Advanced
Characterization and function of human Ly-6/uPAR molecules
Characterization and function of human Ly-6/uPAR molecules
BMB Reports. 2012. Nov, 45(11): 595-603
Copyright © 2012, Korean Society for Biochemistry and Molecular Biology
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
  • Received : October 12, 2012
  • Published : November 30, 2012
Download
PDF
e-PUB
PubReader
PPT
Export by style
Share
Article
Author
Metrics
Cited by
TagCloud
About the Authors
Hyun Kyung Kong
Jong Hoon Park
parkjh@sookmyung.ac.kr

Abstract
Human Ly-6/uPAR molecules are a superfamily composed of two subfamilies; one is the membrane bound proteins with a GPI-anchor and the other are secreted proteins without the GPI-anchor. Ly-6/uPAR molecules have remarkable amino acid homology through a distinctive 8-10 cysteine-rich domain that is associated predominantly with O-linked glycans. These molecules are encoded by multiple tightly linked genes located on Chr. 8q23, and have a conserved genomic organization. Ly-6/uPAR molecules have an interesting expression pattern during hematopoiesis and on specific tumors indicating that Ly-6/uPAR molecules are associated with development of the immune system and carcinogenesis. Thus, Ly-6/uPAR molecules are useful antigens for diagnostic and therapeutic targets. This review summarizes our understanding of human Ly-6/uPAR molecules with regard to molecular structure as well as what is known about their function in normal and malignant tissues and suggest Ly-6/uPAR molecules as target antigens for cancer immunotherapy. [BMB Reports 2012; 45(11): 595-603]
Keywords
INTRODUCTION
Ly-6 molecules were initially identified in mice as lymphocyte differentiation antigens (1) . Ly-6 molecules are encoded by multiple tightly linked genes located on mouse chromosome 15 and have conserved genomic organization (2) . Murine Ly-6 molecules are a set of structurally related and distinct collection of low molecular weight GPI-anchored cell surface glycoproteins such as Ly6a (Sca-1), Ly6b, Ly6c1, Ly6d (Thb), Ly6e (Sca-2), Ly6f, Ly6g, Ly6h, Ly6i, Ly6k, and TSA-1 antigens and are characterized by leukocyte expression (3) . Secreted Ly-6 molecules without a GPI-anchoring sequence have been identified in mouse seminal vesicles (4) . Murine Ly-6 molecules are expressed on fully differentiated cells in specific compartments of peripheral lymphoid tissues including the spleen, lymph nodes, and peripheral blood but limited expression occurs on non-lymphoid tissues (5) . The binding of an anti-Ly-6 monoclonal antibody triggers cellular activation associated with T-cell activation, lymphoblast transformation, and signal transduction through the TcR-CD3 complex (3 , 5) .
The CD59 human Ly-6/uPAR molecule was first identified in human lymphoid cells (6) . Since 1989, several human Ly-6/uPAR family members exhibiting varying degrees of similarity to murine Ly-6 molecules have been identified. To date, a total 20 human Ly-6/uPAR proteins, ranging from 11 to 36 kDa, have been identified and classified into transmembrane protein and secretory protein subfamilies according to the GPIanchored signaling sequence. We review the structure and function of human Ly-6/uPAR molecules in detail as well as their clinical value as biomarkers and molecular targets for cancer therapy.
CHARACTERIZATION OF HUMAN Ly-6/uPAR MOLECULES
A cluster of genes has been mapped to human chromosome 8 for many members of the human Ly-6/uPAR superfamily, particularly 8q24.3, which is synthenic to the murine Ly6 locus, the E band on mouse chromosome 15 (2) . Other genes encoding the human Ly-6/uPAR superfamily members are localized on human chromosome 19q13 (uPAR, LYPD5, SAMP14, and LYPD3), chromosome 2q21-23 (LYPD1, LYPD6, and LYPD7), chromosome 11 (CD59 and SP-10), and chromosome 7 (CD177).
The Ly-6/uPAR superfamily of molecules is a single chain that has one or more LU domains. Ly-6/uPAR molecules have two distinct regions including: (i) a -NH 2 terminal polypeptide, which contains a consensus leader sequence, Leu(Val/Ala) LeuLeuLeu(Ala/Val) Leu(Ala/Val) within a signal peptide 11-30 amino acids long that are destined towards the secretory pathway; and (ii) a peptide that forms a conserved 8-10 cysteine residue, hydrophilic LU domain. Ly-6/uPAR can be classified into two subfamilies based on the theoretical absence or presence of the GPI-anchor domain: one represents transmembrane proteins and the other represents secretory proteins without a GPI anchor. The transmembrane proteins of the Ly-6/uPAR superfamily have a-COOH terminal polypeptide that contains a consensus signal sequence located within 8–10 amino acids of the −NH 2 terminal of a hydrophobic domain, which is required for cleavage of the -COOH peptide during phosphatidyl inositol anchor biosynthesis.
Cell surface expression of CD59, GHPIHBP1, GML, LY-6D, LY-6E, LY-6H, LY-6K, LYPD1, LYPD2, LYPD5, and PSCA and the secretion of SLURP1, SLURP2, SAMP14, and SP-10 is characterized by a single LU domain containing cysteine residues that have remarkable conservation within the mature peptide ( Fig. 1 ). Internal disulfide bonds form between the sulfur atoms of two cysteine residues within the LU domain. In contrast to other cell surface proteins, CD177 and LYPD3 and uPAR contain two and three contiguous copies of the LU domain, respectively. LYPD6 and LYPD7 (also known as LYPD6B) have a LU domain but it contains 12 cysteine residues within the mature peptide. Cysteine residues are numbered in the context of the amino acid sequence of the Ly-6/uPAR superfamily molecules; equal spacing is observed between Cys 3 and Cys 6 , Cys 25 and Cys 37 , and Cys 96 and Cys 102 in CD59, GML, LY-6D, LY-6E, LY-6H, LY-6K, LYPD2, LYPD5, PSCA, SLURP1, SLURP2, LYPD3.1, uPAR(1-3), LYPD6, and LYPD7 amino acid sequences, although the GHPIHBP1, LYPD1, LYPD3.2 and SAMP14 sequences have different cysteine spacing between Cys 25 and Cys 37 . Heterogeneity in cysteine residue spacing, which is observed between Cys 6 and Cys 15 , Cys 15 and Cys 25 , Cys 37 and Cys 62 , Cys 62 and Cys 68 , Cys 68 and Cys 96 in Ly-6/uPAR superfamily molecules, may impart specific structural epitopes.
PPT Slide
Lager Image
Amino acid sequence analysis of human Ly-6/uPAR molecules. The amino acid sequences of human Ly-6/uPAR superfamilies, from Leu1 to Asn103, were aligned with other sequences for comparison. Conserved cysteine residues are represented * and the boxes show amino acid identity.
