HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by VOGEL, W. Search for Related Content PubMed PubMed Citation Articles by VOGEL, W.

Discoidin domain receptors: structural relations and functional implications

Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada

¹Correspondence: Programme in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada. E-mail: vogel{at}mshri.on.ca

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPRESSION PATTERNS OF DDRS DDR-RELATED PROTEINS COLLAGEN AS SIGNALING MOLECULE CLINICAL PROSPECTS REFERENCES

 
Multicellular life relies on the presence of extracellular matrix to provide scaffolding for cells and tissue compartments. To provide communication between cells and tissues, a multitude of cell surface receptors are triggered by soluble ligands and components of the extracellular matrix. A large family of these receptors transmit signals through the use of an intrinsic tyrosine kinase function. The subgroup of discoidin domain receptors (DDRs) is distinguished from other members of the receptor tyrosine kinase family by a discoidin homology repeat in their extracellular domains that is also found in a variety of other transmembrane and secreted proteins. Sequence comparisons show that non-mammalian orthologs of DDRs exist: three closely related genes in Caenorhabditis and one in the sponge Geodia cydonium. Recently, various types of collagen have been identified as the ligands for the two mammalian discoidin domain receptor tyrosine kinases, DDR1 and DDR2. The binding of collagen to DDRs results in a delayed but sustained tyrosine kinase activation. Both receptors display several potential tyrosine phosphorylation sites that are able to relay the signal by interacting with cytoplasmic effector proteins. The potential cross-talk to other receptors for collagen and the clinical aspects of DDR function are discussed.—Vogel, W. Discoidin domain receptors: structural relations and functional implications.

Key Words: receptor tyrosine kinase • collagen signaling

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPRESSION PATTERNS OF DDRS DDR-RELATED PROTEINS COLLAGEN AS SIGNALING MOLECULE CLINICAL PROSPECTS REFERENCES

 
DURING THE SEARCH for tyrosine kinase proteins expressed in human malignancies, a novel subfamily of receptor tyrosine kinases (RTK)²was discovered. This subfamily is distinct from other members of the large RTK group due to a homology domain to discoidin, a lectin first described during the cell aggregation process of the slime mold Dictyostelium discoideum (1 , 2 ). All members share the approximately 160-amino-acid-long amino-terminal discoidin (DS) homology domain followed by a single transmembrane region, an extended juxtamembrane region, and a catalytic tyrosine kinase domain. The cDNAs of this novel RTK subfamily have been cloned from different species by many laboratories. They represent two distinct genes, which have now been renamed DDR1 [previously called DDR, NEP, Cak, Ptk-3, TrkE, MCK-10, RTK6, EDDR1, or NTRK4 (3-11) ] and DDR2 [CCK-2, Tyro10, or TKT (8 , 12 , 13 )]. The homology to the Dictyostelium discoidin protein resulted in the implication that DDRs function in cell adhesion, although nothing was known about their ligands at that time (5) . The recent identification of collagen as a physiological ligand for these orphan receptors will allow further elucidation of the role of DDRs in cellular processes (14 , 15 ).

DDR1 appears in three isoforms a, b, and c, which are generated by alternative splicing. The exon 11, coding for an additional 37 amino acids in the juxtamembrane region, is missing in the transcript of DDR1a, but is present in DDR1b (8 , 16 , 17 ). Another six amino acids (S-F-S-L-F-S) are inserted just at the beginning of the kinase domain to give rise to the c-isoform. Recently, a similar sequence (S-L-S-V-A-Q) was found to be alternatively spliced in the cytoplasmic domain ß₁ integrin (18) . During rat postnatal development, the amount of DDR1b considerably increases in comparison to the a-isoform (19) . DDR1 and DDR2 are detected as approximately 125- and 130-kDa glycosylated proteins in a Western blot of lysates from overexpressing cells (8) . Treatment with tunicamycin shows DDR1a and DDR1b as 102- and 106-kDa proteins, respectively, thereby suggesting that the shorter isoform is more heavily glycosylated than the longer one (unpublished observation). DDR1 is partially processed into a 63-kDa membrane-anchored b-subunit and a soluble 54-kDa a-subunit by a so far unidentified protease (8) . The presence of the recognition sequence RXRR in the extracellular domain suggests the involvement of furin-like proteases in DDR1 processing.

	EXPRESSION PATTERNS OF DDRS

TOP ABSTRACT INTRODUCTION EXPRESSION PATTERNS OF DDRS DDR-RELATED PROTEINS COLLAGEN AS SIGNALING MOLECULE CLINICAL PROSPECTS REFERENCES

 
Using Northern blot and in situ hybridization, both DDRs have been found widely expressed in human and mouse tissues. DDR1 is abundant in the brain and is found in keratinocytes, in the epithelial layer of the colonic mucosa, in the distal tubulus of the kidney, in the lung epithelium, and in the thyroid follicles (3 , 5-9 ). In the pancreas, DDR1 expression is restricted to the islets of Langerhans (8) . During mouse development, DDR1 can be used as an early marker for the formation of neuroectodermal cells (4) . In contrast, little is known about the occurrence of DDR2. Northern blot analysis indicates expression of DDR2 in heart and skeletal muscle, lung, brain, kidney, and connective tissue (8 , 12 , 13 ).

