EXPERIMENTAL CELL RESEARCH 229, 388–397 (1996) ARTICLE NO. 0384 A Chondroitin/Dermatan Sulfate Form of CD44 Is a Receptor for Collagen XIV (Undulin) TOBIAS EHNIS,WALBURGA DIETERICH,MICHAEL BAUER,BERND VON LAMPE, AND DETLEF SCHUPPAN 1 Klinikum Benjamin Franklin, Department of Gastroenterology, Free University of Berlin, Hindenburgdamm 30, D-12200 Berlin, Germany that human placental undulin and C XIV are identical Collagen XIV, a fibril-associated collagen with inter- proteins consisting of functional and structural mod- rupted triple helices, is expressed in differentiated soft ules, such as fibronectin type III repeats and von Wille- connective tissues and in cartilage. However, a cellu- brand factor A domains, which may mediate interac- lar receptor for this protein has not been identified. tions with cellular receptors and collagens [1, 6 – 11, Here we show that human placental collagen XIV, iso- unpublished results]. lated by a mild and simple two-step method, serves C XIV is abundant in soft connective tissues that as adhesive protein for a variety of mesenchymal and contain large amounts of fibrillar collagens such as der- some epithelial cells. Cell adhesion could be inhibited mis, tendon, ligaments, perichondrium, periosteum, by preincubation of the collagen XIV substrate with perimysium, skeletal and cardiac muscle, chicken giz- heparin or with the chondroitin/dermatan sulfate pro- zard, epi- and perineurium, and the dense stroma of teoglycan decorin and by pretreatment of cells with lung, liver, and blood vessels [7, 12, 13]. It is expressed chondroitinase ABC or heparinase III, suggesting a by fibroblasts, osteoblasts, endo- and perineural cells, cell membrane proteoglycan as receptor. Affinity chro- and liver fat-storing cells [13 – 15]. Collagen XII, an- matography of 125 I-labeled fibroblast cell surface pro- other FACIT, is widely expressed in 6-day-old chicken teins on collagen XIV – Sepharose yielded a chondroi- embryos where it gradually disappears from some, but tin/dermatan sulfate proteoglycan with a molecular not all tissues during development [13]. It appears to mass of 97–105 kDa after chondroitinase ABC diges- be substituted increasingly by C XIV, which represents tion and of 60–70 kDa after further treatment with N- the predominant FACIT in the 17-day-old chicken em- glycosidase F. The eluates contained also some high- bryo [13]. In this line C XIV is mainly found in well- molecular-weight material that was susceptible to di- differentiated mesenchymal tissues, but is virtually ab- gestion with heparinase but no detectable integrins. sent in tumor stroma [7], indicating that it might play Immunoprecipitation with a specific monoclonal anti- a role in differentiation. body identified the prominent chondroitin/dermatan sulfate proteoglycan as a member of the CD44 family. The interactions of C XIV with other collagens have The interaction between collagen XIV and cells ap- been characterized by Brown et al., who described its pears to be finely tuned, since matrix-associated gly- binding to collagen VI [10], and we found additional cosaminoglycans, and particularly proteoglycans like weak interactions with collagens I, III, and V [unpub- decorin, could compete with cells for the binding lished results]. The binding characteristics of C XIV site(s) on collagen XIV under physiological conditions. may be similar to those of collagen XII, which interacts  1996 Academic Press, Inc. with nascent collagen I fibrils but binds poorly to ex- isting collagen I fibrils [16]. Using immunoelectron mi- croscopy collagens XII and XIV were shown to be asso- INTRODUCTION ciated with the surface of banded collagen fibrils, possi- bly forming interfibrillar connections in a variety of Collagen XIV (C XIV) is a large, nonfibrillar extracel- tissues [7, 16–18]. lular matrix protein that contains two short inter- Cell adhesion to components of the extracellular ma- rupted collagenous sequences and belongs to the sub- trix directs fundamental cellular activities such as mi- family of fibril-associated collagens with interrupted gration, proliferation, invasion, and metastasis by trig- triple helices (FACITs) [1 – 6]. Although initially consid- gering cytoskeletal changes and initiating signal trans- ered as a noncollagenous glycoprotein [7], it is now duction events that result in a modulation of gene clear from immunological, biochemical, and cDNA data expression. Apart from the well-characterized inte- grins, which require divalent cations for binding to ex- tracellular matrix proteins [19, 20], recent data also 1 To whom correspondence and reprint requests should be ad- dressed. Fax: /49 (0)30 8445 4017. implicate transmembrane proteoglycans as mediators 388 0014-4827/96 $18.00 Copyright  1996 by Academic Press, Inc. All rights of reproduction in any form reserved.