Other obvious amino acid identity and homology regions have been observed ( Fig. 1 ). Many Ly-6 family genes have a highly conserved sequence located at the -NH 2 terminus; a LeuXxxCysXxxXxxCys motif at the -COOH terminus; a CysCysXxxXxxXxxXxxCys Asn motif is found in almost Ly-6/uPAR related amino acid sequence except for SP-10, which has a CysCysXxxXxxXxxXxxXxxCysAsn motif, whereas CD177 does not.
A three-dimensional crystal and solution structure of α-bungarotoxin was the first murine Ly-6/uPAR family structural model, and the amino acid sequence of the predicted β-sheet is shared between snake toxins and murine Ly-6 (7) . The structural confirmation of α-bungarotoxin is maintained by internal disulfide bonds between the first and fifth, second and third, fourth and sixth, seventh and eighth, and ninth and tenth cysteine residues. Similarly, Ly-6/uPAR molecule structure can be predicted. The evolutionary relationship among the Ly-6/uPAR protein family was clarified by constructing a phylogenetic tree and Ly-6/uPAR superfamily amino acid sequences from Leu 1 to Asn 103 ( Fig. 2 ). This analysis showed early divergence of the GML amino acid sequence, and a progenitor sequence of the other formed a common ancestral sequence.
FUNCTIONAL ANALYSIS OF Ly-6/uPAR MOLECULES
- CD59
The plasma membrane glycoprotein CD59 (protectin) was the first member of Ly-6/uPAR sueprfamily found in humans (6) . Complement regulatory protein CD59 functions as a major protective element against C5b-9, thereby blocking assembly of the membrane attack complex for human complementmediated cell lysis (8 , 9) . Second, CD59 induces T lymphocyte activation and participates in regulating the immune response (10) . Third, CD59 acts as a CD2 complex ligand and activates T cells by secreting the cytokines interleukin (IL)-1 alpha, IL-6, and granulocyte-macrophage colony-stimulating factor (11) . Fourth, CD 59 functions as a regulator of tumor cell growth and apoptosis; overexpressed CD59 induces proliferation and reduces anti-apoptotic Bcl-2 expression in MCF7 cells (12) . These results suggest that CD59 may be a promising target for cancer immunotherapy.
PPT Slide
Lager Image
Phylogenetic tree of the human Ly-6/uPAR superfamily of molecules constructed based on the amino acid sequence distance method for Ly-6/uPAR superfamilies from Leu1 to Asn103, using the neighbor-joining algorithm (99) and the WAG alpha substitution model (100). Scale bar indicates branch length.
- CD177
CD177 (human neutrophil antigen-2a, NB1 glycoprotein, or polycythemia rubra vera 1) is a hematopoietic cell surface marker that is exclusively expressed on neutrophils (13) . CD177 regulates neutrophil migration by binding with CD31 (platelet endothelial cell adhesion molecule-1) as a heterophilic binding partner of CD177 and induces the cytokine signaling cascade including thrombopoietin and IL-3-induced proliferation, and proteinase 3 expression, which is target antigen of anti-neutrophil cytoplasm auto-antibodies (14 - 16) . These data indicate that regulating CD177 expression may be a novel strategy for cancer therapy by regulating the immune response.
- GPIHBP1
GPIHBP1 is expressed exclusively in capillary endothelial cells along the capillary lumen and is highly expressed in heart and brown adipose tissue, which are crucial for processing of triglyceride-rich lipoproteins (17 , 18) . These GPIHBP1 expression patterns suggest that GPIHBP1 serves as a lipoprotein lipase binding site within capillaries and may play a particularly important role in lipoprotein metabolism.
- LY-6 molecules
LY-6D (E48 antigen) is expressed exclusively on normal squamous epithelia and transitional epithelium and their malignant counterparts (19) . LY-6D is an effective target antigen for diagnosis and therapeutic exploitation in the management of patients with head and neck squamous cell carcinoma (HNSCC) and micrometastases to lymph nodes from HNSCC (20 , 21) .
LY-6E (RIG-E, stem cell antigen 2, and thymic shared antigen) are expressed in squamous cells, peripheral blood, and bone marrow cells. LY-6E plays an important role in T-cell differentiation, activation of the T-cell receptor signaling pathway, and proliferation and differentiation of T2ECs (transforming growth factor [TGF]-α and TGF-β induced erythrocytic cells) that self-renew primary avian erythroid progenitors (22 - 24) . Interestingly, LY-6E is highly expressed in various human cancers, such as colon cancer and malignant kidney cancer (25) . Thus, LY-6E affects tumorigenesis by changing cell proliferation and differentiation.
LY-6H is highly expressed in the human brain, such as the cerebral cortex and also in acute lymphoblastic leukemia cells; thus, LY-6H might play an important role in both the central nervous (CNS) and immune systems (26) .
LY-6K, as a cancer-testis antigen, was initially identified as a HNSCC diagnostic and therapeutic target antigen similar to LY-6D (27) . Elevated LY-6K is a serologic diagnostic biomarker and therapeutic target for breast cancer, lung and esophageal carcinomas, bladder cancer, and esophageal squamous cell carcinoma (ESCC) (28 - 31) . Induced LY-6K regulates cell growth, invasion, and migration of lung, esophageal, breast, and bladder cancer cell lines (29 , 30 , 32) . Additionally, LY-6K is an immunotherapeutic target of cancer vaccine therapies because LY-6K stimulates cytotoxic T lymphocytes that have specific cytotoxic activity against ESCC cells that endogenously express LY-6K (33) . Taken together, these results suggest that inhibiting LY-6K expression may be a promising target for control of these cancers and that targeting LY-6K may be a novel cancer therapy strategy.
- LYPD molecules
LYPD1 (putative tumor suppressor) acts as a putative tumor suppressor in the Hela cell p53-independent pathway (34) . The LYPD1 gene is highly expressed throughout the CNS, such as the cerebellum, cortex, pons, hippocampus, hypothalamus, striatum, amygdale, and septum based on quantitative reverse transcription-polymerase chain reaction and in situ hybridization analyses (35) . Therefore, LYPD1 may play important roles in both tumorigenesis and the CNS.
LYPD3, also known as metastasis-associated membrane protein C4.4A, has been observed in placental tissue, skin, esophagus, and peripheral blood leukocytes (36) . Human LYPD3, a uPAR structural homologue, has been detected in cancer cell lines, including melanoma, breast, bladder, and renal cell carcinoma, as well as in tumor tissue samples from malignant melanoma, metastatic breast cancer, tumor budding, and the epithelial-mesenchymal transition of colorectal cancer, non-small cell lung carcinoma with a poor prognosis, invasion and metastasis of esophageal squamous cell carcinoma, and urothelial tumors (37 - 42) . Wound healing and metastasis promoted by LYPD3 is associated with α(6)β(4) integrin and MT1-MMP1 (43) . These findings indicate that LYPD3 may also be a cancer therapy target.
LYPD6 is ubiquitously expressed in human tissues but highly expressed in brain and heart and localized in the cytoplasm where it suppresses activator protein-1 (AP-1)-mediated transcriptional activation (44) .