Five different studies have detected an overexpression of DDR1 in human tumors, particularly in primary breast cancer (20) , but also in ovarian (9) , esophageal (21) , and up to threefold in pediatric brain cancer (22) . More importantly, in situ hybridization of adjacent sections of ovarian and lung tumors revealed a mutually exclusive expression of DDR1 and DDR2 (8) . Transcripts for DDR1 are found in highly invasive tumor cells, whereas transcripts for DDR2 are detected only in the surrounding stromal cells, suggesting an involvement of DDR1 and DDR2 in tumor progression. The expression of DDR1 can either be induced by -radiation of rat astrocytes (19) or by the overexpression of p53 in osteosarcoma cells (23) . A targeted deletion of DDR1 or DDR2 in embryonic stem cells will allow the analysis of cellular signaling in the absence of either of the DDRs. The generation of knock-out mice will address the role of DDRs during embryogenesis and later development.

	DDR-RELATED PROTEINS

TOP ABSTRACT INTRODUCTION EXPRESSION PATTERNS OF DDRS DDR-RELATED PROTEINS COLLAGEN AS SIGNALING MOLECULE CLINICAL PROSPECTS REFERENCES

 
Database searches have identified three sequences with homology to DDR1 and DDR2 in the genomes of nematodes, two in Caenorhabditis elegans, and one in Caenorhabditis briggsae (24) . All three proteins show the common features of DDRs: an amino-terminal DS domain and a very long juxtamembrane stretch followed by the catalytic tyrosine kinase domain (Fig. 1 ). Because these genes were identified during the worm genome project, nothing is known about their functional significance. Nevertheless, these receptors could well be activated by collagen. It has been recently shown that related RTKs are able to execute similar functions in nematodes and in mammals, for example the Eph-receptors in the developing nervous system (25) .

View larger version (100K): [in this window] [in a new window]   Figure 1. The family of proteins with DS domains. Schematic representation of transmembrane and secreted proteins. Abbreviations for the domains shown are as follows: F-A, A-domain in Factor V and VIII; CBP, carboxypeptidase; EGF, epidermal growth factor; TK, tyrosine kinase; A5, homology to A5 antigen; Ig, immunoglobulin; LamG, laminin-G; FIB, fibronectin-like; CUB, complement binding; and MAM, meprin/A5/PTPmu. The tyrosines in the N-P-X-Y motives of GCTK and DDR1b are highlighted. Proteolytic processing of DDR1 is indicated.

It is surprising to note that the closest relative to the tyrosine kinase domain of DDR1 is found in the genome of the marine sponge Geodia cydonium (Fig. 1) . The multiple sequence alignment shows that the catalytic core region of DDR1 is 59% identical to the Geodia tyrosine kinase called GCTK (61% for DDR2), whereas the closest mammalian RTK subfamily, the neurotrophin receptors, are only 55–58% related (26) . A common ancestor for the Geodia and human protein would therefore date back more than 600 million years, during the early evolution of multicellular organisms. Detailed sequence analysis revealed that several tyrosines in the cytoplasmic domain are conserved and may function as autophosphorylation sites. The juxtamembrane region of the sponge protein includes the sequence N-P-X-Y, a sequence also seen in the alternatively spliced exon of DDR1 (8 , 26 ). A signaling pathway similar to that in mammals can be postulated in sponges if GCTK activation leads to phosphorylation of the N-P-X-Y site. It is interesting to note that the sponge RTK lacks the amino-terminal DS-homology region found in the DDRs and instead shows two immunoglobulin (Ig) folds (26) . A similar Ig-domain repeat is found in the mammalian nerve growth factor receptors, which are the second-most-related RTK subfamily to the Geodia sequence (Fig. 1) . Previous results suggest that sponges are utilizing their collagen matrix to maintain a polarized epithelial layer (27) . One may speculate that sponges employ GCTK in cell-to-extracellular matrix interactions, possibly for the differentiation of sensory cells.

Two other mammalian, non-tyrosine kinase receptors show DS domains: the neuropilins and the neurexins. As their names imply, both are involved in the development of the nervous system. The neuropilins, and their much earlier identified Xenopus laevis counterpart called A5 antigen, are receptors for the semaphorins, a family of secreted and transmembrane glycoproteins, and for certain isoforms of vascular endothelial growth factor (28) . Neuropilins have a tandem repeat of DS domains flanked by several other domains that are commonly found in cell adhesion proteins. It is interesting to note that the approximately 80-amino-acid stretch following the DS domains in neuropilin/A5 antigen has sequence homology to the corresponding region in the extracellular domain of DDR2 (amino acids 254–336) (12) . During sensory and motor neuronal patterning, the interaction between neuropilins and semaphorins results in growth cone collapse (28) . The neurexins appear to mediate cell-cell contacts, forming a trimeric complex between neurexin, contactin, and RPTPß at the junction of neurons with glial cells (29) .

