keratan sulfate


Summary: A sulfated mucopolysaccharide initially isolated from bovine cornea. At least two types are known. Type I, found mostly in the cornea, contains D-galactose and D-glucosamine-6-O-sulfate as the repeating unit; type II, found in skeletal tissues, contains D-galactose and D-galactosamine-6-O-sulfate as the repeating unit.

Top Publications

  1. Radwanska A, Baczynska D, Nowak D, Brezillon S, Popow A, Maquart F, et al. Lumican affects actin cytoskeletal organization in human melanoma A375 cells. Life Sci. 2008;83:651-60 pubmed publisher
  2. Schaefer L, Grone H, Raslik I, Robenek H, Ugorcakova J, Budny S, et al. Small proteoglycans of normal adult human kidney: distinct expression patterns of decorin, biglycan, fibromodulin, and lumican. Kidney Int. 2000;58:1557-68 pubmed
    ..The chondroitin/dermatan sulfate proteoglycans, decorin and biglycan, and the keratan sulfate proteoglycans, fibromodulin and lumican, were investigated in normal human adult renal cortex by ..
  3. Huebner J, Kraus V. Assessment of the utility of biomarkers of osteoarthritis in the guinea pig. Osteoarthritis Cartilage. 2006;14:923-30 pubmed
    ..Levels of synovial fluid keratan sulfate (KS) and cartilage oligomeric matrix protein (COMP), as well as levels of serum C2C, CPII, and a panel of ..
  4. Funderburgh M, Du Y, Mann M, SundarRaj N, Funderburgh J. PAX6 expression identifies progenitor cells for corneal keratocytes. FASEB J. 2005;19:1371-3 pubmed
    ..In low-mitogen media, selected clonal cultures displayed dendritic morphology and expressed high levels of keratan sulfate, aldehyde dehydrogenase 3A1, and keratocan, molecular markers of keratocyte phenotype...
  5. Holland J, Meehan K, Redmond S, Dawkins H. Purification of the keratan sulfate proteoglycan expressed in prostatic secretory cells and its identification as lumican. Prostate. 2004;59:252-9 pubmed
    Secretory epithelial cells of human prostate contain a keratan sulfate proteoglycan (KSPG) associated with the prostatic secretory granules (PSGs)...
  6. Dunlevy J, Rada J. Interaction of lumican with aggrecan in the aging human sclera. Invest Ophthalmol Vis Sci. 2004;45:3849-56 pubmed
    Lumican is a keratan sulfate proteoglycan originally identified in cornea, but present in a variety of connective tissues where it presumably regulates collagen fibril formation and organization...
  7. Dung V, Tomatsu S, Montano A, Gottesman G, Bober M, Mackenzie W, et al. Mucopolysaccharidosis IVA: correlation between genotype, phenotype and keratan sulfate levels. Mol Genet Metab. 2013;110:129-38 pubmed publisher
    ..sulfatase (GALNS), leading to systemic skeletal dysplasia because of excessive storage of keratan sulfate (KS) in chondrocytes...
  8. Carlson E, Lin M, Liu C, Kao W, Perez V, Pearlman E. Keratocan and lumican regulate neutrophil infiltration and corneal clarity in lipopolysaccharide-induced keratitis by direct interaction with CXCL1. J Biol Chem. 2007;282:35502-9 pubmed
    ..Together, these data support a significant role for lumican and keratocan in a corneal inflammatory response with respect to edema, corneal clarity, and cellular infiltration. ..
  9. Wakitani S, Nawata M, Kawaguchi A, Okabe T, Takaoka K, Tsuchiya T, et al. Serum keratan sulfate is a promising marker of early articular cartilage breakdown. Rheumatology (Oxford). 2007;46:1652-6 pubmed
    ..cartilage oligomeric protein (COMP) were measured using enzyme-linked immunosorbent assay kits and those of keratan sulfate (KS) and chondroitin-6-sulfate (C6S) using high-performance liquid chromatography...

More Information


  1. Geng Y, McQuillan D, Roughley P. SLRP interaction can protect collagen fibrils from cleavage by collagenases. Matrix Biol. 2006;25:484-91 pubmed
    ..Interaction with either recombinant decorin, fibromodulin or lumican results in decreased collagenase cleavage of both fibril types. Thus SLRP interaction can help protect collagen fibrils from cleavage by collagenases. ..
  2. Hayashida Y, Akama T, Beecher N, Lewis P, Young R, Meek K, et al. Matrix morphogenesis in cornea is mediated by the modification of keratan sulfate by GlcNAc 6-O-sulfotransferase. Proc Natl Acad Sci U S A. 2006;103:13333-8 pubmed
    ..The major GAG in cornea is keratan sulfate (KS), which is N-linked to one of three PG core proteins...
  3. Li Y, Aoki T, Mori Y, Ahmad M, Miyamori H, Takino T, et al. Cleavage of lumican by membrane-type matrix metalloproteinase-1 abrogates this proteoglycan-mediated suppression of tumor cell colony formation in soft agar. Cancer Res. 2004;64:7058-64 pubmed
    ..These results suggest that MT1-MMP abrogates lumican-mediated suppression of tumor cell colony formation in soft agar by degrading this proteoglycan, which down-regulates it through the induction of p21. ..
  4. San Martin S, Soto Suazo M, De Oliveira S, Aplin J, Abrahamsohn P, Zorn T. Small leucine-rich proteoglycans (SLRPs) in uterine tissues during pregnancy in mice. Reproduction. 2003;125:585-95 pubmed
    ..As decorin has been shown to inhibit lateral association of collagen fibrils, its disappearance between day 2 and day 5 of pregnancy may be a prerequisite for the formation of large fibrils in decidua in mice. ..
  5. Jepsen K, Wu F, Peragallo J, Paul J, Roberts L, Ezura Y, et al. A syndrome of joint laxity and impaired tendon integrity in lumican- and fibromodulin-deficient mice. J Biol Chem. 2002;277:35532-40 pubmed
  6. Svensson L, Närlid I, