Cd44 variant regulates redox status in cancer cells by. The multiple protein isoforms are encoded by a single gene by alternative splicing and are further modi. Cd44 clustering is involved in monocyte differentiation. Cell adhesion molecules, once believed to function primarily in tethering cells to extracellular ligands, are now recognized as having broader functions in cellular signalling cascades. Cd44 signaling through focal adhesion kinase and its anti.
The winding road from adhesive receptors to the nucleus. Cd44 mediates stem cell mobilization to damaged lung via. May 10, 2018 cd44, a nonkinase transmembrane glycoprotein, is overexpressed in several cell types including cancer stem cells and frequently shows alternative spliced variants that are thought to play a role in cancer development and progression. Cd44 cell adhesion molecules s goodison, v urquidi, d tarin abstract the cd44 proteins form a ubiquitously expressed family of cell surface adhesion molecules involved in cellcell and cell matrix interactions. Cd44 is an adhesion molecule expressed in cancer stemlike cells. Proteolytic release of cd44 intracellular domain and its. Cd44 stimulation induces integrinmediated adhesion of.
After activation of naive t cells, cd44, a widely expressed receptor for extracellular matrix components, is upregulated. Cd44 is a widely expressed cellular adhesion molecule that serves as a principal receptor for extracellular matrix ecm components such as hyaluronan ha, which accumulates in atherosclerotic lesions. Knockdown of cd44 regulates endothelial cell differentiation. Pdf proteolytic cleavage of the cd44 adhesion molecule. Cd44 is a cam that is involved in cellcell and cellmatrix signaling and adhesion 2,3. Cd44 is associated with lipid rafts glycolipid enriched membrane microdomains, gems, through the transmembrane domain. Adhesion receptor signalling, regulation of gene expression and their relevance to cell growth, differentiation, survival and development were the topics of the 2001 european science foundation conference, organized by g.
The biology and role of cd44 in cancer progression. Cadherins are a family of integral membrane glycoproteins, which are the prime mediators of calcium dependent cellcell adhesion in normal cells. Lipidbased nanovectors for targeting of cd44overexpressing. Cd44 is the major surface hyaluronan ha receptor implicated in intercellular and cellmatrix adhesion, cell migration and signaling.
Cd44 is the signaling component of the macrophage migration. The remaining membrane anism involved in the regulation of cd44 function. Most studies have supported an important role for cd44 in promoting leukocyte recruitment, likely mediated by extracellular matrix components triggering changes in the cytoskeletan via cd44 dependent signaling events. Misra s, heldin p, hascall vc, karamanos nk, skandalis ss, markwald rr. Most primary cells express cd44 but in a low affinity state that does not exhibit a. May 15, 2003 clearly, cd44 has different functions on different cell populations. Pdf cd44 acts as a signaling platform controlling tumor. In a bidirectional crosstalk, cell adhesion and signalling receptors ar. Phosphatidylinositol 4,5bisphosphate clusters the cell. Although alternative splicing can produce a large number of different isoforms, they all retain the hyaluronanbinding linkhomology region and a common transmembrane and cytoplasmic domain, which are highly conserved between species. Mechanism and biological significance of cd44 cleavage. Osteopontin can bind to the variants, cd44v6 and v7, to initiate cell survival, migration, invasion and angiongenesis signaling 19. Cd44 integrates signaling in normal stem cell, cancer stem cell and. The disordered cd44ct interacts with ferm only in the presence of phosphatidylinositol 4,5bisphosphate pip2.
The cd44 transmembrane glycoprotein family adds new aspects to these roles by participating in signal transduction processes not only by establishing specific transmembrane complexes, but also by organizing. Cd44dependent regulation in vascular cells such as vsmcs or ecs. Rather, ligand binding, as exemplified for cd44 and other similar adhesion molecules, initiates a cascade of events that can be started by adherence to the extracellular matrix. A mode of cell adhesion and migration facilitated by cd44. Loss of cd44 attenuates aberrant gmcsf signaling in kras. High expression of cd44 remains on memory cells and despite its wide usage as a memory marker, its. Cd44 binding to hyaluronan by glycosylation of variably spliced exons. Sep 18, 2002 as opposed to integrin signaling, however, the cd44.
A critical role of cd44 in monocyte adhesion was further examined in young endothelial cells transfected with the cd44 plasmid construct. Cd44 is a cam that is involved in cellcell and cellmatrix signaling and adhesion 2, 3. Liver cancer initiation requires p53 inhibition by cd44. Among these molecules, cd44 was highly and consistently expressed on all. Cd44 is an adhesion molecule that interacts with hyaluronic acid ha and is implicated in a wide variety of physiological and pathological processes. Cd44 signaling in prostate cancer cells has also been shown to regulate key proteins i.
