hyaluronan; HMMR; multifunctional; RHAMM1. IntroductionHyaluronan is an extracellular matrix component that absorbs water in tissues. Due to its hydratingnature, hyaluronan has many commercial uses, including cosmetic applications, but it also regulatesthe proliferation of certain stem cell populations and may enable certain hallmarks of cancer [1,2].Hyaluronan receptors, such as Cluster of differentiation 44 (CD44), are highly expressed on stem cellsin normal tissues and tumor-initiating cells isolated from neoplastic tissues [2\u20134]. Interestingly, one offew defined receptors for hyaluronan, termed hyaluronan mediated motility receptor (HMMR, alsoknown as RHAMM, XRHAMM, IHABP, or CD168), is a centrosome and microtubule-associated proteinthat regulates cell growth. HMMR associates with breast cancer risk as well as cancer progression inmultiple tumor types. Here, we outline the structure and evolution of HMMR, which supports itsCells 2020, 9, 819; doi:10.3390\/cells9040819 www.mdpi.com\/journal\/cellsCells 2020, 9, 819 2 of 14designation as a homeostasis, mitosis, and meiosis regulator rather than a hyaluronan receptor. Thisreview helps to clarify how the perversion of HMMR function during cell division may support thetumorigenic process.2. A Brief History of Hyaluronan Mediated Motility Receptor (HMMR)HMMR was first identified as a constituent of a novel hyaluronan receptor complex purifiedfrom the supernatants of murine cells [5]. In 1992, a partial Hmmr transcript was cloned and the geneproduct was predicted to be about 58 kDa [5]. Many of the early experiments that described HMMR asa hyaluronan receptor used reagents generated against and\/or recognizing proteins (56\u201375 kDa) that arenow known to be much smaller than full-length HMMR (reviewed in [6]); we now know that murineHmmr contains 18 exons and encodes a 95 kDa protein [6,7]. Often, experiments studied truncatedHmmr cDNA, which lack N-terminal sequence and key domains: for example, RHAMM 1v4, whichonly encodes exon 6\u2013exon 18, and RHAMM2, which only encodes exon 10\u2013exon 18 (reviewed in [6]).In 1999, five additional exons were cloned at the N-terminus of HMMR; as the gene product was foundto be exclusively intracellular, it was suggested that it be renamed Intracellular hyaluronan bindingprotein (IHABP) [8,9]. This complicated history and the confusing nomenclature (i.e., RHAMM1,RHAMM1v4, RHAMM2, or IHABP) serves to cloud our understanding of the gene product\u2019s functionboth as a microtubule-associated spindle assembly factor and as a putative hyaluronan receptor.What\u2019s in a name? That which we call a roseBy any other word would smell as sweet.Romeo and Juliet, 2, 2, 45-46Juliet\u2019s words are eloquent but the sharing of scientific information does rely upon accurate naming,classification, and ontology. Certain proteins assume unconventional roles during pathologicalconditions that may render their classification opaque [10,11]. However, an unbiased examinationof the evolution of the HMMR gene and the gene product\u2019s structure may provide clarity to thephysiological functions and how those functions are perverted during the tumorigenic process.3. The Conserved Basic C-Terminal Domain in HMMR Is a Leucine Zipper MotifTo interact with hyaluronan, CD44 and other link module-based binding proteins use tandemrepeat loops with homology to the cartilage link protein [12]. HMMR, however, was shown to interactwith hyaluronan in an ionic manner through a basic, 35 amino acid, C-terminal region, which can befurther subdivided into two motifs of 10 amino acids and 11 amino acids, respectively [13]. Thesemotifs correspond with human HMMR amino acids 636\u2013646 and amino acids 658\u2013667, which are highlybasic regions that became known as Basic (B) (X)7 Basic (B X7 B) motifs [13,14] (Figure 1A). Perhapsunsurprisingly, these basic residues in HMMR are essential for an ionic interaction with hyaluronan aswell as heparin [13,14], and these interactions are abolished with increasing concentrations of salt [13].It is important to note, however, the so-called \u201cX7\u201d residues are in fact highly ordered andevolutionarily conserved. When represented as a heptad repeat, this motif contains a leucine everyseven residues (position 1) and conserved hydrophobic (interior) and polar (exterior) residues