Regulation of CD44 binding to hyaluronan by glycosylation of variably spliced exons.

Bennett, Kelly L.; Modrell, Brett; Greenfield, B. W.; Bartolazzi, Armando; Stamenkovic, Ivan; Peach, R; Jackson, David G.; Spring, F A; Aruffo, Alejandro

doi:10.1083/jcb.131.6.1623

Cited by 143 publications

(121 citation statements)

References 56 publications

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“…Furthermore, we demonstrate that incorporation of the peptide sequence encoded by exon v7 into CD44 in some instances abrogates HA binding. This has also been observed for other exons (41), and further suggests that alterations in the tertiary structure of the protein regulate HA binding. In this regard, it is interesting to note that glycosylation can have a positive or negative effect on HA binding (33,(41)(42)(43)(44)).…”

Section: Discussionsupporting

confidence: 55%

“…This has also been observed for other exons (41), and further suggests that alterations in the tertiary structure of the protein regulate HA binding. In this regard, it is interesting to note that glycosylation can have a positive or negative effect on HA binding (33,(41)(42)(43)(44)). Here we demonstrate a novel twist in this structural story, namely that the incorporation of the amino acid sequences encoded by variant exons 6 and 7 into the CD44 protein permits the N-terminal HA binding motif to bind to several different types of GAG in addition to HA.…”

Section: Discussionsupporting

confidence: 55%

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Variant Exons v6 and v7 Together Expand the Repertoire of Glycosaminoglycans Bound by CD44

Sleeman¹,

Kondo²,

Moll³

et al. 1997

Journal of Biological Chemistry

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Isoforms of the glycoprotein CD44 are cell surface receptors for the glycosaminoglycan hyaluronate. They have been implicated in many biological processes, but their function in these is poorly understood and cannot be explained solely by hyaluronate binding. In the present work we examine the ligand binding properties of alternatively spliced CD44 variant isoforms which are functionally involved in the immune system, embryonic development, and tumor behavior. We show that these isoforms bind directly to the purified glycosaminoglycans chondroitin sulfate, heparin, and heparin sulfate, in addition to being able to bind to hyaluronate. Binding to this extended repertoire of glycosaminoglycans by CD44 depends on the inclusion of peptide sequences encoded by the alternatively spliced exons v6 and v7, and occurs both when the CD44 is solubilized from the plasma membrane and when it is expressed on intact cells. A single point mutation in the most N-terminal hyaluronate binding motif of CD44 ablates both hyaluronate and chondroitin sulfate binding, suggesting that glycosaminoglycans are bound through a common motif, and that only one of the hyaluronate binding motifs is responsible for the majority of glycosaminoglycan binding by CD44 on the cell surface. Taken together, these observations indicate that alternative splicing regulates the ligand binding specificity of CD44 and suggest that structural changes in the CD44 protein have a profound effect on the range of ligands to which this molecule can bind with potentially wide-ranging functional consequences.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionsupporting

confidence: 55%

Variant Exons v6 and v7 Together Expand the Repertoire of Glycosaminoglycans Bound by CD44

Sleeman¹,

Kondo²,

Moll³

et al. 1997

Journal of Biological Chemistry

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“…modulating of the binding to hyaluronan (Bennett et al, 1995). Gould et al (1992) postulated that the multiple O-linked oligosaccharides of syndecan-3 might interact with the lectin domain of versican, since these interactions are involved in cartilage and nerve development.…”

Section: Figmentioning

confidence: 99%

Identification of the Core Protein Carrying the Tn Antigen in Mouse Brain: Specific Expression on Syndecan-3.

Akita

Fushiki

Fujimoto

et al. 2001

Cell Struct. Funct.

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ABSTRACT. We isolated glycoproteins carrying the Tn antigen, which was expressed spatiotemporally in the developing mouse brain. The Tn antigen was expressed on two molecular species with a molecular weight from 200 to 350 kDa and 110 to 160 kDa, as judged on SDS-PAGE. Although the two glycoproteins showed different susceptibilities to heparitinase I and solubilities in a salt solution, after treatment with V8 protease they showed the same mobility corresponding to a molecular weight of 90 kDa on SDS-PAGE, suggesting that these two molecules shared a common core protein. Partial N-terminal sequences of the glycoproteins were determined, i.e. AQRXRNENFERPV and ALAAPXAPAMLP, which were identified as the sequences of the N-terminal and central portions of syndecan-3, respectively. Both glycoproteins were reactive to anti-mouse syndecan-3 antibody. These results suggest that one is a soluble syndecan-3 cleaved between mucin-like domain and transmembrane domain, and the other is a membrane-bound syndecan-3 lacking N-terminal glycosaminoglycan attachment sites, and that both glycoproteins have a mucin-like domain characteristic of syndecan-3, in which the Tn antigen may be expressed.

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“…Expression of certain CD44 splice variants are found in several human cancers (Matsumura and Tarin, 1992;Tanabe et al, 1993a;Okamoto et al, 1998;. The alternative splicing represents one of the mechanisms for regulation of hyaluronate recognition by CD44 Bartolazzi et al, 1995;Bennett et al, 1995;Sleeman et al, 1996). Moreover, the ectodomain of CD44 is subject to posttranslational glycosylation, which both negatively and positively in¯uences its ability to bind hyaluronate (Katoh et al, 1995;Lesley et al, 1995;Bartolazzi et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

CD44 cleavage induced by a membrane-associated metalloprotease plays a critical role in tumor cell migration

et al. 1999

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CD44 is a cell surface receptor for hyaluronate, a component of the extracellular matrix (ECM). Although CD44 has been implicated in tumor invasion and metastasis, the molecular mechanisms remain to be elucidated. Here we ®nd that CD44 expressed in cancer cells is cleaved at the membrane-proximal region of the ectodomain and the membrane-bound cleavage product can be detected using an antibody against the cytoplasmic domain of CD44. Furthermore, we report that CD44 cleavage is mediated by a membraneassociated metalloprotease expressed in cancer cells. A tissue inhibitor of metalloproteases-1 (TIMP-1), as well as metalloprotease inhibitors, inhibit CD44 cleavage in the cell-free assay. Contrary, serine protease inhibitors enhance CD44 cleavage, and the enhancement can be prevented by pretreatment with a metalloprotease inhibitor. Thus, CD44 cleavage is regulated by an intricate balance between some proteases and their inhibitors. Interestingly, treatment with the metalloprotease blocker 1,10-phenanthroline, which strongly prevent the CD44 cleavage, suppressed RERF-LC-OK lung cancer cell migration on a hyaluronate substrate, but not on several other substrates. These results suggest that CD44 cleavage plays a critical role in an ecient celldetachment from a hyaluronate substrate during the cell migration and consequently promotes CD44-mediated cancer cell migration. Our present data indicate that CD44, not only ECM per se, is one of the targets of pericellular proteolysis involved in tumor invasion and metastasis.

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Regulation of CD44 binding to hyaluronan by glycosylation of variably spliced exons.

Cited by 143 publications

References 56 publications

Variant Exons v6 and v7 Together Expand the Repertoire of Glycosaminoglycans Bound by CD44

Variant Exons v6 and v7 Together Expand the Repertoire of Glycosaminoglycans Bound by CD44

Identification of the Core Protein Carrying the Tn Antigen in Mouse Brain: Specific Expression on Syndecan-3.

CD44 cleavage induced by a membrane-associated metalloprotease plays a critical role in tumor cell migration

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