DS domains are found in a variety of secreted proteins, most notably as a tandem carboxy-terminal repeat in the blood coagulation cofactors V and VIII (Fig. 1) . During blood coagulation, the DS domains of factor V and VIII are thought to bind to phospholipids at the surface of platelets (30) . The three-dimensional structure of the DS domains of factor V has been recently predicted using the homologous structure of galactose oxidase (31) . In an adipocyte transcriptional repressor protein, called AEBP1, the DS domain is followed by a domain with carboxypeptidase activity (32) . The MFG-E8, BA46, Del-1 group of DS-domain proteins have a similar overall structure but diverse expression and function: MFG-E8 was originally identified as milk fat protein, but was also found at the acrosomal cap of sperm cells, suggesting a role in fertilization (33 , 34 ); BA46 (also called lactadherin) was found to be expressed in breast carcinomas as well as in human milk fat (35-37) , whereas Del-1 is expressed in endothelial cells (38) . Both proteins are suggested to be involved in _vß₃ integrin-mediated cell adhesion (36 , 38 ). A human X-linked inherited disease (retinoschisis) resulting in retinal deterioration was mapped to the XLRS-1 gene (39) . XLRS-1 codes for a 224-amino-acid protein, which almost entirely consists of a single DS domain. A majority of the retinoschisis patients show missense mutations in the DS domain sequence affecting conserved amino acid residues (40) . So far little is known about the function of XLRS-1 in early eye development. The progenitors of all DS domains, the discoidin I and II proteins, are produced during cell aggregation of Dictyostelium and are secreted while the amoebas convert into a multicellular organism (1 , 2 ). Discoidins are lectins binding to galactose and N-acetyl-galactosamine. It is presently unknown whether any of the mammalian proteins with DS domains could act as lectins as well.

	COLLAGEN AS SIGNALING MOLECULE

TOP ABSTRACT INTRODUCTION EXPRESSION PATTERNS OF DDRS DDR-RELATED PROTEINS COLLAGEN AS SIGNALING MOLECULE CLINICAL PROSPECTS REFERENCES

 
The revelation that collagens function as ligands for DDR1 and DDR2 suggests that some of the other mammalian DS domains may interact with matrix proteins as well. To date, 19 different collagens have been described. Collagen type I, II, III, and IV are ubiquitous and tend to form fibers or sheet-like structures. The others appear to regulate the size of fibers or have more restricted expression pattern in specialized cells and tissues (41) . Point mutations or deletions in genes coding for collagens can impair collagen assembly and result in severe disorders of the skeleton, tendon, or skin.

DDR1 is activated by all collagens so far tested (type I to type V), whereas DDR2 is selectively stimulated by fibrillar collagens only (14 , 15 ). The activation process is surprisingly slow, requiring collagen treatment for 18 h to reach maximal tyrosine kinase activity. The activation is sustained and no significant down-regulation by endocytosis or receptor degradation is observed for up to 4 days. The native, triplet configuration of collagen is essential for DDR1 and DDR2 activation, whereas collagen glycosylation is only important for DDR2 stimulation (14) . It is not yet clear which part of the DDR extracellular domain is essential for ligand binding. Conversely, the regions in the collagen molecule that harbor the binding epitopes for DDR1 or DDR2 are not yet defined. A synthetic collagen, comprised of 10 collagen repeats [(Gly-Pro-Hyp)₁₀] and cross-linked to form a mini-triple helix, is not sufficient to activate DDRs (unpublished observation). The functional significance of DDR signaling waits to be fully determined. However, it was found in an initial experiment that prolonged activation of DDR2 by collagen is associated with an up-regulation of matrix-metalloprotease-1 (MMP1), an enzyme that specifically cleaves native fibrillar collagen (14) . The culture of human skin fibroblasts in three-dimensional collagen gels induces down-regulation of collagen synthesis and a tyrosine kinase-dependent up-regulation of MMP1 expression (42) . Mechanical force applied to cells may influence DDR signal transduction as well, as suggested by the recent observation that MMP1 is up-regulated in response to stretch relaxation of fibroblasts (43) .

Ligand binding to RTKs is thought to induce receptor dimerization and subsequent transphosphorylation of specific tyrosine residues in the cytoplasmic domain. These tyrosines are embedded in consensus sequences, which on phosphorylation allow the binding of downstream effector molecules containing Src-homology 2 (SH2) or phosphotyrosine-binding (PTB) domains (44) . The activation of DDR1 by collagen induces phosphorylation of the L-X-N-P-X-Y site in the alternatively spliced insert. The adaptor molecule Shc, which consists of an amino-terminal PTB and a carbxy-terminal SH2 domain, binds with its PTB domain to this site (14) . Another PTB-domain-containing protein, FRS2, has been shown to interact with the juxtamembrane region of the a-isoform of DDR1 (Foehr, E. D., Tatavos, A., Tanabe, E., Raffioni, S., Goetz, S., DiMarco, E., DeLuca, M., and Bradshaw, R. A., unpublished observations). However, it remains to be shown that the DDR1a-FRS2 interaction requires ligand-induced receptor activation. Other tyrosines that are conserved in DDR1 and DDR2 display the consensus sequence for the SH2 domains of Nck, GAP, and the p85 subunit of PI3-kinase. A potential binding site for proteins with SH3 domains (P-R-G-P-G-P-P-T-P) is present in the alternatively spliced exon of DDR1. Furthermore, the sequence L-N-T-V at the carboxy terminus of DDR1 may serve as binding site for proteins with PDZ domains.