LYPD7 is also known as LYPD6B and is highly expressed in testis, lung, stomach, and prostate, localized in the cytoplasm and activates AP-1 and phorbol myristate actetate-mediated transcriptional activation (45) . Further studies are needed to gain a better understanding of the role of LYPD under normal conditions and diseases.
- PSCA
Previous studies have reported that PSCA expression is upregulated in prostate cancer, pancreatic adenocarcinoma, transitional cell carcinoma, clear cell renal cell carcinoma, diffuse-type gastric cancer, endometrial adenocarcinoma, non small cell lung cancer, cervical squamous cell carcinoma, invasive micropapillary carcinoma, and glioma (46 - 55) . In contrast, PSCA is downregulated in esophageal, gastric, stomach tumors, HNSCC, and gallbladder carcinogenesis (27 , 56 , 57) . PSCA genetic variations affect susceptibility to diffuse-type gastric cancer, urinary bladder cancer, stomach cancer, and breast cancer (50 , 58 - 60) . Additionally, PSCA regulates cell growth through the p53-related or immune signaling pathways, adhesion of epithelial cells, and tumor migration and metastasis (61 - 64) . Therefore, PSCA expression may be a diagnostic marker and therapeutic target antigen for cancer therapy.
- SAMP14
SAMP14 is localized near the uPAR shows testis-specific expression through the outer and inner acrosomal membranes as well as the acrosomal matrix. Antibodies against SAMP14 inhibit binding and fusion of human sperm to zona-free eggs (65) . These results suggest that SAMP14 may regulate the sperm-egg interaction. However, further studies are needed to gain a better understanding of the role of SAMP14.
- SLURP1 and SLURP-2
SLURP1 was the first secreted mammalian member of the Ly-6/uPAR protein superfamily identified without a GPI-anchoring signal sequence (66) . SLURP1 and SLUPR2 have been identified in Mal de Meleda and hyperproliferative skin of patients with psoriasis vulgaris, respectively (67 , 68) . SLURP1 regulates epidermal homeostasis, inflammation, keratinization, and programmed cell death as well as tumorigenesis of the colon, survival of fibroblasts, and T cell activation (69 - 72) . SLURP2 plays a role not only in kerationcyte hyperproliferation and T cell differentiation/activation but is also competes with SLURP1 for the human nicotinic acetylcholine receptor (hAChR), thereby delaying keratinocyte differentiation and preventing apoptosis (68 , 73) . Both SLURP1 and SLURP2 are efficient autocrine and paracrine ligands of keratinocyte nAChRs and activating the nAChR-mediated signaling pathways prevents malignant transformation of oral cells by regulating lymphocyte function and the immune system (74) . Taken together, these results suggest that SLURP1 and SLURP2 may also be a target for cancer therapy by regulating the immune system and tumorigenesis.
- SP-10
SP-10 is also known as acrosomal protein SP-10 or acrosomal vesicle protein 1 and has been identified as a potential contraceptive immunogen with germ cell specificity because a monoclonal antibody specific to SP-10 inhibits sperm penetration (75) . SP-10, like the SAMP14 testis-specific acrosomal protein, is a spermatid differentiation marker localized to the developing acrosome of round and elongating spermatids and is associated with the inner and outer acrosomal membranes of most mature spermatids (76 , 77) .
- uPAR
uPAR was first identified in human blood monocytes and the histolytic lymphoma cell line U937 (78) . uPAR plays an important role regulating degradation of extracellular matrix proteins and intravascular fibrinolysis on the cell surface (79) . uPAR expression is overexpressed in various cancers, including colon cancer, invasive breast, melanocytic tumor progression, invasive brain tumor, squamous cell lung carcinoma, renal cell carcinoma, hepatocellular carcinoma, gastric cancer, ovarian cancer, HNSCC, oral cancer, aggressiveness lingual squamous cell carcinoma, and ductal pancreatic carcinoma (80 - 92) . uPAR influences cellular behavior during proliferation, inflammation, wound healing repair, adhesion, angiogenesis, and metastasis by forming a complex with integrins and uPA, which activates the ERK signaling pathway (93) . uPAR activation also leads to extravasation and migration of activated T lymphocytes and chemotaxis of polymophonuclear leukocytes (94 , 95) . Interestingly, soluble uPAR is observed in ovarian cancer, multiple myeloma, breast cancer, burn-injuries, and severe sepsis and regulates uPA enzymatic activity and mobilization of hematopoietic stem cells (96 - 98) .
CONCLUSION
The first human Ly-6/uPAR molecule was discovered relatively recently, and various Ly-6/uPAR family proteins have been identified. The studies described in this review have revealed many interesting properties of the human Ly-6/uPAR family of molecules in the context of tissue expression, molecular structure, and function. These molecules share remarkable amino acid homology in terms of conserved cysteine residues, which are crucial for the conformation of the Ly-6/uPAR domain. Some of the Ly-6/uPAR encoding tumor-specific antigens and their recognition by tumor specific cytotoxicity T lymphocytes have opened new avenues for developing effective anticancer immunotherapies. The Ly-6/uPAR members are considered promising candidates for cancer immunotherapy because they are strictly tumor specific and are shared by many kinds of tumors. The Ly-6/uPAR molecules are considered not only cancer vaccine targets but also target antigens for antibody-based immunotherapy. Other Ly-6/uPAR molecules such as SAMP14 and SP-10 are associated with testis-specific expression, and their function in tumorigenesis is unknown. Many aspects of the Ly-6/uPAR family are not fully understood, and future studies in the context of: (i) the relationship between the regulation of human Ly-6/uPAR expression in hematopoiesis and peripheral tissues to cell development and function in vivo and (ii) understanding the mechanisms of tumorigenesis or migration will allow insight into the functional roles of Ly-6/uPAR molecules in vivo .
Acknowledgements
This research was supported by the Sookmyung Women’s University Research Grants 2010.