By dynamic regulation of actin cytoskeleton that attaches with the cytoplasmic domain of cd44 receptor, formation of cells adhesive structure is. Hyaluronan, the main ligand for cd44, binds to and activates cd44 resulting in activation of cell signaling pathways that induces cell proliferation, increases. Roesler j, srivatsan e, moatamed f, peters j and livingston eh 1997 tumor suppressor activity of neural cell adhesion molecule in colon carcinoma. Cd44 is a cell adhesion molecule that functions in cell proliferation. One of the adhesionstrengthening signalling pathways proceeds via the cd44 associationinitiated activation of a rho guanine exchange factor. Metastasis of circulating tumor cells requires a multistep cascade of events initiated by adhesion of tumor cells to the vascular endothelium of involved tissues. Expression of cell adhesion molecules in oesophageal. Cd44 is a singlechain molecule that is made up of three main parts extracellular, intracellular and transmembrane domains 4. A link between the references presence of specific cd44 isoforms on cscs and their function 1. The cams control cell behavior by mediating contact between cells or between cells and the extracellular matrix and are essential for maintaining tissue integrity. The cd44 antigen is a cellsurface glycoprotein involved in cellcell interactions, cell adhesion and migration. In addition to providing structural tethering points for cells, some adhesion molecules transduce signals that result in a broad range of cellular processes. Pdf proteolytic cleavage of the cd44 adhesion molecule in. Cleavage of hyaluronan and cd44 adhesion molecule regulate.
The loss of cell adhesion molecules is reported to be associated with the metastasis and invasion of crc, since the activation of cell motility and detachment from other cells, the stroma and the ecm represent the biological. Characterizing cd44 regulatory micrornas as putative. Adhesion, migration and growth regulation marhaba, r zoller, m. This process occurs under the forces of blood flow and is promoted by adhesion molecules specialized to interact under shear conditions. Dec 01, 2018 cd44 is a cam that is involved in cellcell and cellmatrix signaling and adhesion 2,3. For an adhesion receptor to mediate its affects, it must not only bind to its extracellular ligands but must also engage the cytoskeleton and coordinate signalling. Nov 29, 2010 the present study has identified new candidate molecules interacting with the cytoplasmic tail of cd44 which may be important for the effect of cd44 on cell migration, cell proliferation and tumorigenesis. It is a transmembrane, highly glycosylated protein with several isoforms resulting from alternative gene splicing. Transfection of young huvecs with the cd44 construct increased cd44 expression and led to a significant enhancement of monocyte adhesion, even in the absence of tnf. Cd44 is a singlechain molecule that is made up of three main parts extracellular, intracellular and transmembrane domains.
Recently, proteolytic cleavages of cd44 have been emerging as key regulatory events for the cd44 dependent cellmatrix interaction and signaling pathway. Some adhesion molecules have been reported to play an important role in cell differentiation. Expression of the adhesion molecules, icam1, vcam1, ncam, cd44, cd49d vla4. Review novel cd44downstream signaling pathways mediating. During rolling, eselectin ligands on neutrophils transduce signals that partially. In the first step, we assessed the expression of multiple adhesion molecules including lfa1. Integrins in turn are involved in the regulation of cell adhesion, pr. Frontiers cd44 acts as a signaling platform controlling. Cd44 receptor belongs to the family of cell adhesion molecules cams together with selectins, integrins, and cadherins. Identification of cd44 as a senescenceinduced cell adhesion. Cd44 is an important adhesion molecule that mediates cellcell and cellmatrix interaction, and participates in a wide variety of cellular functions. One such molecule, osteopontin opn, functions as both a cell attachment protein and a cytokine that signals through two cell adhesion molecules. Nov 05, 2019 upon binding to its ligand, the extracellular matrix ecm component hyaluronic acid ha, cd44 plays a key role in various physiological functions by activating different signal transduction pathways leading to cell proliferation, adhesion, migration, angiogenesis and inflammation, but also in pathophysiologic processes, such as self. Among these molecules, cd44 was highly and consistently expressed on all but one colon cancer cell line hct115.
Regulation of cellular adhesion molecule expression in murine. All cd44 isoforms are encoded by one single gene located on chromosome 11 in humans and chromosome 2 in mice. May 25, 2017 ponta h, sherman l, herrlich pa 2003 cd44. Cd44 is a transmembrane protein of cell adhesion molecules and is a wellknown surface marker of human mscs. Cd44 is a widely expressed cellular adhesion molecule that serves as a. Thus, it is possible that integrins are not involved in this signaling from cd44 to fak. Chondrocytes are regulated by cellular adhesion through. Cd44 a transmembrane glycoprotein associated with several vital functions, including cell division, migration, adhesion, and signaling. Often, these physiological changes are regulated by cell signaling molecules, which target signal transduction pathways and, ultimately, gene expression. Cd44 is a multistructural and multifunctional cell surface molecule involved in cell proliferation, cell differentiation, cell migration, angiogenesis, presentation of cytokines, chemokines, and growth factors to the corresponding receptors, and docking of proteases at the cell membrane, as well as in signaling for cell survival. Here, we show that a cd44 variant cd44v interacts with xct, a glutamatecystine transporter, and controls the intracellular level of reduced glutathione gsh. Cd44 is a widely distributed type i transmembrane glycoprotein and functions as the major hyaluronan receptor on most cell types. Effect of cd44 on differentiation of human amniotic. In humans, the cd44 antigen is encoded by the cd44 gene on chromosome 11.