Collagen acts not only as a ligand for DDRs, but binds and activates members of the integrin family, which are heterodimers of one and one ß subunit (Fig. 2 ). The ₁ß₁, ₂ß₁, and ₁₀ß₁ integrins have been shown to be functional receptors for collagen (45-47) . Lacking intrinsic catalytic activity, integrins mediate their responses using cytoplasmic tyrosine kinases, particularly Fak, Syk, and Src. The interaction of integrins with collagen has been extensively studied in various cell types, including fibroblasts and platelets. In platelets, the contact of ₂ß₁ with collagen and _IIbß₃ with fibrinogen leads to an increase in tyrosine phosphorylation of phospholipase C2 (PLC2), Vav, and Cas, an adaptor molecule, that provides multiple SH2 domain interaction sites (48) . The complex between the Fc receptor -chain and the uncharacterized glycoprotein VI (GPVI) serves as additional collagen receptor in platelets (Fig. 2) . In fibroblasts, the formation of the cytoskeleton is regulated mainly by the action of integrins, and an involvement of the signal of DDRs in maintaining the filamentous network could be envisioned. Experiments in three-dimensional collagen gels will address the question of whether DDR phosphorylation can be induced by mechanical forces. Initial data from epithelial cells and fibroblasts indicate that DDR1 signaling takes place independent of ß₁ integrin activation.

View larger version (104K): [in this window] [in a new window]   Figure 2. Receptors for collagen and their potential downstream signaling pathways. It is worth noting that these receptors are expressed in a variety of different cell types. The depicted pathways and cellular responses are most likely more complex because they are also triggered by other extracellular stimuli than collagen. Abbreviations are described in the text.

	CLINICAL PROSPECTS

TOP ABSTRACT INTRODUCTION EXPRESSION PATTERNS OF DDRS DDR-RELATED PROTEINS COLLAGEN AS SIGNALING MOLECULE CLINICAL PROSPECTS REFERENCES

 
The overexpression of DDR1 in several different human cancers suggests a function in tumor progression. Although experimental evidence argues against a classification of DDRs as transforming oncogenes, subsequent steps after the initial cellular transformation such as invasion and metastasis might be mediated by DDRs. The ability of malignant cells to penetrate tissue barriers requires the breakdown of extracellular matrix, which is mediated by a variety of proteases (49) . The observed up-regulation of MMP1 by collagen-activated DDR2 is potentially only one out of several downstream targets. Other human diseases with deregulated matrix production, including lung fibrosis, liver cirrhosis, osteoporosis, and rheumatoid arthritis may present aberrant DDR expression or signaling.

It is tempting to speculate that one major function of DDRs is to monitor the formation of collagenous extracellular matrices by regulating the synthesis of collagens and their degrading enzymes. The challenge in future work will be to identify the relevant receptor targets and to analyze DDR function by designing suitable reagents such as monoclonal antibodies or dominant negative receptors that inhibit DDR signaling.

	ACKNOWLEDGMENTS

 
This work was supported by grants from the National Cancer Institute of Canada, the Medical Research Council of Canada, the Protein Engineering Network of Centers of Excellence, and the Howard Hughes Medical Institute. The author is the recipient of a fellowship from the Deutsche Forschungsgemeinschaft. I would like to thank T. Pawson for his encouragement and ongoing support. I thank V. Jassal for commenting on the manuscript and F. Alves for reagents and discussion. I am grateful to A. Ullrich for generously providing cDNA plasmids.

	FOOTNOTES

 
² Abbreviations: DDR, discoidin domain receptor; RTK, receptor tryosine kinases; DS, discoidin; PTB, phosphotyrosine binding.

	REFERENCES

TOP ABSTRACT INTRODUCTION EXPRESSION PATTERNS OF DDRS DDR-RELATED PROTEINS COLLAGEN AS SIGNALING MOLECULE CLINICAL PROSPECTS REFERENCES

 

1. Rosen, S. D., Kafka, J. A., Simoson, D. L., Barondes, S. H. (1973) Developmentally regulated carbohydrate binding protein in Dictyostelium discoideum. Proc. Natl. Acad. Sci. USA 70,2554-2557[Abstract/Free Full Text]
2. Springer, W. R., Cooper, D. N. W., Barondes, S. H. (1984) Discoidin I is implicated in cell-substratum attachment and ordered cell migration of Dictyostelium discoideum and resembles fibronectin. Cell 39,557-564[Medline]
3. Johnson, J. D., Edman, J. C., Rutter, W. J. (1993) A receptor tyrosine kinase found in breast carcinoma cells has an extracellular discoidin I-like domain. Proc. Natl. Acad. Sci. USA 90,5677-5681[Abstract/Free Full Text]
4. Zerlin, M., Julius, M. A., Goldfarb, M. (1993) NEP: a novel receptor-like tyrosine kinase expressed in proliferative neuroepithelia. Oncogene 8,2731-2739[Medline]
5. Perez, J. L., Shen, X., Finkernagel, S., Sciorra, L., Jenkins, N. A., Gilbert, D. J., Copeland, N. G., Wong, T. W. (1994) Identification and chromosomal mapping of a receptor tyrosine kinase with putative phospholipid binding sequence in its ectodomain. Oncogene 9,211-219[Medline]
6. Sanchez, M. P., Tapley, P., Saini, S. S., He, B., Pulido, D., Barbacid, M. (1994) Multiple tyrosine kinases in rat hippocampal neurons: isolation of ptk-3, a receptor expressed in proliferative zones of the developing brain. Proc. Natl. Acad. Sci. USA 91,1819-1823[Abstract/Free Full Text]
7. Di Marco, E., Cutuli, N., Guerra, L., Cancedda, R., De Luca, M. (1993) Molecular cloning of trkE, a novel trk-related putative tyrosine kinase receptor isolated from normal human keratinocytes and widely expressed by normal human tissues. J. Biol. Chem. 268,24290-24295[Abstract/Free Full Text]
8. Alves, F., Vogel, W., Mossie, K., Millauer, B., Höfler, H., Ullrich, A. (1995) Distinct structural characteristics of discoidin I subfamily receptor tyrosine kinases and complementary expression in human cancer. Oncogene 10,609-618[Medline]
9. Laval, S., Butler, R., Shelling, A. N., Handby, A. W., Poulsom, R., Ganesan, T. S. (1994) Isolation and characterisation of an epithelial-specific receptor tyrosine kinase from an ovarian cancer cell line. Cell Growth Diff. 5,1173-1183[Abstract]
10. Shelling, A. N., Butler, R., Jones, T., Laval, S., Boyle, J. M., Ganesan, T. S. (1995) Localization of an epithelial-specific receptor (EDDR1) to chromosome 6q16. Genomics 25,584-587[Medline]
11. Valent, A., Meddeb, M., Danglot, G., Duverger, A., Nguyen, V. C., Bernheim, A. (1996) Assignment of the NTRK4 (trkE) gene to chromosome 6p21. Human Genet. 98,12-15[Medline]
12. Lai, C., Lemke, G. (1994) Structure and expression of the tyro 10 receptor tyrosine kinase. Oncogene 9,877-883[Medline]
13. Karn, T., Holtrich, U., Bräuninger, A., Böhme, B., Wolf, G., Rübsamen-Waigmann, H., Strebhardt, K. (1993) Structure, expression and chromosomal mapping of TKT from man and mouse: a new subclass of receptor tyrosine kinases with a factor VIII-like domain. Oncogene 8,3433-3440[Medline]
14. Vogel, W., Gish, G., Alves, F., Pawson, T. (1997) The discoidin domain receptor tyrosine kinases are activated by collagen. Mol. Cell 1,13-23[Medline]
15. Shrivastava, A., Radziejewski, C., Campbell, E., Kovac, L., McGlynn, M., Ryan, T. E., Davis, S., Goldfarb, M. P., Glass, D. J., Lemke, G., Yancopoulos, G. D. (1997) An orphan receptor tyrosine kinase family whose members serve as nonintegrin collagen receptors. Mol. Cell 1,25-34[Medline]
16. Perez, J. L., Jing, S. Q., Wong, T. W. (1996) Identification ot two isoforms of the Cak receptor kinase that are coexpressed in breast tumor cell lines. Oncogene 12,1469-1477[Medline]
17. Playford, M. P., Butler, R. J., Wang, X. C., Katso, R. M., Cooke, I. E., Ganesan, T. S. (1996) The genomic structure of discoidin receptor tyrosine kinase. Genome Res. 6,620-627[Abstract/Free Full Text]
18. Svineng, G., Fässler, R., Johansson, S. (1998) Identification of beta1c-2, a novel variant of the integrin beta subunit generated by utilization of an alternative splice acceptor site in exon C. Biochem. J. 330,1255-1263
19. Sakuma, S., Sya, H., Ijichi, A., Tofilon, P. J. (1995) Radiation induction of the receptor tyrosine kinase ptk-3 in normal rat astrocytes. Radiat. Res. 143,1-7[Medline]
20. Barker, K. T., Martindale, J. E., Mitchell, P. J., Kamalati, T., Page, M. J., Phippard, D. J., Dale, T. C., Gusterson, B. A., Crompton, M. R. (1995) Expression patterns of the novel receptor-like tyrosine kinase, DDR, in human breast tumours. Oncogene 11,569-575
21. Nemoto, T., Ohashi, K., Akashi, T., Johnson, J. D., Hirokawa, K. (1997) Overexpression of protein tyrosine kinases in human esophageal cancer. Pathobiol. 65,165-203
22. Weiner, H. L., Rothman, M., Miller, D. C., Ziff, E. B. (1996) Pediatric brain tumors express receptor tyrosine kinases including novel cell adhesion kinases. Pediatr. Neurosurg. 25,64-72[Medline]
23. Sakuma, S., Saya, H., Tada, M., Nakao, M., Fujiwara, T., Roth, J. A., Sawamura, Y., Shinohe, Y., Abe, H. (1996) Receptor protein tyrosine kinase DDR is up-regulated by p53 protein. FEBS Lett. 398,165-169[Medline]
24. Baumgartner, S., Hofmann, K., Chiquet-Ehrismann, R., Bucher, P. (1998) The discoidin domain family revisited: new members from prokaryotes and a homology-based fold prediction. Protein Sci. 7,1626-1631[Abstract]
25. George, S. E., Simokat, K., Hardin, J., Chrisholm, A. D. (1998) The VAB-1 Eph receptor tyrosine kinase functions in neural and epithelial morphogenesis. C. elegans. Cell 92,633-643[Medline]
26. Gamulin, V., Skorokhod, A., Kavsan, V., Müller, I. M., Müller, W. E. G. (1997) Experimental indication in favor of the introns-late theory: the receptor tyrosine kinase gene from the sponge Geodia cydonium. J. Mol. Evol. 44,242-252[Medline]
27. Müller, W. E. G., Schäcke, H. (1996) Characterization of the receptor protein-tyrosine kinase gene from the marine sponge Geodia cydonium. Prog. Mol. Subcell. Biol. 17,183-208[Medline]
28. Soker, S., Takashima, S., Miao, H. Q., Neufeld, G., Klagsbrun, M. (1998) Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor receptor. Cell 92,735-745[Medline]
29. Peles, E., Nativ, M., Lustig, M., Schilling, J., Martinez, R., Plowman, G. D., Grumet, M., Schlessinger, J. (1997) Identification of a novel contactin-associated transmembrane receptor with multiple domains implicated in protein-protein interactions. EMBO J. 16,978-988[Medline]
30. Kane, W. H., Davie, E. W. (1988) Blood coagulation factors V and VIII: structural and functional similarities and their relationship to hemorrhagic and thrombotic disorders. Blood 71,539-551[Free Full Text]
31. Villoutreix, B. O., Bucher, P., Hofmann, K., Baumgartner, S., Dahlbäck, B. (1998) Molecular models for the two discoidin domains of blood coagulation factor V. J. Mol. Model 4,268-275
32. Ohno, I., Hashimoto, J., Shimizu, K., Takaoka, K., Ochi, T., Matsubara, K., Okubo, K. (1996) A cDNA cloning of human AEBP1 from primary cultured osteoblasts and its expression in a differentiating osteoblastic cell line. Biochem. Biophys. Res. Commun. 228,411-414[Medline]
33. Stubbs, J. D., Lekutis, C., Singer, K. L., Bui, A., Yuzuki, D., Srinivasan, U., Parry, G. (1990) cDNA cloning of a mouse mammary epithelial cell surface protein reveals the excitance of epidermal growth factor-like domains linked to factor VIII-like sequences. Proc. Natl. Acad. Sci. USA 87,8417-8421[Abstract/Free Full Text]
34. Ensslin, M., Vogel, T., Calvete, J. J., Thole, H. H., Schmidtke, J., Matsuda, T., Töpfer-Petersen, E. (1998) Molecular cloning and characterization of P47, a novel boar sperm-associated zona pellucida-binding protein homologous to a family of mammalian secretory proteins. Biol. Reprod. 58,1057-1064[Abstract/Free Full Text]
35. Larocca, D., Peterson, J. A., Urrea, R., Kuniyoshi, J., Bistrain, A. M., Ceriani, R. L. (1991) A M_r 46,000 human milk fat globule protein that is highly expressed in human breast tumors contains factor VIII-like domains. Cancer Res. 51,4994-4998[Abstract/Free Full Text]
36. Taylor, M. R., Cuoto, J. R., Scallan, C. D., Ceriani, R. L., Peterson, J. A. (1997) Lactadherin (formerly BA46), a membrane-associated glycoprotein expressed in human milk and breast carcinomas, promotes Arg-Gly-Asp (RGD)-dependent cell adhesion. DNA Cell. Biol. 16,861-869[Medline]
37. Giuffrida, M. G., Cavaletto, M., Giunta, C., Conti, A., Godovac-Zimmermann, J. (1998) Isolation and characterization of full and truncated forms of human breast carcinoma proteon BA46 from human milk fat globule membranes. J. Protein Chem. 17,143-148[Medline]
38. Hidai, C., Zupancic, T., Penta, K., Mikhail, A., Kawana, M., Quertermous, E. E., Aoka, Y., Fukagawa, M., Matsui, Y., Platika, D., Auerbach, R., Hogan, B. L. M., Snodgrass, R., Quertermous, T. (1998) Cloning and characterization of the developmental endothelial locus-1: An embryonic endothelial cell protein that binds to _vß₃ integrin receptor. Genes Dev. 12,21-33[Abstract/Free Full Text]
39. Sauer, C. G., Gehrig, A., Warneke-Wittstock, R., Marquardt, A., Ewing, C. C., Gibson, A., Lorenz, B., Jurklies, B., Weber, B. H. F. (1997) Positional cloning of the gene associated with X-linked juvenile retinoschisis. Nat. Gen. 17,164-170[Medline]
40. . The Retinoschisis Consortium (1998) Functional implications of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis. Hum. Mol. Genet. 7,1185-1192[Abstract/Free Full Text]
41. Prockop, D. J., Kivirikko, K. I. (1995) Collagens: molecular biology, diseases, and potentials for therapy. Annu. Rev. Biochem. 64,403-434[Medline]
42. Broberg, A., Heino, J. (1996) Integrin ₂ß₁-dependent contraction of floating collagen gels and induction of collagenase are inhibited by tyrosine kinase inhibitors. Exp. Cell Res. 228,29-35[Medline]
43. Lambert, C. A., Lapière, C. M., Nusgens, B. V. (1998) An interleukins-1 loop is induced in human skin fibroblasts upon stress relaxation in a three-dimensional collagen gel but is not involved in the upregulation of MMP-1. J. Biol. Chem. 273,23143-23149[Abstract/Free Full Text]
44. Pawson, T., Scott, J. D. (1997) Signaling through scaffold, anchoring and adaptor proteins. Science 278,2075-2080[Abstract/Free Full Text]
45. Gullberg, D., Gehlsen, K. R., Turner, D. C., Ahlen, K., Zijenah, L. S., Barnes, M. J., Rubin, K. (1992) Analysis of ₁ß₁, ₂ß₁ and ₃ß₁ integrins in cell-collagen interactions: identification of conformation dependent ₁ß₁ binding sites in collagen type I. EMBO J. 11,3865-3873[Medline]
46. David, S., Kern, A., Marcantonio, E. E. (1997) Post-ligand binding events: outside-in signaling through the integrins. Kühn, K. Eble, J. eds. Integrin-Ligand Interaction ,241-252 Springer Heidelberg, Germany.
47. Camper, L., Hellman, U., Lundgren-Akerlund, E. (1998) Isolation, cloning and sequence analysis of the integrin subunit alpha10, beta1-associated collagen binding integrin expressed in chondrocytes. J. Biol. Chem. 273,20383-20389[Abstract/Free Full Text]
48. Moroi, M., Jung, S. M. (1998) Integrin-mediated platelet adhesion. Front. Biosci. 3,D719-D728
49. Edwards, D. R., Murphy, G. (1998) Proteases—invasion and more. Nature 394,527-528[Medline]

This article has been cited by other articles:

				Y. Zeng, Y. Takada, S. Kjellstrom, K. Hiriyanna, A. Tanikawa, E. Wawrousek, N. Smaoui, R. Caruso, R. A. Bush, and P. A. Sieving RS-1 Gene Delivery to an Adult Rs1h Knockout Mouse Model Restores ERG b-Wave with Reversal of the Electronegative Waveform of X-Linked Retinoschisis Invest. Ophthalmol. Vis. Sci., September 1, 2004; 45(9): 3279 - 3285. [Abstract] [Full Text] [PDF]

				Y. Takada, R. N. Fariss, A. Tanikawa, Y. Zeng, D. Carper, R. Bush, and P. A. Sieving A Retinal Neuronal Developmental Wave of Retinoschisin Expression Begins in Ganglion Cells during Layer Formation Invest. Ophthalmol. Vis. Sci., September 1, 2004; 45(9): 3302 - 3312. [Abstract] [Full Text] [PDF]

				V. A. Heinzelmann-Schwarz, M. Gardiner-Garden, S. M. Henshall, J. Scurry, R. A. Scolyer, M. J. Davies, M. Heinzelmann, L. H. Kalish, A. Bali, J. G. Kench, et al. Overexpression of the Cell Adhesion Molecules DDR1, Claudin 3, and Ep-CAM in Metaplastic Ovarian Epithelium and Ovarian Cancer Clin. Cancer Res., July 1, 2004; 10(13): 4427 - 4436. [Abstract] [Full Text] [PDF]

				W. Matsuyama, L. Wang, W. L. Farrar, M. Faure, and T. Yoshimura Activation of Discoidin Domain Receptor 1 Isoform b with Collagen Up-Regulates Chemokine Production in Human Macrophages: Role of p38 Mitogen-Activated Protein Kinase and NF-{kappa}B J. Immunol., February 15, 2004; 172(4): 2332 - 2340. [Abstract] [Full Text] [PDF]

				C.-H. Piao, M. Kondo, M. Nakamura, H. Terasaki, and Y. Miyake Multifocal Electroretinograms in X-Linked Retinoschisis Invest. Ophthalmol. Vis. Sci., November 1, 2003; 44(11): 4920 - 4930. [Abstract] [Full Text] [PDF]

				W. W. H. Wu and R. S. Molday Defective Discoidin Domain Structure, Subunit Assembly, and Endoplasmic Reticulum Processing of Retinoschisin are Primary Mechanisms Responsible for X-linked Retinoschisis J. Biol. Chem., July 18, 2003; 278(30): 28139 - 28146. [Abstract] [Full Text] [PDF]

				T. R. Varney, H. Ho, C. Petty, and D. D. Blumberg A novel disintegrin domain protein affects early cell type specification and pattern formation in Dictyostelium Development, March 7, 2003; 129(10): 2381 - 2389. [Abstract] [Full Text] [PDF]