thatenable a predicted coiled-coil structure and a basic leucine zipper (bZip) motif. Importantly, this bZipmotif is conserved throughout chordates, including in the sea squirt Ciona intestinalis, as well as inspecies of insects (Figure 1B). That this highly basic stretch of amino acids binds in an ionic mannerto hyaluronic acid in vitro is expected; that an urochordate and several species of insects encode aputative hyaluronan receptor (Hmmr) is remarkable, given these animals lack evidence for hyaluronananabolism or synthesis, which first appears in amphioxus [15].Cells 2020, 9, 819 3 of 14Cells 2020, 9, x  3 of 14  3 Figure 1. Conserved structural domains in chordate and insect Hyaluronan mediated motility receptor (HMMR). (A). The N-terminal microtubule-binding domain (blue) is separated from a C-terminal basic leucine zipper motif (bZIP, black) by a large predicted coiled-coil domain. The C-terminus targets the protein to the centrosome and regulates ubiquitination. Somatic mutations in HMMR occur at a hotspot in the bZIP motif and give rise to frameshift mutations that truncate or alter the C-terminus (ex. MDA-MB-231). The basic motifs in HMMR that interact with hyaluronan (HA) are boxed in grey. Conserved leucines are indicated in green for the bZIP motif, which is underlined in black. (B). Conservation of the bZip motif in vertebrate and invertebrate animals. Leucines (position 1) and hydrophobic residues (position 5) that comprise the hydrophobic face (green) are conserved. Polar residues (red) are also conserved while positions 3 and 6 show more variability (grey). (C). Hydrophobicity plots (AlignMe) comparing human HMMR (075330) with an Hmmr-like product in Red Flour beetle (D2A2B7, 813 aa). (D). Length represented as a fraction of total protein size for the predicted coiled coil length in human HMMR (red) and Hmmr-like gene products identified in insect species. (E). MDA-MB-231 cells contain an A664 frameshift mutation and express reduced levels of HMMR. The reduced expression for HMMR in MDA-MB-231 cells is not due to cell cycle distribution as levels are reduced in lysates from nocodazole-synchronized G2\/M cells. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) serves as a loading control and Aurora Figure 1. Conserved structural domains in chordate and insect Hyaluronan mediated motility receptor(HMMR). (A). The N-terminal microtubule-binding domain (blue) is separated from a C-terminalbasic leucine zipper motif (bZIP, black) by a large predicted coiled-coil domain. The C-terminustargets the protein to the centrosome and regulates ubiquitination. Somatic mutations in HMMRoccur at a hotspot in the bZIP motif and give rise to frameshift mutations that truncate or alter theC-terminus (ex. MDA-MB-231). The basic motifs in HMMR that interact with hyaluronan (HA) areboxed in grey. Conserved leucines are indicated in green for the bZIP motif, which is underlinedin black. (B). Conservation of the bZip motif in vertebrate and invertebrate animals. Leucines(position 1) and hydrophobic residues (position 5) that comprise the hydrophobic face (green) areconserved. Polar residues (red) are also conserved while positions 3 and 6 show more variability (grey).(C). Hydrophobicity plots (AlignMe) comparing human HMMR (075330) with an Hmmr-like productin Red Flour beetle (D2A2B7, 813 aa). (D). Length represented as a fraction of total protein size for thepredicted coil d coil le gth in human HM R (red) and Hmmr-like gene product identified i i sectsp cies. (E). MDA-MB-231 cells contain an A664 frame hift mutation a d express redu d levels ofHMMR. The reduce expression for HMMR in MDA-MB-231 cells is not due t cell cycle d stribution aslevels are reduced in lysates from nocodazole-synchronized G2\/M cells. Glyceraldehyde 3-phosphatedehydrogenase (GAPDH) serves as a loading control and Aurora kinase A (AURKA) serves as a controlfor the expression of a cell cycle-regulated gene product in the cell lysates.Cells 2020, 9, 819 4 of 143.1. Structural Domains in HMMRHMMR is predicted to be a hydrophilic protein (Figure 1C) and lacks a hydrophobic signal peptideor potential hydrophobic transmembrane domains. In fact, HMMR lacks the structural propertiesrequired for canonical extracellular export. Across chordate and insect species, HMMR is predictedto be a largely coiled-coil protein (Figure 1D, 80\u201385% of total amino acids) with microtubule bindingdomains at the N-terminus and a bZip motif [16] and degradation domains [17] at the C-terminus.These structural features\u2014N-terminal microtubule binding, largely coiled-coil structure, C-terminalbZip motif\u2014support its role as a non-motor spindle assembly factor.The central region of human HMMR is a coiled-coil stalk (amino acids 69\u2013681) that acts as apotential dimerization domain and binding region for other proteins. That is, HMMR interactswith CHICA\/FAM83D through amino acids 365\u2013546 [18], while amino acids 574\u2013602 act as acalcium-dependent calmodulin binding domain [19]. Through its interaction with CHICA, HMMRlocates dynein light chain 1 (DYNLL1) and CK1alpha to the spindle [20], and HMMR plays a similarrole in docking BACH1 at the spindle [21], although the needed interaction domain is unknown. Theseprotein complexes, formed through interactions with the coiled-coil stalk, play critical roles in thecorrect orientation of the mitotic spindle and the establishment of the cell division axis.At the N-terminus, human HMMR possesses two microtubule binding subdomains at aminoacids 40\u201359 and amino acids 76\u201390, respectively, with the latter domain encoded by exon 4 [19].Through these domains, HMMR binds directly to microtubules [19]. While full-length HMMR isable to locate to centrosomes and bind to microtubules [16], the naturally occurring splice variantHMMR (-exon 4) localizes to the mitotic spindle during mitosis but shows nuclear localization duringinterphase [16,19]. Localization to the nucleus is also seen for a phosphorylated form of HMMR atThr703 [22]. Phosphorylation at Thr703 was identified by phospho-proteomics [23] and, through theuse of antibodies specific for phospho-Thr703 HMMR, it was revealed that phospho-Thr703 not onlydirects the protein to the nucleus but also may assist in the regulation of the Ran-dependent nucleartransport of targeting protein for Xklp2 (TPX2) [22].The very N-terminal residues in HMMR are uniquely similar to those of mira\/Miranda [24],a determinant of asymmetric neuroblast divisions in Drosophila. Miranda is a docking protein inneuroblasts that is responsible for the asymmetric cortical localization of key proteins and mRNAsthat regulate neuroblast cell fate, including Prospero and brain tumor (Brat) [25,26]. Despite thiscritical role in Drosophila neurodevelopment, Miranda has no known orthologs outside the orderDiptera. Importantly, Miranda and HMMR share significant similarity in their very N-terminalsequence [24]. These N-terminal residues in Miranda are needed for microtubule-dependent asymmetriclocalization [27]. Moreover, both Miranda and HMMR are largely coiled-coil proteins that bindmicrotubules but HMMR has not yet been determined to play an orthologous function duringasymmetric cell divisions.The conserved, C-terminal bZip motif in HMMR overlaps with the designated B-X7-B motifs,which bind in an ionic manner to hyaluronan and heparin [13,14]. The bZip motif of HMMRcontains 72% homology with a C-terminal bZip motif in kinesin-like protein Kif15\/hKlp2 (amino acids1342\u20131388) [16]. Importantly, the bZip motif in hKlp2 locates the protein to microtubule minus endsthrough an interaction with targeting protein for Xklp2 (TPX2) [28]. While TPX2 was first defined bycomplexing with the bZip motif in hKlp2 and targeting the complex to microtubule minus ends [28,29],TPX2 has now been extensively characterized as both a critical activator for the mitotic kinase Aurorakinase A as well as other functions (reviewed in [30]). For HMMR, the bZip motif locates the protein tothe centrosome and HMMR complexes with a significant fraction of TPX2 in a cell cycle-dependentmanner [31\u201334]. These complexes serve to both regulate mitotic kinase activities [33] and alter Eg5motor protein processivity [35,36].Taken together, the structure of HMMR is one of a largely coiled-coil microtubule-associatedprotein, which can bind to microtubules directly through its N-terminus and localize to the centrosomethrough its C-terminal bZip motif. HMMR serves as a binding partner for spindle assembly factors,Cells 2020, 9, 819 5 of 14such as TPX2, DYNLL1, and CHICA\/FAM83D, to regulate the assembly, stability and positioning ofspindle microtubules during mitosis and meiosis.3.2. Evolution of HMMRThe presence of hmmr orthologs amongst invertebrate animals has not been examined likelybecause arthropods do not express hyaluronan [37]. By using the conserved bZip motif as a landmark,we identified putative hmmr orthologs in many, but not all, orders of insects (Table S1). The bZipmotif in hmmr homologs are most highly conserved in Isoptera, the earliest insect lineage represented(Figure 1B). We found no evidence for hmmr homologs in genomes in the order Diptera, whichincludes Drosophila.We discovered that hmmr and mira are mutually exclusive amongst insect species with miraencoded exclusively in Dipterans. Comparison of N-terminal homology regions [24] from 127 knownand predicted Miranda and HMMR\/Hmmr sequences identified conservation in critical residues (Ala6and Ala18, [24]), suggesting that mira potentially evolved in Diptera from an ancestral hmmr (Table S1).It is a striking finding that a defined receptor (Hmmr) is encoded within multiple species that donot produce its putative ligand (hyaluronan). As Hmmr-like orthologs are encoded in species thatpredate the first appearance of hyaluronan by millions of years (in amphioxus [15]), we must concludethat Hmmr did not originally evolve as a hyaluronan receptor.3.3. Conserved HMMR-NudC Domain-Containing Protein 2 (NUDCD2) Gene ClusterThe appearance of HMMR in multiple species that lack hyaluronan strongly argues against itplaying an evolutionarily-conserved role in hyaluronan binding. Indeed, the conserved gene locationof HMMR across multiple species of tetrapods and fish may implicate an evolutionarily-conservedrole related to cell cycle and dynein motor activity. That is, HMMR is found in a small four genecluster, along with NUDCD2 (NudC domain-containing protein 2), CCNG1 (cyclin G1), and MAT2B(methionine adenosyltransferase 2B), at 163.5 MB of human chromosome 5q34 (Figure 2A).The HMMR-NUDCD2 gene cluster is proximal to a cluster of gamma-aminobutyric acid (GABA)A receptor subunit genes at 162 MB of human chromosome 5q33.3; this region of human chromosome5q associates with human diseases related to neural development and\/or homeostasis, includingaddiction, schizophrenia, memory, seizures (for 5q33.1), prominent forehead, and mental retardation(for 5q34). The proximity of these two small gene clusters has been maintained through the evolutionof jawed vertebrates (Figure 2B): one cluster encodes cell cycle and dynein related gene products(CCNG1-NUDCD2-HMMR) while the other encodes GABAA receptor subunits.In cartilaginous fish and Ciona, which is potentially the closest invertebrate to humans, HMMR,NUDCD2, GABRB2, and CCNG1 are located at different chromosomal sites (Figure 2B). Initiating withbony fish, however, NUDCD2 and CCNG1 are clustered with GABRA1 and GABRA6 while HMMR islocated relatively proximal on chromosome 14 (Figure 2B). In lobe-fin fish, the two clusters separateand their organization and overall structure are maintained through tetrapod evolution (Figure 2B).It is important to note the conserved orientation of HMMR and NUDCD2 in these small geneclusters. That is, the genes are oriented in opposite directions; for example, on human chromosome 5q,HMMR is in a forward orientation (163,460 kB\u2013163,492 kB) and NUDCD2 is in a reverse orientation(163,446 kB\u2013163,460 kB) so that the 5\u2032 ends of the genes are 530 base-pairs apart. This conserved, closeproximity of NUDCD2-HMMR may be a chance of nature. But, importantly, HMMR and NUDCD2perform similar cell cycle-regulated functions as adaptors for dynein motor proteins and each havecritical roles in the process of neural development and homeostasis.Cells 2020, 9, 819 6 of 14Cells 2020, 9, x  6 of 14  6 Figure 2. Conserved HMMR-NUDC domain-containing protein 2 (NUDCD2) gene cluster in tetrapods. (A). Chromosome location for the CCNG1-NUDCD2-HMMR and GABAA gene clusters on human chromosome 5q33.1. Importantly, NUDCD2 and HMMR are oriented in opposite directions such that their 5\u2032-ends are separated by only 530 base-pairs. The proximity of these gene clusters is conserved throughout chordates. In humans, this region of chromosome 5q associates with numerous human diseases and phenotypes related to neural development and homeostasis. (B). Chromosome locations for the CCNG1-NUDCD2-HMMR and GABAA gene clusters