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Histol Histopathol (2 00 1) 16: 1287-1293 Histology and 001: 10.14670/HH-16.1287 Histopathology http://www.hh.um.es Cellular and Molecular Biology

Review

Recent progress in T-cadherin (CDH13, H-cadherin) research

T. Takeuchi and Y. Ohtsuki Department of Path ology, Kochi Medical School, Nankoku, Kochi, Japan

Summary. T-cadh erin is a un ique cadh erin ce ll ad hesion ti ssue or orga n in whi ch th ey are stro ngly ex ppressed, it molecul e th at is anchored to th e ce ll sur face membrane ee ms reasonabl e to use "T-cadh erin " in stead of CDH 13 th ro ugh a glycosy l ph osph at id yl in os itol (G PI ) moiety. or H-cadherin give n the hi story outlin ed above. The cy topl as mic domain , whi ch T-cadherin lacks. is be li eved to bc criti ca l fo r homophilic bin ding th ro ugh Molecular structure of T-cadherin int erac ti on with subm cmbrane cytoskeletal protc in s. Docs thi s mea n th at T- cadh erin is an un importanl Class ical cadh erin s are comp osed of a hi g hl y molec ul e? Howcvcr, th e T-cadh erin amino ac id moti f con. erve d cy topl asmi c domain of approx im ately 160 has bee n we ll conserve d thro ug h evoluti o n in amino ac id s, a s in gle transmembrane domain , and a ve rt ebrates, s ugges tin g th at T-c adh e rin may have large ex trace llul ar portion that is orga ni zed in a se ri es of bi ologica l signifi ca nce in hi gher anim als. Consistent fi ve structurally- related tandem repea ts (Ranscht , 1994). wi th thi s hypothesis, recent studies have thrown li ght on T he co nserve d intrace llul ar do ma in of c lass ica l th e re levance of T-cadh erin in the field s of onco logy, cadherin s is be li eved to bind to a group of cy topl asmi c neurology, respi ro logy and ca rdi ovascular ph ys iology. In pro tein s, term ed catenins, which serve as a link betwee n thi s manu script, we review current adva nces in T­ cad herin s and th e cy toskeleton (Nagafuchi and Takeichi , cad herin research. 19S8; Ozawa et aI. , 1989). T-cad herin has a strikingly diverse stru cture, as illustrated in Figure I. T-cadh erin Key words: T-cadherin , Can ce r, Angiogenesis, Ne uron, has five tande m repeat s in it s ex trace llul ar po rti o n: Alveolar proteinosis however, it is att ac hed to the pl asma membrane th ro ugh a GPI anchor without a cy topl asmi c domain (Ransc ht and Dours-Zimm erm ann , 199 1: Tanih ara et aI. , 1994; Nomenclature Lee, 1996). HPT- I, Ksp-cadherin , and L1-cadh erin also each have a short cy topl as mi c domain th at consists of T-cadherin was first identi fied in chicken as a unique onl y about 20 am in o acids ex hibiting no homology with glycosyl ph osph ati dy l in osit ol (G PI )-linked membrane thi s hi g hl y conserved region of class ica l cadh erin s cadh erin (Ranscht and Do urs-Zimmermann, 199 1). (Bernd orff et a\. , 1994; Dantzig et aI. , 1994; Thomso n et I-Ium an CDH 13, cadh erin 13, was subse qu entl y report ed a \. , J 995). A lth o ug h L1- cadh e rin lac ks a typi ca l by Ta nihara et al. ( 1994). Independ entl y, Lee ( 1996) cy topl asmi c domain which induces reorgani za ti on of the ide ntified a ca ndid ate ge ne, ex pression of whi ch is actin cy toskeleton, L1 -cadherin was still abl e to medi ate altered in hum an breast ca ncer. This ca ndidate ge ne, Ca 2+- depend ent ce ll-cell adh esion. A rece nt stud y whi ch was strongly expressed in hea rt , was term ed H­ further revealed th at an arti ficiall y constru cted GPI­ cadh erin and appea red to be id enti ca l to CDH 13. As anchored fo rm of L1- cadherin still ca n induce Ca 2+­ show n in Table 1, molecular homology betwee n th ese depende nt , homophilic cell-ce ll adhesion in transfected species clea rl y in dica ted th at CDH 13 (H-cadh erin ) is a ce ll s ( Kr eft et al.. 1997). T- cadhe rin also induced hum an homologue of chicken T-cadherin . The cadh erin s homophilic ad hes ion between transfected cell s (Vestal have bee n di v id ed int o mo re th an 10 s ubclasses, and Ranscht , 1992). These findings indicated th at a depending on th eir ti ssue distribution; th ese include E­ cy to pl as mic do ma in may no t be necessa ry fo r (epitheli al), N- (neuronal) and P- (pl ace nt al) cadherin s. homophili c binding of several cad herin molecul es. Alth ough the classica l cad herin s we re designated by th e T-cadherin homology among species Offprint requests to: Takeuchi. Tamotsu. M.D ., Depart ment of Pathology, Kochi Medical School. Nankoku , Koch i 783 -8505. Japan. Hum an, go rill a, mouse, chi cke n, frog, and zebrafish Fax: +81 -88-880-2336. e-mail: takeuti [email protected] T- cadh erin cDNAs in cluding parti al sequ ences have 1288 T-cadherin