References
McKenzie I. F. , Gardiner J. , Cherry M. , Snell G. D. (1977) Lymphocyte antigens: Ly-4, Ly-6, and Ly-7. Transplant Proc. 9 667 - 669
LeClair K. P. , Rabin M. , Nesbitt M. N. , Pravtcheva D. , Ruddle F. H. , Palfree R. G. , Bothwell A. (1987) Murine Ly-6 multigene family is located on chromosome 15. Proc. Natl. Acad. Sci. U.S.A. 84 1638 - 1642    DOI : 10.1073/pnas.84.6.1638
Gumley T. P. , McKenzie I. F. , Sandrin M. S. (1995) Tissue expression, structure and function of the murine Ly-6 family of molecules. Immunol. Cell. Biol. 73 277 - 296    DOI : 10.1038/icb.1995.45
Li S. H. , Lee R. K. , Lin M. H. , Hwu Y. M. , Lu C. H. , Chen Y. J. , Chen H. C. , Chang W. H. , Chang W. C. (2006) SSLP-1, a secreted Ly-6 protein purified from mouse seminal vesicle fluid. Reproduction 132 493 - 500    DOI : 10.1530/rep.1.01183
Havran W. L. , Lancki D. W. , Moldwin R. L. , Dialynas D. P. , Fitch F. W. (1988) Characterization of an anti-Ly-6 monoclonal antibody which defines and activates cytolytic T lymphocytes. J. Immunol. 140 1034 - 1042
Davies A. , Simmons D. L. , Hale G. , Harrison R. A. , Tighe H. , Lachmann P. J. , Waldmann H. (1989) CD59, an LY-6-like protein expressed in human lymphoid cells, regulates the action of the complement membrane attack complex on homologous cells. J. Exp. Med. 170 637 - 654    DOI : 10.1084/jem.170.3.637
Fleming T. J. , O'HUigin C. , Malek T. R. (1993) Characterization of two novel Ly-6 genes. Protein sequence and potential structural similarity to alpha-bungarotoxin and other neurotoxins. J. Immunol. 150 5379 - 5390
Meri S. , Morgan B. P. , Davies A. , Daniels R. H. , Olavesen M. G. , Waldmann H. , Lachmann P. J. (1990) Human protectin (CD59), an 18,000-20,000 MW complement lysis restricting factor, inhibits C5b-8 catalysed insertion of C9 into lipid bilayers. Immunology 71 1 - 9
Chang C. P. , Husler T. , Zhao J. , Wiedmer T. , Sims P. J. (1994) Identity of a peptide domain of human C9 that is bound by the cell-surface complement inhibitor, CD59. J. Biol. Chem. 269 26424 - 26430
Treon S. P. , Shima Y. , Grossbard M. L. , Preffer F. I. , Belch A. R. , Pilarski L. M. , Anderson K. C. (2000) Treatment of multiple myeloma by antibody mediated immunotherapy and induction of myeloma selective antigens. Ann. Oncol. 11 (Suppl 1) 107 - 111    DOI : 10.1093/annonc/11.suppl_1.S107
Naderi S. , Hofmann P. , Seiter S. , Tilgen W. , Abken H. , Reinhold U. (1999) CD2-mediated CD59 stimulation in keratinocytes results in secretion of IL-1alpha, IL-6, and GM-CSF: implications for the interaction of keratinocytes with intraepidermal T lymphocytes. Int. J. Mol. Med. 3 609 - 614
Li B. , Chu X. , Gao M. , Xu Y. (2011) The effects of CD59 gene as a target gene on breast cancer cells. Cell Immunol. 272 61 - 70    DOI : 10.1016/j.cellimm.2011.09.006
Temerinac S. , Klippel S. , Strunck E. , Roder S. , Lubbert M. , Lange W. , Azemar M. , Meinhardt G. , Schaefer H. E. , Pahl H. L. (2000) Cloning of PRV-1, a novel member of the uPAR receptor superfamily, which is overexpressed in polycythemia rubra vera. Blood 95 2569 - 2576
Sachs U. J. , Andrei-Selmer C. L. , Maniar A. , Weiss T. , Paddock C. , Orlova V. V. , Choi E. Y. , Newman P. J. , Preissner K. T. , Chavakis T. , Santoso S. (2007) The neutrophil-specific antigen CD177 is a counter-receptor for platelet endothelial cell adhesion molecule-1 (CD31). J. Biol. Chem. 282 23603 - 23612    DOI : 10.1074/jbc.M701120200
Dillon M. , Minear J. , Johnson J. , Lannutti B. J. (2008) Expression of the GPI-anchored receptor Prv-1 enhances thrombopoietin and IL-3-induced proliferation in hematopoietic cell lines. Leuk Res. 32 811 - 819    DOI : 10.1016/j.leukres.2007.09.018
Korkmaz B. , Kuhl A. , Bayat B. , Santoso S. , Jenne D. E. (2008) A hydrophobic patch on proteinase 3, the target of autoantibodies in Wegener granulomatosis, mediates membrane binding via NB1 receptors. J. Biol. Chem. 283 35976 - 35982    DOI : 10.1074/jbc.M806754200
Beigneux A. P. , Davies B. S. , Gin P. , Weinstein M. M. , Farber E. , Qiao X. , Peale F. , Bunting S. , Walzem R. L. , Wong J. S. , Blaner W. S. , Ding Z. M. , Melford K. , Wongsiriroj N. , Shu X. , de Sauvage F. , Ryan R. O. , Fong L. G. , Bensadoun A. , Young S. G. (2007) Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 plays a critical role in the lipolytic processing of chylomicrons. Cell Metab. 5 279 - 291    DOI : 10.1016/j.cmet.2007.02.002
Davies B. S. , Beigneux A. P. , Barnes R. H. 2nd , Tu Y. , Gin P. , Weinstein M. M. , Nobumori C. , Nyren R. , Goldberg I. , Olivecrona G. , Bensadoun A. , Young S. G. , Fong L. G. (2010) GPIHBP1 is responsible for the entry of lipoprotein lipase into capillaries. Cell Metab. 12 42 - 52    DOI : 10.1016/j.cmet.2010.04.016
Quak J. J. , Balm A. J. , van Dongen G. A. , Brakkee J. G. , Scheper R. J. , Snow G. B. , Meijer C. J. (1990) A 22-kd surface antigen detected by monoclonal antibody E 48 is exclusively expressed in stratified squamous and transitional epithelia. Am. J. Pathol. 136 191 - 197
Bartelink H. , Keus R. B. (1991) Progress in radiotherapy by treatment tailoring in head and neck cancer. Curr. Opin. Oncol. 3 523 - 528    DOI : 10.1097/00001622-199106000-00013
Nieuwenhuis E. J. , Leemans C. R. , Kummer J. A. , Denkers F. , Snow G. B. , Brakenhoff R. H. (2003) Assessment and clinical significance of micrometastases in lymph nodes of head and neck cancer patients detected by E48 (Ly-6D) quantitative reverse transcription-polymerase chain reaction. Lab. Invest. 83 1233 - 1240    DOI : 10.1097/01.LAB.0000083532.46536.56
Antica M. , Wu L. , Scollay R. (1997) Stem cell antigen 2 expression in adult and developing mice. Immunol. Lett. 55 47 - 51    DOI : 10.1016/S0165-2478(96)02682-X
Noda S. , Kosugi A. , Saitoh S. , Narumiya S. , Hamaoka T. (1996) Protection from anti-TCR/CD3-induced apoptosis in immature thymocytes by a signal through thymic shared antigen-1/stem cell antigen-2. J. Exp. Med. 183 2355 - 2360    DOI : 10.1084/jem.183.5.2355
Saitoh S. , Kosugi A. , Noda S. , Yamamoto N. , Ogata M. , Minami Y. , Miyake K. , Hamaoka T. (1995) Modulation of TCR-mediated signaling pathway by thymic shared antigen-1 (TSA-1)/stem cell antigen-2 (Sca-2). J. Immunol. 155 5574 - 5581
Bresson-Mazet C. , Gandrillon O. , Gonin-Giraud S. (2008) Stem cell antigen 2: a new gene involved in the self-renewal of erythroid progenitors. Cell Prolif. 41 726 - 738    DOI : 10.1111/j.1365-2184.2008.00554.x
Horie M. , Okutomi K. , Taniguchi Y. , Ohbuchi Y. , Suzuki M. , Takahashi E. (1998) Isolation and characterization of a new member of the human Ly6 gene family (LY6H). Genomics 53 365 - 368    DOI : 10.1006/geno.1998.5462
de Nooij-van Dalen A. G. , van Dongen G. A. , Smeets S. J. , Nieuwenhuis E. J. , Stigter-van Walsum M. , Snow G. B. , Brakenhoff R. H. (2003) Characterization of the human Ly-6 antigens, the newly annotated member Ly-6K included, as molecular markers for head-and-neck squamous cell carcinoma. Int. J. Cancer 103 768 - 774    DOI : 10.1002/ijc.10903
Lee J. W. , Lee Y. S. , Yoo K. H. , Lee K. H. , Park K. , Ahn T. , Ko C. , Park J. H. (2006) LY-6K gene: a novel molecular marker for human breast cancer. Oncol. Rep. 16 1211 - 1214
Ishikawa N. , Takano A. , Yasui W. , Inai K. , Nishimura H. , Ito H. , Miyagi Y. , Nakayama H. , Fujita M. , Hosokawa M. , Tsuchiya E. , Kohno N. , Nakamura Y. , Daigo Y. (2007) Cancer-testis antigen lymphocyte antigen 6 complex locus K is a serologic biomarker and a therapeutic target for lung and esophageal carcinomas. Cancer Res. 67 11601 - 11611    DOI : 10.1158/0008-5472.CAN-07-3243
Matsuda R. , Enokida H. , Chiyomaru T. , Kikkawa N. , Sugimoto T. , Kawakami K. , Tatarano S. , Yoshino H. , Toki K. , Uchida Y. , Kawahara K. , Nishiyama K. , Seki N. , Nakagawa M. (2011) LY6K is a novel molecular target in bladder cancer on basis of integrate genome-wide profiling. Br. J. Cancer 104 376 - 386    DOI : 10.1038/sj.bjc.6605990
Zhang B. , Zhang Z. , Zhang X. , Gao X. , Kernstine K. H. , Zhong L. (2012) Serological antibodies against LY6K as a diagnostic biomarker in esophageal squamous cell carcinoma. Biomarkers 17 372 - 378    DOI : 10.3109/1354750X.2012.680609
Choi S. H. , Kong H. K. , Park S. Y. , Park J. H. (2009) Metastatic effect of LY-6K gene in breast cancer cells. Int. J. Oncol. 35 601 - 607    DOI : 10.3892/ijo_00000320
Suda T. , Tsunoda T. , Daigo Y. , Nakamura Y. , Tahara H. (2007) Identification of human leukocyte antigen-A24-restricted epitope peptides derived from gene products upregulated in lung and esophageal cancers as novel targets for immunotherapy. Cancer Sci. 98 1803 - 1808    DOI : 10.1111/j.1349-7006.2007.00603.x
Yu D. H. , Fan W. , Liu G. , Nguy V. , Chatterton J. E. , Long S. , Ke N. , Meyhack B. , Bruengger A. , Brachat A. , Wong-Staal F. , Li Q. X. (2006) PHTS, a novel putative tumor suppressor, is involved in the transformation reversion of HeLaHF cells independently of the p53 pathway. Exp. Cell Res. 312 865 - 876    DOI : 10.1016/j.yexcr.2005.12.006
Egerod K. L. , Holst B. , Petersen P. S. , Hansen J. B. , Mulder J. , Hokfelt T. , Schwartz T. W. (2007) GPR39 splice variants versus antisense gene LYPD1: expression and regulation in gastrointestinal tract, endocrine pancreas, liver, and white adipose tissue. Mol. Endocrinol. 21 1685 - 1698    DOI : 10.1210/me.2007-0055
Wurfel J. , Seiter S. , Stassar M. , Claas A. , Klas R. , Rosel M. , Marhaba R. , Savelyeva L. , Schwab M. , Matzku S. , Zoller M. (2001) Cloning of the human homologue of the metastasis-associated rat C4.4A. Gene 262 35 - 41    DOI : 10.1016/S0378-1119(00)00515-1
Seiter S. , Stassar M. , Rappl G. , Reinhold U. , Tilgen W. , Zoller M. (2001) Upregulation of C4.4A expression during progression of melanoma. J. Invest. Dermatol. 116 344 - 347    DOI : 10.1046/j.1523-1747.2001.01230.x
Fletcher G. C. , Patel S. , Tyson K. , Adam P. J. , Schenker M. , Loader J. A. , Daviet L. , Legrain P. , Parekh R. , Harris A. L. , Terrett J. A. (2003) hAG-2 and hAG-3, human homologues of genes involved in differentiation, are associated with oestrogen receptor-positive breast tumours and interact with metastasis gene C4.4a and dystroglycan. Br. J. Cancer 88 579 - 585    DOI : 10.1038/sj.bjc.6600740
Paret C. , Hildebrand D. , Weitz J. , Kopp-Schneider A. , Kuhn A. , Beer A. , Hautmann R. , Zoller M. (2007) C4.4A as a candidate marker in the diagnosis of colorectal cancer. Br. J. Cancer 97 1146 - 1156    DOI : 10.1038/sj.bjc.6604012
Hansen L. V. , Skov B. G. , Ploug M. , Pappot H. (2007) Tumour cell expression of C4.4A, a structural homologue of the urokinase receptor, correlates with poor prognosis in non-small cell lung cancer. Lung Cancer 58 260 - 266    DOI : 10.1016/j.lungcan.2007.06.025
Hansen L. V. , Laerum O. D. , Illemann M. , Nielsen B. S. , Ploug M. (2008) Altered expression of the urokinase receptor homologue, C4.4A, in invasive areas of human esophageal squamous cell carcinoma. Int. J. Cancer 122 734 - 741    DOI : 10.1002/ijc.23082