shows conservation of clusters within tetrapod species and lobe-fin fish species. The orientation of genes is indicated as forward (+) or reverse (\u2212). It is important to note the conserved orientation of HMMR and NUDCD2 in these small gene clusters. That is, the genes are oriented in opposite directions; for example, on human chromosome 5q, HMMR is in a forward orientation (163,460 kB\u2013163,492 kB) and NUDCD2 is in a reverse orientation (163,446 kB\u2013163,460 kB) so that the 5\u2032 ends of the genes are 530 base-pairs apart. This conserved, close proximity of NUDCD2-HMMR may be a chance of nature. But, importantly, HMMR and NUDCD2 perform similar cell cycle-regulated functions as adaptors for dynein motor proteins and each have critical roles in the process of neural development and homeostasis. 4. HMMR Functions as a Homeostasis, Mitosis, and Meiosis Regulator Figure 2. Conserved HMMR-NUDC domain-containing protein 2 (NUDCD2) gene cluster in tetrapods.(A). Chromosome location for the CCNG1-NUDCD2-HMMR and GABAA gene clusters on humanchromosome 5q33.1. Importantly, NUDCD2 and HMMR are oriented in opposite directions such thattheir 5\u2032-ends are separated by only 530 base-pairs. The proximity of these gene clusters is conservedthroughout chordates. In humans, this region of chromosome 5q associates with numerous humandiseases and phenotypes related to neural development and homeostasis. (B). Chromosome locationsfor the CCNG1-NUDCD2-HMMR and GABAA gene clusters shows conservation of clusters withintetrapod species and lobe-fin fish species. The orientation of genes is indicated as forward (+) orreverse (\u2212).4. HMMR Functions as a Homeostasis, Mitosis, and Meiosis Regulator4.1. HM R Is Needed for Tissue Homeos asis and Neural DevelopmentHMMR is expressed in the developing nervous system [38] as well as in the proliferative regionsof the adult mouse brain [39]. The mutation or loss of HMMR in vertebrate animal models inducesneurodevelopmental defects [7,40,41]. Hmmrtm1a\/tm1a mice encode Hmmr with targeted disruptionfollowing exon 2 while Hmmrm\/m mice encode Hmmr that potentially retain N-terminal HMMRstructure due to targeted disruption after exon 10. As a consequence, loss-of Hmmr phenotypes differCells 2020, 9, 819 7 of 14in these animals. Hmmrtm1a\/tm1a mice suffer neonatal lethality and display heterogeneous cortical sizes,enlarged ventricles, and alterations in neural cell subsets [7]. However, Hmmrm\/m mice are viable but,Hmmrm\/m embryos undergo transient megalencephaly during development [40]. In both mouse models(Hmmrtm1a\/tm1a mice and Hmmrm\/m mice), the C-terminus of Hmmr is required to orient neural stem celldivisions [7,40].A third animal model, Xenopus embryos treated with morpholinos targeting hmmr, also presentwith neurodevelopmental defects. Hmmr morphant embryos develop brain defects, including defectiveneural tube closure, narrowed forebrains, loss of hemispheric separation, and smaller olfactorybulbs [41]. In this model, hmmr morphant cells rescued with a mutant lacking the N-terminal 130 aminoacids were rounded and displayed web-like microtubule arrays rather than the linear arrays observedin wild-type neural cells [41]. Thus, the N-terminus of Hmmr was required for the polarization of cellsin the deep neural layer.Loss of Hmmr\/hmmr phenotypes are reminiscent, but not overlapping with those seen for LIS1(Lissencephaly 1), an alternate cytoplasmic dynein partner protein; classical lissencephaly, a braindevelopmental disease characterized by decreased cortical complexity and generally larger brainsize, results from mutations in the LIS1 gene [42]. A complex between dynein and the coiled-coiladaptor proteins LIS1, NUDC (nuclear distribution C, dynein complex regulator) and NUDE-like1 (NDEL1) is required for correct corticogenesis. The loss of this complex, mediated through LIS1mutations, can result in a cortical malformation disorder associated with severe cognitive impairmentand epilepsy [43].Importantly, NDEL1 relies upon post-translational modification by Aurora kinase A and TPX2to modify microtubule dynamics, neuronal migration and neurite extension downstream [44\u201346].Provocatively, NUDCD2 also regulates the LIS1-dynein complex [47], centrosome function [48], andmitotic spindle integrity [49]. Thus, the evolutionally conserved HMMR-NUDCD2 gene cluster encodestwo coiled-coil centrosome proteins that complex with dynein and play critical roles in homeostasis,centrosome function, and mitotic spindle integrity.In mouse models, the mutation or loss of HMMR\/Hmmr expression also disrupts the correctdevelopment or homeostasis of gonadal tissues [7,50,51]. While the mechanisms responsible are yetto be determined, these phenotypes are likely reflective of the high expression of HMMR in gonadaltissues and the necessary role played by dynein, and its adaptor proteins, during the processes ofgametogenesis and spermatogenesis [52\u201354].4.2. HMMR Regulates Spindle Assembly in Mitotic Cells and Meiotic Extracts.HMMR is a largely coiled-coil protein that can bind to microtubules directly through itsN-terminus [19] and localize to the centrosome through a C-terminal bZip motif [16], which isstructurally very similar to the C-terminal bZip motif in Xklp2 that enables an interaction withTPX2 [16,28]. The similarity in these domain structures seeded the hypothesis that HMMR also interactswith TPX2, which has been confirmed experimentally through the study of HMMR\/RHAMM in humanmitotic cells [16,33,35] and Xenopus RHAMM (XRHAMM) in Xenopus meiotic extracts [32,34,36,55].The interaction between HMMR and TPX2 is important for Ran-dependent microtubule assemblynear chromosomes [32,34], the activity of Aurora kinase A and microtubule nucleation at spindlepoles [33], and the regulation of the processivity of the kinesin motor Eg5 [35,36]. The C-terminal bZipmotif in Xklp2 regulates its location to microtubule minus ends in a dynein-dependent manner [28];similarly, the C-terminal bZip motif in HMMR regulates its location to centrosomes and interactionwith dynein [31].HMMR is critical for the orientation of the mitotic spindle in human mitotic cells. HMMR locatesDYNLL1 indirectly through an interaction with CHICA\/FAM83D [18], which serves to modulatethe position of the mitotic spindle through three complementary mechanisms: 1. HMMR localizesDYNLL1 at spindle poles, which dampens local dynein motor activities when brought proximal to theCells 2020, 9, 819 8 of 14cell cortex [18]; 2. HMMR modulates the local activity of PLK1 and locates Ran-GTP to the spindlepole [7]; and, HMMR binds CHICA\/FAM83D to locate and activate the protein kinase CK1alpha [20].Each of the preceding mitotic and meiotic functions were predicted by the domain structureof HMMR. In addition to such hypothesis-based studies, a number of non-biased, genome-wideanalyses also indicate similar mitotic roles of HMMR. The All RNA-Seq and Chip-Seq Sample andSignature Search (ARCHS4) tool, which mines sequencing data from 103,083 mouse and 84,863human samples [56], predicts HMMR functions in processes related to mitosis and chromosomesegregation, kinetochore, and nuclear pore complex assembly, which have all been independentlyand experimentally validated [16,22,35]. Using this tool [56], HMMR is found to be co-expressedwith TOP2A, KIF11, TPX2, ECT2, BUB1, KIF20A, NUSAP1, KIF20B, SMC2, and CCNA2; each ofthese gene products are involved with cell cycle regulation, spindle organization, and chromosomesegregation. A complementary proteome-wide analysis of mitotic substages, which combined specificintracellular immunolabeling protocols and FACS separation of interphase and mitotic cells, identifiedHMMR as one of 14 proteins that peak in abundance in G2-phase and mitosis along with othercell cycle gene products, such as Aurora A and B, Polo-like kinase 1, and CENPF [57]. Finally, theMitocheck consortium combined several powerful screening tools, such as RNA interference, time-lapsemicroscopy and computational image processing that assessed chromosome and nuclear morphology,to profile the roles of ~21,000 gene products during mitosis [58]. HMMR depletion was associatedwith mitosis-specific phenotypes, such as strange nuclear shape, polylobed nuclei and chromosomesegregation errors, leading to HMMR being designated a validated mitotic hit [58].Given the critical mitotic functions of HMMR, it is unsurprising that HMMR is predicted tobe regulated by proliferation associated transcription factors, FOXM1, E2F4, and MYC [56] and,experimentally, by YAP-TEAD of the Hippo pathway [59]. Similarly, it is unsurprising that HMMRexpression is transcriptionally downregulated by the tumor