bee n cloned. As shown in Tabl e 1, th e T-cadhe rin ex pression in two human oseteosarcoma cell lin es, HOS molecule is highly conserved between these species. The and SaOS cells, but not in other cancer cell lines degree of identity of it among is much higher than for E­ examined. Sato et al. (1998b) examined T-cadherin cadherin. This suggests that th e T-cadherin amino acid ex pression in human lung cancer cell lin es an d found motif ha s been well conserved through evolution in that 3 out of 7 lung cancer cell lines expressed T­ vertebrates. The availability of th e euchromatic genomic cadherin. We also examined T-cadhe rin mRNA sequ ences of Drosophila melanogaster (Adams et aI., expression in various human cultured cells, and found 2000; Rubin et aI., 2000) makes it possible to examine that most osteosarcoma cell lines strongly ex pressed T­ how cadherin molecules developed through evolution. cadherin. Most cultured sa rcoma cell lin es, including Hynes and Zhao (2000) described the cadherin those from patie nt s with rhabdomyosa rcoma, o r superfamily in D. melanogaster. Three cadherins of D. leiomyosarcoma but not neuroblastoma, ex pressed T­ melanogasler exhibit homology with the catenin-binding cadherin mRNA (unpublished data). In conclusion, thi s cytoplasmic domains of vertebrate cadherins. These broad ex pression in various human ti ssues and cells three molecules may have developed int o class ical suggests that T-cadherin may play multiple rol es in vertebrate cadherins through evolution. However, no T­ biological processes, since it seems unlikely th at T­ cadherin homologue, or GPI-anchored cad herin , has cadherin plays only a si ngl e rol e in th ese been found in D. melanogaster. It is thus likely that T­ polymorphorous cell types. cadherins newly developed in vertebrates. The high degree of homology among T-cadherin s in vertebrates T-cadherin in cancer research suggests that th ese molecul es play critical roles in biological processes of higher animals. T-cadherin as a tumor suppressor factor