Oshiro R. , Yamamoto H. , Takahashi H. , Ohtsuka M. , Wu X. , Nishimura J. , Takemasa I. , Mizushima T. , Ikeda M. , Sekimoto M. , Matsuura N. , Doki Y. , Mori M. (2012) C4.4A is associated with tumor budding and epithelial-mesenchymal transition of colorectal cancer. Cancer Sci. 103 1155 - 1164    DOI : 10.1111/j.1349-7006.2012.02263.x
Ngora H. , Galli U. M. , Miyazaki K. , Zoller M. (2012) Membrane-bound and exosomal metastasis-associated C4.4A promotes migration by associating with the alpha(6)beta(4) integrin and MT1-MMP. Neoplasia 14 95 - 107
Zhang Y. , Lang Q. , Li J. , Xie F. , Wan B. , Yu L. (2010) Identification and characterization of human LYPD6, a new member of the Ly-6 superfamily. Mol. Biol. Rep. 37 2055 - 2062    DOI : 10.1007/s11033-009-9663-7
Ni J. , Lang Q. , Bai M. , Zhong C. , Chen X. , Wan B. , Yu L. (2009) Cloning and characterization of a human LYPD7, a new member of the Ly-6 superfamily. Mol. Biol. Rep. 36 697 - 703    DOI : 10.1007/s11033-008-9231-6
Reiter R. E. , Gu Z. , Watabe T. , Thomas G. , Szigeti K. , Davis E. , Wahl M. , Nisitani S. , Yamashiro J. , Le Beau M. M. , Loda M. , Witte O. N. (1998) Prostate stem cell antigen: a cell surface marker overexpressed in prostate cancer. Proc. Natl. Acad. Sci. U.S.A. 95 1735 - 1740    DOI : 10.1073/pnas.95.4.1735
Argani P. , Rosty C. , Reiter R. E. , Wilentz R. E. , Murugesan S. R. , Leach S. D. , Ryu B. , Skinner H. G. , Goggins M. , Jaffee E. M. , Yeo C. J. , Cameron J. L. , Kern S. E. , Hruban R. H. (2001) Discovery of new markers of cancer through serial analysis of gene expression: prostate stem cell antigen is overexpressed in pancreatic adenocarcinoma. Cancer Res. 61 4320 - 4324
Amara N. , Palapattu G. S. , Schrage M. , Gu Z. , Thomas G. V. , Dorey F. , Said J. , Reiter R. E. (2001) Prostate stem cell antigen is overexpressed in human transitional cell carcinoma. Cancer Res. 61 4660 - 4665
Elsamman E. M. , Fukumori T. , Tanimoto S. , Nakanishi R. , Takahashi M. , Toida K. , Kanayama H. O. (2006) The expression of prostate stem cell antigen in human clear cell renal cell carcinoma: a quantitative reverse transcriptase-polymerase chain reaction analysis. BJU Int. 98 668 - 673    DOI : 10.1111/j.1464-410X.2006.06350.x
Sakamoto H. , Yoshimura K. , Saeki N. , Katai H. , Shimoda T. , Matsuno Y. , Saito D. , Sugimura H. , Tanioka F. , Kato S. , Matsukura N. , Matsuda N. , Nakamura T. , Hyodo I. , Nishina T. , Yasui W. , Hirose H. , Hayashi M. , Toshiro E. , Ohnami S. , Sekine A. , Sato Y. , Totsuka H. , Ando M. , Takemura R. , Takahashi Y. , Ohdaira M. , Aoki K. , Honmyo I. , Chiku S. , Aoyagi K. , Sasaki H. , Yanagihara K. , Yoon K. A. , Kook M. C. , Lee Y. S. , Park S. R. , Kim C. G. , Choi I. J. , Yoshida T. , Nakamura Y. , Hirohashi S. (2008) Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer. Nat. Genet. 40 730 - 740    DOI : 10.1038/ng.152
Liu W. K. , Jiang X. Y. , Zhang Z. X. (2010) Expression of PSCA, PIWIL1, and TBX2 in endometrial adenocarcinoma. Onkologie 33 241 - 245    DOI : 10.1159/000305098
Kawaguchi T. , Sho M. , Tojo T. , Yamato I. , Nomi T. , Hotta K. , Hamada K. , Suzaki Y. , Sugiura S. , Kushibe K. , Nakajima Y. , Taniguchi S. (2010) Clinical significance of prostate stem cell antigen expression in non-small cell lung cancer. Jpn. J. Clin. Oncol. 40 319 - 326    DOI : 10.1093/jjco/hyp181
Liu W. K. , Jiang X. Y. , Zhang Z. X. (2010) Expression of PSCA, PIWIL1 and TBX2 and its correlation with HPV16 infection in formalin-fixed, paraffin-embedded cervical squamous cell carcinoma specimens. Arch. Virol. 155 657 - 663    DOI : 10.1007/s00705-010-0635-y
Hao J. Y. , Yang Y. L. , Li S. , Qian X. L. , Liu F. F. , Fu L. (2011) PSCA expression in invasive micropapillary carcinoma of breast. Zhonghua Bing Li Xue Za Zhi 40 382 - 386
Geiger K. D. , Hendruschk S. , Rieber E. P. , Morgenroth A. , Weigle B. , Juratli T. , Senner V. , Schackert G. , Temme A. (2011) The prostate stem cell antigen represents a novel glioma-associated antigen. Oncol Rep. 26 13 - 21
Bahrenberg G. , Brauers A. , Joost H. G. , Jakse G. (2000) Reduced expression of PSCA, a member of the LY-6 family of cell surface antigens, in bladder, esophagus, and stomach tumors. Biochem. Biophys. Res. Commun. 275 783 - 788    DOI : 10.1006/bbrc.2000.3393
Ono H. , Hiraoka N. , Lee Y. S. , Woo S. M. , Lee W. J. , Choi I. J. , Saito A. , Yanagihara K. , Kanai Y. , Ohnami S. , Chiwaki F. , Sasaki H. , Sakamoto H. , Yoshida T. , Saeki N. (2012) Prostate stem cell antigen, a presumable organ-dependent tumor suppressor gene, is down-regulated in gallbladder carcinogenesis. Genes Chromosomes Cancer 51 30 - 41    DOI : 10.1002/gcc.20928
Wu X. , Ye Y. , Kiemeney L. A. , Sulem P. , Rafnar T. , Matullo G. , Seminara D. , Yoshida T. , Saeki N. , Andrew A. S. , Dinney C. P. , Czerniak B. , Zhang Z. F. , Kiltie A. E. , Bishop D. T. , Vineis P. , Porru S. , Buntinx F. , Kellen E. , Zeegers M. P. , Kumar R. , Rudnai P. , Gurzau E. , Koppova K. , Mayordomo J. I. , Sanchez M. , Saez B. , Lindblom A. , de Verdier P. , Steineck G. , Mills G. B. , Schned A. , Guarrera S. , Polidoro S. , Chang S. C. , Lin J. , Chang D. W. , Hale K. S. , Majewski T. , Grossman H. B. , Thorlacius S. , Thorsteinsdottir U. , Aben K. K. , Witjes J. A. , Stefansson K. , Amos C. I. , Karagas M. R. , Gu J. (2009) Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer. Nat. Genet. 41 991 - 995    DOI : 10.1038/ng.421
Matsuo K. , Tajima K. , Suzuki T. , Kawase T. , Watanabe M. , Shitara K. , Misawa K. , Ito S. , Sawaki A. , Muro K. , Nakamura T. , Yamao K. , Yamamura Y. , Hamajima N. , Hiraki A. , Tanaka H. (2009) Association of prostate stem cell antigen gene polymorphisms with the risk of stomach cancer in Japanese. Int. J. Cancer 125 1961 - 1964    DOI : 10.1002/ijc.24519