suppressor TP53 [60]. Perhaps lesspredictable are the mechanisms utilized for post-transcriptional regulation of HMMR expression.Along with Bard1 and other Ran-dependent spindle assembly factors, Hmmr was identified as asubstrate for the ubiquitin ligase anaphase-promoting complex\/cyclosome (APC\/C) [17]; the recognitionand proteolysis of Hmmr and Bard1 (as well as complexed Brca1) relied upon APC\/C recognitionmotifs, such as destruction (D) box, KEN box, or TEK box [17]. For Hmmr, D, KEN, and TEK boxeswere identified in the C-terminal domain [17]. HMMR is also a substrate for the BRCA1\/BARD1E3 ubiquitin ligase [61] and deficient BRCA1 function leads to the stabilization of HMMR [61,62].The HMMR-BRCA1 interaction influences mammary tumorigenesis as indicated by the associationbetween HMMR polymorphisms and breast cancer risk in carriers of BRCA1 mutations but not BRCA2mutations [63]. Similarly, a HMMR partner protein, DYNLL1, has been correlated with progressionfree survival in carriers of BRCA1 mutations but not BRCA2 mutations and shown to modulatePARP inhibitor sensitivity in BRCA1-mutant cells [64]. The potential importance of HMMR-DYNLL1mediated control of the cell division axis in the context of BRCA1 mutations is not yet known but mayhelp to explain how BRCA1 mutations perturb the differentiation hierarchy present in the normalhuman mammary gland [65\u201367].5. HMMR Associates with Breast Cancer risk, Cancer Prognosis, and ProgressionThe expression of HMMR is cell cycle-regulated with peak expression between late G2 phaseand early mitosis [31]. Consistently, HMMR expression is low in most healthy tissues but is elevatedin proliferative tissues, such as the testis, spleen, placenta, and thymus [7,8]. Moreover, elevatedHMMR expression associates with poor prognosis in a variety of cancers, such as breast cancer [68],colorectal cancer [69], stomach cancer [70], endometrial cancer [71], prostate cancer [72], and multiplemyeloma [73]. But, the association between HMMR and cancer is not as simple as high HMMRexpression demarcates very mitotic tumors, which correlates with more aggressive tumor growth andpoor patient survival.Cells 2020, 9, 819 9 of 14For several types of cancers, poor patient survival also associates with low HMMR expression. Forexample, hemizygous deletion of HMMR is present in almost half of malignant peripheral nerve sheathtumors [74,75]; HMMR expression is diminished in 96% of human seminomas [50]; and, germlineHMMR variants that associate with lower expression also associate with increased breast cancer risk insome patient cohorts [61,76,77]. Moreover, an HMMR splice variant that loses microtubule bindingactivity is expressed at an elevated level in a variety of cancers. That is, the N-terminal domain ofHMMR binds microtubules, encoded in part by exon 4 [16,19], and the expression of a naturallyoccurring splice variant that lacks exon 4 (-exon 4) correlates with progression of multiple myeloma [73]and breast cancers [78]. HMMR (-exon 4) expression is also sufficient to promote pancreatic islet tumorgrowth and metastasis to lymph nodes and liver [79]. As indicated by the cancer cell-line encyclopediaand COSMIC databases, HMMR contains a mutational hotspot encoded by a homopolymeric adeninetract within the C-terminal basic leucine zipper motif (Figure 1A). Indeed, immortal MDA-MB-231breast cancer cells contain an A664 frameshift mutation (cDNA change c.1992_1993insA), and theexpression of HMMR is greatly reduced in lysates from nocodazole-synchronized, G2\/M phase lysatesgenerated from MDA-MB-231 cells relative to MCF7 cells or MCF10A cells (Figure 1E). Thus, aggressivecancers may contain either abnormally high or abnormally low expression of HMMR, and tumorsare frequently characterized by the expression of a putative loss of function HMMR splice variant(-exon 4) or frameshift mutations in the homopolymeric adenine tract within the C-terminal bZip motif(Figure 1A).HMMR is a low penetrance breast cancer susceptibility gene [61]; genotyping of three HMMRhaplotype-tagging single nucleotide polymorphisms (htSNPs) identified statistically significantassociations with risk of breast cancer [61]. Importantly, HMMR htSNPs showed an associationwith either germline overexpression (rs10515860 SNP; A-C-A haplotype) or germline downregulationof HMMR (G-C-A-T-G haplotype) [61]. HMMR is also a key substrate for the BRCA1-BARD1 E3ubiquitin ligase during the process of spindle assembly [61]; dysfunction of BRCA1 is well-documentedto stabilize HMMR protein expression [50,55,61,62]. Moreover, common HMMR variants modify therisk of developing breast cancer for carriers of BRCA1, but not BRCA2, mutations [63]. Thus, there isevidence to support the hypothesis that HMMR protein abundance must be tightly regulated throughtranscriptional control by TP53 [60] and the Hippo pathway [59] and post-translational turnover byBRCA1-BARD1 [61] and the anaphase promoting complex [17]. Consistent with this, silencing orelevating HMMR expression disrupts microtubule-based processes during cell division, and results inmitotic spindle abnormalities, genome instability, and changes to the cell division axis and progenitorcell fate.6. ConclusionsIt is also possible, and has not been disproven, that the unconventional export of HMMR duringpathological states may enable non-physiological functionalities, such as ionic interaction between theC-terminal bZip motif and acidic hyaluronan or heparin. However, hmmr is encoded in numerousspecies that lack hyaluronan, which argues strongly that HMMR did not evolve as a hyaluronanreceptor; rather, the evolution of HMMR in a small gene cluster with the dynein adaptor NUDCD2and the structure of the HMMR gene product support the designation of HMMR as a homeostasis,mitosis, and meiosis regulator. Indeed, HMMR is a largely coiled coil gene product with evolutionarilyconserved N-terminal and C-terminal domains that target the protein to microtubules and centrosomes,respectively. Consistent with these structural features defining the protein\u2019s physiological function,recent studies indicate necessary roles for HMMR during cell division and microtubule-associatedprocesses related to neural development, control of the cell division axis, and progenitor cell fate inthree different vertebrate animal models.Supplementary Materials: The following are available online at http:\/\/www.mdpi.com\/2073-4409\/9\/4\/819\/s1,Table S1: HMMR and Miranda sequences and domains in insect species.Cells 2020, 9, 819 10 of 14Author Contributions: Conceptualization, Z.H., M.C., and C.A.M.; formal analysis, M.C.; investigation, Z.H.,and M.C.; writing\u2014original draft preparation, Z.H., M.C. and C.A.M.; writing\u2014review and editing, Z.H., L.M.,M.C., and C.A.M.; supervision, C.A.M.; funding acquisition, Z.H., M.C., and C.A.M. All authors have read andagreed to the published version of the manuscript.Funding: This research was funded by: Michael Cuccione Foundation (MCF) brain tumour award (CAM), CanadaInstitutes for Health Research (CIHR), in partnership with the Avon Foundation for Women, operating grant(CAM), CIHR New Investigator Salary Award (CAM), CFRI scientist level 1 salary award (CAM), University ofBritish Columbia 4-year fellowship (ZH), and MCF fellowship (MC).Acknowledgments: The authors acknowledge the support of the Michael Cuccione Foundation.Conflicts of Interest: The authors declare no conflict of interest.References1. Caon, I.; Bartolini, B.; Parnigoni, A.; Carava, E.; Moretto, P.; Viola, M.; Karousou, E.; Vigetti, D.; Passi, A.Revisiting the hallmarks of cancer: The role of hyaluronan. Semin. Cancer Biol. 2019. [CrossRef] [PubMed]2. Skandalis, S.S.; Karalis, T.; Heldin, P. Intracellular hyaluronan: Importance for cellular functions. Semin.Cancer Biol. 2019. [CrossRef] [PubMed]3. 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Receptor for hyaluronan-mediated motility isoform Bpromotes liver metastasis in a mouse model of multistep tumorigenesis and a tail vein assay for metastasis.Proc. Natl. Acad. Sci. USA 2011, 108, 16753\u201316758. [CrossRef]\u00a9 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open accessarticle distributed under the terms and conditions of the Creative Commons Attribution(CC BY) license (http:\/\/creativecommons.org\/licenses\/by\/4.0\/).","attrs":{"lang":"en","ns":"http:\/\/www.w3.org\/2009\/08\/skos-reference\/skos.html#note","classmap":"oc:AnnotationContainer"},"iri":"http:\/\/www.w3.org\/2009\/08\/skos-reference\/skos.html#note","explain":"Simple Knowledge Organisation System; Notes are used to provide information relating to SKOS concepts. 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