Distribution of T-cadherin molecule in various As shown in Table 2, T-cadherin has been mapped to human tissues and cells human chromosome 16q24, for which loss of heterozygosity in patients with sporadic breast, prostate, Lee (1996), using Northern blotting, found th at T­ liver, ovary and lung cancer has been reported (Carter et cadherin is highly ex pressed in human hea rt , ex pressed aI., 1990; Tsuda et aI. , 1990; Sa to et aI. , 1991, 1998a; to a lesser extent in brain, lung, muscle and kidney, and Tsud a et a I. , 1994). Lee (L 996) first mapped th e T­ hardly detectable in th e pancreas and liver. We also cadherin (H-cadherin) gene to 16q24 by FISH, and examined T-cadherin expression in developing and adult reported that T-cadherin acts as a tumor suppressor human brain by Northern blotting, in situ hybridization , factor in breast cancer. Miki et al. (1997) exam ined 48 and immunohistochemical staining (Takeuchi et aI., primary breast cancers in which loss of 16q24 had bee n 2000a). T-cadherin was expressed in neural cell surface detected. They found no mutaions other than in a singl e membrane and neurites in adult cerebral cortex, medulla, oblongata, and nucleus olivaris. Interestingly, T-cadherin was less expressed in developing brain and ad ult spinal c GPI anchor cord. In lung ti ssue, T-cadherin molecule was ex pressed cytoplasmic not only in the pulmonary vasculature but also in bronchioloalveolar type II cells (Takeuchi et aI., 200 I). Surface membrane Very recently, T-cadherin expression in th e human extracellular vasculature was reported (Ivanov et aI., 2001). Ivanov et al. found that T-cadherin is present in both th e aortic intima and media and was ex pressed in endoth elial cells, smooth muscle cells, and pericytes. In the adventitia, T­ cadherin is present in the walls of the vasa vasorum. Lee ~ (1996) reported that T-cadherin is predo minatl y OQNDN expressed in normal cells, but not in th e maj ority of human cancer cells. He detected T-cadherin mRNA ~ N N

Table 1. Homology of T-cadherin and E-cadherin in various species. human T cadherm AA human E -cadhefln AA Deduced amino acid sequence of cadherins of various species was Cons.ensus mF~~f~aJF~f!tf~7 ~~ m compared with human cadherins. human T cadhefm AA human E-cadh&ftn AA ~:IIR~~0~~fllll_~~~I~ ~gg T-CADHERIN E-CADHERIN N-CADHERIN P-CADHERIN Consensus Fig. 1. Protein structures of E-cadherin (left) and T-cadherin (right) are Human 100% 100% 100% 100% schemati cally shown. Five cadherin repeats are indicated by the box . Mouse 92% 69% 84% 74% Homology of the first cadherin repeat is representatively aligned. The Chicken 74% 62% 77% 58% LORE cluster and the putative calcium-bindin g site , DQNON , Zebrafish 74% 51% 68% not found characteristic of cadherin cell-adhesion molecules, are well conseNed.

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breast cancer; however, they also reported that T­ cadherin mRNA expression was reduced in 5 out of 10 " breast cancers compared with that in normal mammary epithelial cells. They suggested that the decreased expression of T-cadherin in breast cancers is probably caused by repression of transcription and/or translation of T-cadherin. Subsequently, Sato et al. (1998b) found .: :;. that the T-cadherin gene was inactivated in a ~ "~~ . . . considerable number of human lung cancer specimens. ' ." They reported that hypermethylation related to inactivation of the T-cadherin molecule was found in 45 % of primary lung cancers. Methylation of DNA is an epigenetic modification that can play an important role in the control of gene expression in mammalian cells. The presence of hyper-methylated epG islands in the promoter region of various genes can suppress their expression and is involved in tumorigenesis (Jones, AS PRl 1996). Recently, we confirmed by in situ hybridization technique that T-cadherin mRNA level was significantly .. ~. reduced in a considerable number of lung cancer specimens (Fig. 2). To address the question as to whether T-cadherin expression in lung cancers correlated with histological classification or metastatic activity, we immunostained primary lung cancer specimens and found that lack of T-cadherin expression was neither related to histopathological classification nor metastasis to lymph nodes. Specifically, 57% (16 out of 28 cases) and 50% (19 out of 38 cases) of squamous cell carcinoma and adnocarcinoma specimens, respectively, did not express T-cadherin. Respectively, 12 out of 25 and 15 out of 27 lung cancer specimens with and without •• lymph node metastasis expressed T-cadherin (unpublished data). In contrast, T-cadherin expression in B osteosarcoma cells appears to be correlated with lung metastasis, as determined by immunohistochemical staining (Takeuchi et aI., 2000b). In a study of ovarian cancer, Kawakami et al. (1999) reported that loss of heterozygosity (LOH) in the T-cadherin gene region was observed in 6 of 17 specimens examined. They also reported that hypermethylation of the T-cadherin gene was observed in 4 out of 6 ovarian tumors. No reports are available describing the involvement of T-cadherin in hepatocellular carcinoma or prostatic cancer. Recently, we examined whether noncancerous human hepatocytes or prostatic gland expressed T-cadherin. Preliminary immunohistochemical staining demonstrated that neither ...,- noncancerous hepatocytes nor prostatic gland cells expressed T-cadherin.