				T. Wang, C. T. Waters, A. M.K. Rothman, T. J. Jakins, K. Romisch, and D. Trump Intracellular retention of mutant retinoschisin is the pathological mechanism underlying X-linked retinoschisis Hum. Mol. Genet., November 15, 2002; 11(24): 3097 - 3105. [Abstract] [Full Text] [PDF]

				N. Ortega and Z. Werb New functional roles for non-collagenous domains of basement membrane collagens J. Cell Sci., November 15, 2002; 115(22): 4201 - 4214. [Abstract] [Full Text] [PDF]

				C. A. Curat, M. Eck, X. Dervillez, and W. F. Vogel Mapping of Epitopes in Discoidin Domain Receptor 1 Critical for Collagen Binding J. Biol. Chem., November 30, 2001; 276(49): 45952 - 45958. [Abstract] [Full Text] [PDF]

				S. Yamashiro, H. Kamohara, J.-M. Wang, D. Yang, W.-H. Gong, and T. Yoshimura Phenotypic and functional change of cytokine-activated neutrophils: inflammatory neutrophils are heterogeneous and enhance adaptive immune responses J. Leukoc. Biol., May 1, 2001; 69(5): 698 - 704. [Abstract] [Full Text]

				W. F. Vogel, A. Aszódi, F. Alves, and T. Pawson Discoidin Domain Receptor 1 Tyrosine Kinase Has an Essential Role in Mammary Gland Development Mol. Cell. Biol., April 15, 2001; 21(8): 2906 - 2917. [Abstract] [Full Text]

				C. J. Kuo, K. R. LaMontagne , Jr., G. Garcia-Cardena, B. D. Ackley, D. Kalman, S. Park, R. Christofferson, J. Kamihara, Y.-H. Ding, K.-M. Lo, et al. Oligomerization-dependent Regulation of Motility and Morphogenesis by the Collagen XVIII NC1/Endostatin Domain J. Cell Biol., March 19, 2001; 152(6): 1233 - 1246. [Abstract] [Full Text] [PDF]

				L. L. Molday, D. Hicks, C. G. Sauer, B. H. F. Weber, and R. S. Molday Expression of X-Linked Retinoschisis Protein RS1 in Photoreceptor and Bipolar Cells Invest. Ophthalmol. Vis. Sci., March 1, 2001; 42(3): 816 - 825. [Abstract] [Full Text]

				J. Varani, D. Spearman, P. Perone, S. E. G. Fligiel, S. C. Datta, Z. Q. Wang, Y. Shao, S. Kang, G. J. Fisher, and J. J. Voorhees Inhibition of Type I Procollagen Synthesis by Damaged Collagen in Photoaged Skin and by Collagenase-Degraded Collagen in Vitro Am. J. Pathol., March 1, 2001; 158(3): 931 - 942. [Abstract] [Full Text] [PDF]

				R. S. Bhatt, T. Tomoda, Y. Fang, and M. E. Hatten Discoidin domain receptor 1 functions in axon extension of cerebellar granule neurons Genes & Dev., September 1, 2000; 14(17): 2216 - 2228. [Abstract] [Full Text]

				J. Lu, S.-Y. Chen, H.-H. Chua, Y.-S. Liu, Y.-T. Huang, Y. Chang, J.-Y. Chen, T.-S. Sheen, and C.-H. Tsai Upregulation of Tyrosine Kinase TKT by the Epstein-Barr Virus Transactivator Zta J. Virol., August 15, 2000; 74(16): 7391 - 7399. [Abstract] [Full Text]

				C. Grayson, S. N.M. Reid, J. A. Ellis, A. Rutherford, J. C. Sowden, J. R.W. Yates, D. B. Farber, and D. Trump Retinoschisin, the X-linked retinoschisis protein, is a secreted photoreceptor protein, and is expressed and released by Weri-Rb1 cells Hum. Mol. Genet., July 22, 2000; 9(12): 1873 - 1879. [Abstract] [Full Text] [PDF]

				E. W. RAINES, H. KOYAMA, and N. O. CARRAGHER The Extracellular Matrix Dynamically Regulates Smooth Muscle Cell Responsiveness to PDGF Ann. N.Y. Acad. Sci., May 1, 2000; 902(1): 39 - 52. [Abstract] [Full Text] [PDF]

				W. Vogel, C. Brakebusch, R. Fassler, F. Alves, F. Ruggiero, and T. Pawson Discoidin Domain Receptor 1 Is Activated Independently of beta 1 Integrin J. Biol. Chem., February 25, 2000; 275(8): 5779 - 5784. [Abstract] [Full Text] [PDF]

				K. Kobuke, Y. Furukawa, M. Sugai, K. Tanigaki, N. Ohashi, A. Matsumori, S. Sasayama, T. Honjo, and K. Tashiro ESDN, a Novel Neuropilin-like Membrane Protein Cloned from Vascular Cells with the Longest Secretory Signal Sequence among Eukaryotes, Is Up-regulated after Vascular Injury J. Biol. Chem., August 31, 2001; 276(36): 34105 - 34114. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by VOGEL, W. Search for Related Content PubMed PubMed Citation Articles by VOGEL, W.