Kim S. Y. , Yoo J. Y. , Shin A. , Kim Y. , Lee E. S. , Lee Y. S. (2012) Prostate stem cell antigen single nucleotide polymorphisms influence risk of estrogen receptor negative breast cancer in Korean females. Asian Pac. J. Cancer Prev. 13 41 - 48    DOI : 10.7314/APJCP.2012.13.1.041
Saffran D. C. , Raitano A. B. , Hubert R. S. , Witte O. N. , Reiter R. E. , Jakobovits A. (2001) Anti-PSCA mAbs inhibit tumor growth and metastasis formation and prolong the survival of mice bearing human prostate cancer xenografts. Proc. Natl. Acad. Sci. U.S.A. 98 2658 - 2663    DOI : 10.1073/pnas.051624698
Feng H. C. , Tsao S. W. , Ngan H. Y. , Xue W. C. , Kwan H. S. , Siu M. K. , Liao X. Y. , Wong E. , Cheung A. N. (2008) Overexpression of prostate stem cell antigen is associated with gestational trophoblastic neoplasia. Histopathology 52 167 - 174    DOI : 10.1111/j.1365-2559.2007.02925.x
Moore M. L. , Teitell M. A. , Kim Y. , Watabe T. , Reiter R. E. , Witte O. N. , Dubey P. (2008) Deletion of PSCA increases metastasis of TRAMP-induced prostate tumors without altering primary tumor formation. Prostate 68 139 - 151    DOI : 10.1002/pros.20686
Marra E. , Uva P. , Viti V. , Simonelli V. , Dogliotti E. , De Rinaldis E. , Lahm A. , La Monica N. , Nicosia A. , Ciliberto G. , Palombo F. (2010) Growth delay of human bladder cancer cells by Prostate Stem Cell Antigen downregulation is associated with activation of immune signaling pathways. BMC Cancer 10 129 -    DOI : 10.1186/1471-2407-10-129
Shetty J. , Wolkowicz M. J. , Digilio L. C. , Klotz K. L. , Jayes F. L. , Diekman A. B. , Westbrook V. A. , Farris E. M. , Hao Z. , Coonrod S. A. , Flickinger C. J. , Herr J. C. (2003) SAMP14, a novel, acrosomal membrane-associated, glycosylphosphatidylinositol-anchored member of the Ly-6/urokinase-type plasminogen activator receptor superfamily with a role in sperm-egg interaction. J. Biol. Chem. 278 30506 - 30515    DOI : 10.1074/jbc.M301713200
Adermann K. , Wattler F. , Wattler S. , Heine G. , Meyer M. , Forssmann W. G. , Nehls M. (1999) Structural and phylogenetic characterization of human SLURP-1, the first secreted mammalian member of the Ly-6/uPAR protein superfamily. Protein. Sci. 8 810 - 819    DOI : 10.1110/ps.8.4.810
Fischer J. , Bouadjar B. , Heilig R. , Huber M. , Lefevre C. , Jobard F. , Macari F. , Bakija-Konsuo A. , Ait-Belkacem F. , Weissenbach J. , Lathrop M. , Hohl D. , Prud J. F. (2001) Mutations in the gene encoding SLURP-1 in Mal de Meleda. Hum. Mol. Genet 10 875 - 880    DOI : 10.1093/hmg/10.8.875
Tsuji H. , Okamoto K. , Matsuzaka Y. , Iizuka H. , Tamiya G. , Inoko H. (2003) SLURP-2, a novel member of the human Ly-6 superfamily that is up-regulated in psoriasis vulgaris. Genomics 81 26 - 33    DOI : 10.1016/S0888-7543(02)00025-3
Arredondo J. , Chernyavsky A. I. , Webber R. J. , Grando S. A. (2005) Biological effects of SLURP-1 on human keratinocytes. J. Invest. Dermatol. 125 1236 - 1241    DOI : 10.1111/j.0022-202X.2005.23973.x
Pettersson A. , Nordlander S. , Nylund G. , Khorram-Manesh A. , Nordgren S. , Delbro D. S. (2008) Expression of the endogenous, nicotinic acetylcholine receptor ligand, SLURP-1, in human colon cancer. Auton Autacoid. Pharmacol. 28 109 - 116    DOI : 10.1111/j.1474-8673.2008.00424.x
Phan T. C. , Ooi J. , Goonewardene M. S. (2010) A novel molecule, SLURP-1, enhances the survival of periodontal ligament fibroblasts. J. Periodontal. Res. 45 331 - 336    DOI : 10.1111/j.1600-0765.2009.01240.x
Tjiu J. W. , Lin P. J. , Wu W. H. , Cheng Y. P. , Chiu H. C. , Thong H. Y. , Chiang B. L. , Yang W. S. , Jee S. H. (2011) SLURP1 mutation-impaired T-cell activation in a family with mal de Meleda. Br. J. Dermatol. 164 47 - 53    DOI : 10.1111/j.1365-2133.2010.10059.x
Arredondo J. , Chernyavsky A. I. , Jolkovsky D. L. , Webber R. J. , Grando S. A. (2006) SLURP-2: A novel cholinergic signaling peptide in human mucocutaneous epithelium. J. Cell. Physiol. 208 238 - 245    DOI : 10.1002/jcp.20661
Moriwaki Y. , Yoshikawa K. , Fukuda H. , Fujii Y. X. , Misawa H. , Kawashima K. (2007) Immune system expression of SLURP-1 and SLURP-2, two endogenous nicotinic acetylcholine receptor ligands. Life Sci. 80 2365 - 2368    DOI : 10.1016/j.lfs.2006.12.028
Anderson D. J. , Johnson P. M. , Alexander N. J. , Jones W. R. , Griffin P. D. (1987) Monoclonal antibodies to human trophoblast and sperm antigens: report of two WHO-sponsored workshops, June 30, 1986-Toronto, Canada. J. Reprod. Immunol. 10 231 - 257    DOI : 10.1016/0165-0378(87)90089-1
Herr J. C. , Flickinger C. J. , Homyk M. , Klotz K. , John E. (1990) Biochemical and morphological characterization of the intra-acrosomal antigen SP-10 from human sperm. Biol. Reprod. 42 181 - 193    DOI : 10.1095/biolreprod42.1.181
Kurth B. E. , Klotz K. , Flickinger C. J. , Herr J. C. (1991) Localization of sperm antigen SP-10 during the six stages of the cycle of the seminiferous epithelium in man. Biol. Reprod. 44 814 - 821    DOI : 10.1095/biolreprod44.5.814
Vassalli J. D. , Baccino D. , Belin D. (1985) A cellular binding site for the Mr 55,000 form of the human plasminogen activator, urokinase. J. Cell Biol. 100 86 - 92    DOI : 10.1083/jcb.100.1.86
Mondino A. , Resnati M. , Blasi F. (1999) Structure and function of the urokinase receptor. Thromb Haemost 82 (Supp 1) 19 - 22