c Table 2. Location of various cadherins in a short arm of human Fig. 2. In situ hybridization with human T-cadherin antisense cRNA chromosome 16. probe . Bronchioloalveolar cells exhibit positive signals in non-cancerous regions of lung tissues from a patient with primary bronchioloalveolar CDH 8 16q22.1 carcinoma (A). In contrast, adenocarcinoma cells from the same patient CDHll 16q22.1 demonstrate lack of staining whereas, tumor endothium exhibited VE-cadherin (CDH5) 16q22.1 staining (arrow, 6). No significant reactivity is observed with sense E-cadherin (CDH 1) 16q22.1 cRNA probe (C). The procedure used , including the generation of cRNA P-cadherin (CDH3) 16q22 probes, was previously described in detail (Takeuchi et al. 2000a). A, T-cadherin (CDH 13/H-cadherin) 16q24.2-24.3 x 200;B,x400; C,x400 M-cadherin (CDH 15) 16q24.3 1290 T-cadherin

Lack of staining of hyperpl as ti c prostatic gland s ca nce rs. Hype rm eth ylation of CpG island s in th e with T-cadh erin antibody is demonstrated in Figure 3. pro moter region may dec rease T-cadh erin expression Moreover, several prostati c carcinoma specim ens were and affect th e tumori ge ni city of these ca nce rs. not stain ed with anti-T-cadherin antibody. It is thus unlikely th at T-cadh erin ac ts as a tum or suppressor T-cadherin is overexpressed in tumor endothelium fa ct or in eith er hepatocellul ar carcin oma or prostati c carcinoma. Rece nt adva nces in targeting th erapy aga inst tum or In summ ary, it is possibl e that T-cadh erin acts as a neovascul ari za ti on have hi ghlighted a molec ul e whi ch tum or suppressor fac tor in breast, lung, and ova ri an was se lective ly expressed in tum or endoth eli al ce ll s but

Fig. 3. Immunohistochemical staining of nodular hyperp lastic prostatic glands with affi nity-puri fied ra bbit antibody to human T-cadherin pep ti de (B) . Generation and characterization of antibody was described previously (Takeuchi et al. 2000a) Note the lack of staining in prostatic glands but endothelial cells in small vessels are strongly stained with anti-T-cadherin antibody (B. arrow). Hematoxylin­ eosin (HE) stai ning is shown in A. A. -_ .. _. _ ------