The role of the cd44 family members in tumor progression and metastasis is most likely linked to the function of the various isoforms as signaling hubs. Ha cd44 interactions as potential targets for cancer therapy. Significance of ecadherin and cd44 expression in patients. Proteomic identification of cd44 interacting proteins. Cell adhesion molecules, once believed to function primarily in tethering cells to extracellular ligands, are now recognized as having broader functions in cellular signalling cascades, the cd44 transmembrane glycoprotein family adds new aspects to these roles by participating in signal transduction processes not only by establishing specific transmembrane complexes, but also by organizing. Dec 10, 2020 cd44 is involved in the regulation of diverse vital signaling pathways that modulate cancer proliferation, invasion, metastasis and therapyresistance, and it is also modulated by a variety of molecules in cancer cells. Synaptic cell adhesion molecules regulate signal transduction, synaptic function, and plasticity. Its interaction with appropriate extracellular matrix ligands promotes the migration and invasion processes involved in metastases.
Cd44 regulates survival and memory development in th1. However, their role in neuronal interactions with the extracellular matrix ecm is not well understood. This allows dnadamaged hepatocytes to respond to proliferative signals. Cd44 isoforms participate in several signaling pathways ranging from growth factorinduced signaling to wntregulated pathways. Article information, pdf download for cd44 integrates signaling in normal stem cell, cancer stem cell. May 10, 2016 in this study, we investigated the role of hyaluronan, cd44 adhesion molecule and associated cellular signaling events regulating astrocyte morphology. These data demonstrate that spectrin and actin networks regulate cd44 clustering and.
Adhesive receptors are responsible for general tissue architecture and cell behaviour. The cd44 molecule consists of several domains serving different functions. Regulation and signal transduction mediators of cd44 extracellular proteins including hyaluronan ha, collagen, flaminin, fibronectin and osteopontin are the known ligands for cd44 1418. A multifunctional cell surface adhesion receptor is a. The role of the cd44 transmembrane and cytoplasmic domains. In addition, cd44 can serve as an adverse prognostic marker among cancer population. Adhesion, migration and growth regulation cd44 in cancer progression. Cd44 expression is also upregulated in subpopulations of cancer cells and is recognized as a molecular marker for cancer stem cells csc 3. Cd44 is required for spatial memory retention and sensorimotor functions. Mar 10, 2014 ponta h, sherman l, herrlich pa 2003 cd44. Identification of cd44 as a senescenceinduced cell. The cadherin family is one comprised of celltocell adhesion molecules, whilst cd44 is a celltoecm adhesion molecule. Cell adhesion molecules in normal and malignant hematopoiesis. The endothelial molecule eselectin is a major mediator of these adhesive events, and there is.
Chondrocytes are regulated by cellular adhesion through cd44. May 15, 2003 ponta h, sherman l and herrlich pa 2003 cd44. Cd44 regulates survival and memory development in th1 cells. Osteopontindependent cd44v6 expression and cell adhesion. The expression of cd44 at the transcriptional level was decreased significantly during the chondrogenic differentiation in the present study, and this was consistent with a previous study 32. Optimal immunity to microorganisms depends upon the regulated death of clonally expanded effector cells and the survival of a cohort of cells that become memory cells. The term cd44 designates a large family of transmembrane glycoproteins belonging to the class of cell adhesion molecules. Cd44 on ls174t colon carcinoma cells possesses eselectin. A multifaceted molecule in cancer progression medcrave. Because cd44 is the principal receptor for ha on plasma membranes of most cell types, including fibroblasts, and because ha is a critical regulator of profibrotic signaling and mf differentiation in some tissues see the introduction, we investigated whether ha is involved in regulating the expression of. Jan 01, 2003 cell adhesion molecules, once believed to function primarily in tethering cells to extracellular ligands, are now recognized as having broader functions in cellular signalling cascades. Cd44 functions as a receptor for hyaluronan and many other extracellular matrix components, as well as a cofactor for growth factors and cytokines, and thus, cd44 is a signaling platform that integrates cellular microenvironmental cues with growth factor and cytokine. Human gastrointestinal cancer cells with a high level of cd44 expression showed an enhanced capacity for gsh synthesis and defense against reactive oxygen species ros. The question remained as to how a single adhesion molecule can fulfil that task.
Ishimoto t, nagano o, yae t, tamada m, motohara t, et al. The reception and integration of the plethora of signals a cell receives from its microenvironment determines the cells fate. Raber j, olsen rh, su w, foster s, xing r, acevedo sf, sherman ls 2014. Pip2 clusters cd44ct and facilitates the assembly of a specific cd44 ezrin heterotetramer complex. Most primary cells express cd44 but in a low affinity state that does not exhibit a capacity to bind to ha. Moreover, the hyaluronan receptor cd44 ponta et al. Immunohistochemical evaluation of cd44 expression in. A multifunctional cell surface adhesion receptor is. Members of the cd44 family of transmembrane glycoproteins emerge as major signal transduction control units. The regulation of the affinity of cell adhesion molecules is prerequisite for regulating cellcell and cellmatrix interactions mediated by broadly expressed receptors that are exposed continuously to their ligands.
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