Schlechte W. , Murano G. , Boyd D. (1989) Examination of the role of the urokinase receptor in human colon cancer mediated laminin degradation. Cancer Res. 49 6064 - 6069
Del Vecchio S. , Stoppelli M. P. , Carriero M. V. , Fonti R. , Massa O. , Li P. Y. , Botti G. , Cerra M. , D G. , Esposito G. , Salvatore M. (1993) Human urokinase receptor concentration in malignant and benign breast tumors by in vitro quantitative autoradiography: comparison with urokinase levels. Cancer Res. 53 3198 - 3206
de Vries T. J. , Quax P. H. , Denijn M. , Verrijp K. N. , Verheijen J. H. , Verspaget H. W. , Weidle U. H. , Ruiter D. J. , van Muijen G. N. (1994) Plasminogen activators, their inhibitors, and urokinase receptor emerge in late stages of melanocytic tumor progression. Am. J. Pathol. 144 70 - 81
Mohanam S. , Sawaya R. E. , Yamamoto M. , Bruner J. M. , Nicholson G. L. , Rao J. S. (1994) Proteolysis and invasiveness of brain tumors: role of urokinase-type plasminogen activator receptor. J. Neurooncol. 22 153 - 160    DOI : 10.1007/BF01052890
Pedersen H. , Brunner N. , Francis D. , Osterlind K. , Ronne E. , Hansen H. H. , Dano K. , Grondahl- Hansen J. (1994) Prognostic impact of urokinase, urokinase receptor, and type 1 plasminogen activator inhibitor in squamous and large cell lung cancer tissue. Cancer Res. 54 4671 - 4675
Wagner S. N. , Atkinson M. J. , Thanner S. , Wagner C. , Schmitt M. , Wilhelm O. , Rotter M. , Hofler H. (1995) Modulation of urokinase and urokinase receptor gene expression in human renal cell carcinoma. Am. J. Pathol. 147 183 - 192
Morita Y. , Hayashi Y. , Wang Y. , Kanamaru T. , Suzuki S. , Kawasaki K. , Ohta K. , Yamamoto M. , Saitoh Y. , Itoh H. , Doe W. F. (1997) Expression of urokinase-type plasminogen activator receptor in hepatocellular carcinoma. Hepatology 25 856 - 861    DOI : 10.1002/hep.510250412
Yonemura Y. , Nojima N. , Kawamura T. , Ajisaka H. , Taniguchi K. , Fujimura T. , Fujita H. , Bandou E. , Fushida S. , Endou Y. , Obata T. , Sasaki T. (1997) Correlation between expression of urokinase-type plasminogen activator receptor and metastasis in gastric carcinoma. Oncol. Rep. 4 1229 - 1234
Sier C. F. , Stephens R. , Bizik J. , Mariani A. , Bassan M. , Pedersen N. , Frigerio L. , Ferrari A. , Dano K. , Brunner N. , Blasi F. (1998) The level of urokinase-type plasminogen activator receptor is increased in serum of ovarian cancer patients. Cancer Res. 58 1843 - 1849
Schmidt M. , Hoppe F. (1999) Increased levels of urokinase receptor in plasma of head and neck squamous cell carcinoma patients. Acta. Otolaryngol. 119 949 - 953    DOI : 10.1080/00016489950180342
Nozaki S. , Endo Y. , Nakahara H. , Yoshizawa K. , Hashiba Y. , Kawashiri S. , Tanaka A. , Nakagawa K. , Matsuoka Y. , Kogo M. , Yamamoto E. (2005) Inhibition of invasion and metastasis in oral cancer by targeting urokinase- type plasminogen activator receptor. Oral Oncol. 41 971 - 977    DOI : 10.1016/j.oraloncology.2005.05.013
Wang J. , Guo F. , Wei H. , Dong J. , Wu J. (2006) Expression of urokinase-type plasminogen activator receptor is correlated with metastases of lingual squamous cell carcinoma. Br. J. Oral. Maxillofac. Surg. 44 515 - 519    DOI : 10.1016/j.bjoms.2005.10.009
Hildenbrand R. , Niedergethmann M. , Marx A. , Belharazem D. , Allgayer H. , Schleger C. , Strobel P. (2009) Amplification of the urokinase-type plasminogen activator receptor (uPAR) gene in ductal pancreatic carcinomas identifies a clinically high-risk group. Am. J. Pathol. 174 2246 - 2253    DOI : 10.2353/ajpath.2009.080785
Ossowski L. , Aguirre-Ghiso J. A. (2000) Urokinase receptor and integrin partnership: coordination of signaling for cell adhesion, migration and growth. Curr. Opin. Cell Biol. 12 613 - 620    DOI : 10.1016/S0955-0674(00)00140-X
Nykjaer A. , Moller B. , Todd R. F. 3rd , Christensen T. , Andreasen P. A. , Gliemann J. , Petersen C. M. (1994) Urokinase receptor. An activation antigen in human T lymphocytes. J. Immunol. 152 505 - 516
Gyetko M. R. , Sitrin R. G. , Fuller J. A. , Todd R. F. 3rd , Petty H. , Standiford T. J. (1995) Function of the urokinase receptor (CD87) in neutrophil chemotaxis. J. Leukoc. Biol. 58 533 - 538
Pedersen N. , Schmitt M. , Ronne E. , Nicoletti M. I. , Hoyer-Hansen G. , Conese M. , Giavazzi R. , Dano K. , Kuhn W. , Janicke F. , Blasi F. (1993) A ligand-free, soluble urokinase receptor is present in the ascitic fluid from patients with ovarian cancer. J. Clin. Invest. 92 2160 - 2167    DOI : 10.1172/JCI116817
Rigolin G. M. , Tieghi A. , Ciccone M. , Bragotti L. Z. , Cavazzini F. , Della Porta M. , Castagnari B. , Carroccia R. , Guerra G. , Cuneo A. , Castoldi G. (2003) Soluble urokinase-type plasminogen activator receptor (suPAR) as an independent factor predicting worse prognosis and extra-bone marrow involvement in multiple myeloma patients. Br. J. Haematol. 120 953 - 959    DOI : 10.1046/j.1365-2141.2003.04176.x
Nijziel M. R. , Van Oerle R. , Hellenbrand D. , Van Pampus E. C. , Hillen H. F. , Hamulyak K. (2003) The prognostic value of the soluble urokinase-type plasminogen activator receptor (s-uPAR) in plasma of breast cancer patients with and without metastatic disease. J. Thromb. Haemost. 1 982 - 986    DOI : 10.1046/j.1538-7836.2003.00207.x
Saitou N. , Nei M. (1987) The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol. Biol. Evol. 4 406 - 425
Whelan S. , Goldman N. (2001) A general empirical model of protein evolution derived from multiple protein families using a maximum-likelihood approach. Mol. Biol. Evol. 18 691 - 699    DOI : 10.1093/oxfordjournals.molbev.a003851