1291 T-cadherin

bare ly fo und in intact vasc ul ar e ndo th e li al ce ll s exampl e, mye lin-associated glycoprotein pro motes (Schlinge mann et aI., 199 1; Folkm an, 1992; Burrows neurite growth in one set of culture conditions, and and Thorpe, 1994). Wyder and Kl emenz et al. (2000) inhi bit s ne urit e o ut growth in othe r co nd iti o ns. first report ed th at T-cadh erin was overex pressed in (McKerrac her et aI. , 1994: Matsud a et aI. , 1996) N­ murine tum or penetrating blood vessels. They used the cadh erin can stimulate mi gratory processes such as suhstrac ti ve hybridiza tion meth od to identify protein s axonal growth and cell mi gration (Dohert y and Walsh, th at are specifica ll y ex pressed o n th e sur face of 1996). Notabl y, T-cadh erin ex hibits a homology with N­ endo theli al ce lls in tum ors and successfull y isolated T­ cadhe rin (ded uced a mino acid ho mology of ca dh erin cDNAs fr om tumor vessels of murine Lewi s approx im ately 43%). Furthe r studies in cluding lung ca rcin oma lung metastases. They reported th at T­ ge ne rati o n of ge ne-t a rge ting mi ce a re needed to cadherin was ubiquitously expressed on endotheli al ce lls determine th at T-cadh erin represses neural grow th ill in several, but not all , transpl ant ed tum ors examined. vivo. Murine T-ca dh erin was ex pressed in onl y a sub set of vesse ls within ce rtain orga ns such as lung, li ve r, spl een, T-cadherin in respiratory sciences brain , hea rt, and kidney. Very recentl y, we also observed th at hum an T- cadh erin was overexpressed in tumor Recentl y, we found th at T cadh erin could regul ate sinu soidal endoth eli al cell s in hepatocellular carcinoma surfactant protein (S P)-D gene expression in human (manu script in pre parati on). Studies to determin e bro nchi oloa lveolar type- II ce lls (Takeuchi et aI. , 2001). w heth er T-cadh erin is a good cand id ate for We transfected T-cadherin ex pression vector into A549 anti angioge nic therapy are now in progress. cell s. Cultured A549 cell s with alveolar type-II ce ll characteri stics lacked T-cadherin ; however, hum an T-cadherin in vasculocirculology alveolar type-II ce ll s were fo und to ex press T-cadh erin on immunohi stochemical staining. Interestingly, A5 49 Recent stu dies have revealed th at T-cadh erin may ce ll s transfected with expression vector cont aining T­ pl aya signi ficant role in angiogenesis. Tkac huk et al. cadherin cDNA lost production of surfac tant protein SP­ ( 1998) id enti fied T-cadherin as an atypica l lipoprotein­ D. (As ex pected the transfected A549 cells expressed T­ binding prote in in membranes of vascular smooth cadherin ). In contrast, ori gin al and control vector­ mu scle cell s th at is di stinct fr om currentl y kn own trasfected A549 cells produced SP-D. SP-D is a member lipoprotein recept ors. Subse qu entl y, Ku zmenk o et al. of th e fa mil y of coll age nous host defense lectin s, (1998) characteri zed T-cadherin as a negati ve regul ator designated coll ectins (Crouch et aI. , 2000). SP-D is in rat aorti c smooth mu scle cell s. In a seri es of believed to be an important component of th e innate ex perim ent s, Resink et al. obtain ed result s suggesting immune response to microbi al chall enge (Clements et that low-density lipoprotein is a ph ys iologically relevant aI. , 1998). We fo und th at alveolar type-II ce ll s in li ga nd fo r T-cadh erin and GPI moiety of T-cadh erin is pro tein osis specim ens lacked T- cadh erin expression. necessary and sufficient fo r medi ati on of lipoprotein Pulmonary alveolar protein osis is a chronic intersititial binding (Res ink et aI. , 1999; Stambolsky et aI. , 1999; pn eum oni a with filling of alveoli by dense, gra nul ar, Nie rm ann et a I. , 2000). Hype rlipide mi a inhibits eosinophilic materi al. Recent studies have implicated proli fe rati o n of e nd oth e li a l ce ll s in c ulture a nd granulocyte-macrophage colony-stimulating fa ctor (G M­ angiogenesis in vivo and in art eri al expl ants (Chen et aI. , CSF) in the pathogenesis of hum an pulmonary al veolar 20(0). These findings, together with the finding that T­ cadh erin is overexpressed in tum or vessels, suggest th at T-cadherin may be a positi ve regulator of angiogenesis. Cancer Researcl Vasculocirculology It is likely th at T-cadh erin adsorbs lipoprotein and that it is in vo lved in angiogenesis. CD tumor suppressor factor CD atypical lipoprotein a. breast cancer -binding protein b. lung cancer T-cadherin in neurology c. ovary cancer ® overexpression in tumor T- ca dherin was first cloned fr om chick embryo endothelium brain . Fredette et al. (1 996) report ed that T-cadherin is a negati ve guid ance cue for motor axon projecti ons. We also reported th at T-cadherin acts as a negative grow th regul ator of epiderm al growth fac tor in human neuro blastoma ce ll s (Takeuchi et aI. , 2000a). Notabl y, T­ Neurology Respiratory Science cadh erin ex pression in developing brain is much weaker CD negative gu idance cue CD negative regulator of th an in adult brain . These findings indicate th at T­ for motor axon projection surfactant protein-D cadh erin is a nega ti ve growth regul ator of neural growth . ® negative growth regulator However, it mu st be recall ed th at th e effect of a of epidermal growth factor molec ul e on neur al growth or development alw ays in human neuroblasts celis depend s on th e experime nt al conditions used. For Fig. 4. Expan ding world of T-cadherin research. 1292 T-cadherin

proteinosis (Dranoff et aI. , 1994; Huffman et aI., 1996; R,T" Dickersin G.R., Bachurski C,J " Mark E,L. , Whitsett JA and Reed and Whitsett, 1998). Therefore, downregulation of Mulligan R.C , (1 994). Involvement of granulocyte-macrophage T-cadherin may not be a primary event in the colony-stimulating factor in pu lmonary homeostasis. Science 264 , pathogenesis of alveolar proteinosis, but may be 713-716. correlated with SP-D overexpression in alveolar type-II Folkman J, (1992). The role of angiogenesis in tumor growth. Semin, cells. High levels of SP-D in bronchoalv eolar lavage Cancer BioI. 3, 65-713. fluid of patients with pulmonary alveolar proteinosis has Fredette B.J. , Miller J, and Ranscht B, (1996) , Inhibition of motor axon been reported (Kuroki et aI., 1998). In summary, T­ growth by T-cad herin substrata. Development 122, 3163-3171 . cadherin may regulate surfactant protein production in Huffman J.A" Hull W.M " Dranoff G., Mu lligan R.C. and Whitsett J.A. bronchioalveolar cells. (1996). Pu lmonary epithelial cell expression of GM-CSF co rrects the alveolar proteinosis in GM-CSF-deficient mice. J. Clin, Invest. 97, Concluding comments 649-655. Hynes R,O. and Zhao O. (2000), The evoluti on of ce ll adhesion. J. CAli Cadherin mol ecul es have long been thought to be BioI. 150, F89-F96 , simple sticky molecules. However, in recent years Ivanov D., Philippova M" Antropova J., Gubaeva F., II jinskaya 0 " cadherins have emerged as a growing superfamily of Tararak E., Bochkov V" Erne P., Res ink T. and Tkachuk V. (2001). mol ecules. T-cadherin has an interesting structure, and Expression of cell adhesion molecule T-cadherin in the human ha s recentl y attracted many researchers in various vasculature, Histochem. Cell Bio I. 115, 23 1-242. biologies and pathologies as summarized in Fig. 4. As Jones PA (1996) , DNA methylation errors and cancer. Cancer Res, 56 , described in this review, T-cadherin may participate in 2463-2467. many biological processes in various ti ssues, including Kawakami M., Staub J., Cliby W" Hartmann L., Smith D.1. and Shridhar intercellular adhesion , cell communication , V, (1999). Involvement of H-cadherin (CD H1 3) on 16q in the region morphogenesis, angiogenesis, tumorigenicity, and even of fr equent deletion in ovarian cancer. Int. J, On col. 15, 71 5-720 regulation of surfactant protein production. Kreft B" Berndorff D., B6ttinger A. , Finnemann S., Wedlich D" Hortsch M., Tauber R. and GeSner R. (1997) . LI -Cadherin-mediated cell-cell References adhesion does not require cytoplasmic interactions, J. Cell BioI. 136, 1109-11 21. Adams M.D., Ce lniker S.E., Holt R.A., Evans CA, Gocayne J.D ., Kuroki Y. , Takahashi H., Chiba H. and Akino T. (1998) . Surfactant Amanatides P.G. and Venter J.C. (2000). The genome sequence of proteins A and D: disease markers. Biochim . Biophys Acta. Drosophila melanogaster. Science 287, 2185-2 195. 1408,334-345. Berndorff D.R., Gessner B. , Kreft N., Schnoy A. -M. , Lajous-Petter N., Kuzmenko Y.S. , Kern F., Bochkov V,N. , Tkachuk VA and Resink T.J , Loch w. , Reutter M., Hortsc and Tauber R. (1 994). Liver-intestine (1998), Densi ty- and proliferation status-dependent expression of T­ cadherin: molecular cloning and characterization of a novel Ca(2+) - cadherin , a novel lipoprotein-binding glycoprotein: a function in dependent cell adhesion molecule expressed in liver and intestine. negative regulation of smooth muscle cell growth? FEBS Lett. 434, J. Cell Bioi. 125, 1353-1369. 183-187, Burrows F.J. and Thorpe P.E. (1994). Vascular targeting- a new Lee SOW, (1996). H-cadherin, a novel cadherin with growth inhibitory approach to therapy of solid tumors. Pharmacol. Ther. 64, 155-174. functions and diminished expression in human breast cancer. Carter B.S., Ewing C.M. , Ward W .S., Treiger B.F., Aald er T.W., Nature Med. 2, 776-782, Schalken J.A" Epstein J.I. and Isaacs W.B. (1990). Allelic loss of Matsuda Y., Ok itsu A. , Sato S., Koito H, and Yamamoto H, (1996). chromosomes 16q and 10q in human prostate cancer. Proc. Nat! . Soluble myelin-associated glycoprotein-immunoglobulin G 1 chimera Acad. Sci. USA 87,8751-8755, protein promotes neurite outgrowth from mouse cerebellar neurons. Chen C,H. , Jiang w. , Via D.P" Luo S., Li T.R., Lee Y.T, and Henry PD. Neurosci Lett. 205, 87-90. (2000) . Oxidized low-density lipoproteins inhibit endothelial cell McKerracher L., David S" Jackson D.L. , Kottis V., Dunn R.J . and Braun proliferati on by suppressing basic fibroblast growth factor P,E, (1994). Identification of myelin-as sociated glycoprotein as a expression, Circulation 101 ,171 -177. major myelin-derived inhibitor of neurite growth. Neuron 13, 805-811 Clements J" Carlson E" Gillespie A.M " Epstein C. and Hawgood S. Miki Y., Katagiri T. and Nakamura Y .• (1997). Infrequent mutaion of the (1998). Altered surfactant homeostasis and alveolar type II cell H-cadherin gene on chromosome 16q24 in human breast cancers. morphology in mice lacking surfactant protein D, Proc. Nat!. Acad . Jpn. J, Cancer Res . 88 , 701-704, Sci. USA 95, 11869-11874. Nagafuchi A. and Takeichi M, (1988) , Cell binding function of E-cadherin Crouch E., Hartshorn K, and Ofek I. (2000) . Collecti ns and pu lm onary is regulated by the cytoplasmic domain, EMBO J, 7. 3679-3684. innate immunity, Immunol. Rev. 173, 52-65. Niermann T ., Kern F" Erne p , and Resink T. (2000), The glycosyl Dantzig A.H ., Hoskins JA, Tabas L.B ., Bright S" Shepard R,L" Jenkins phosphatidylinositol anchor of humafl T-cadherin binds lipoproteins, I.L.. Duckworth D,C" Sportsman J.R., Mackensen D" Rosteck P.R. Biochem, Biophys. Res. Commun. 276, 1240-1247, Jr and Skatrud P.L. (1 994). Association of intestinal peptide Ozawa M., Baribault H, and Kemler R. 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-_.. - .. _- _._----_._--- 1293 T-cadherin

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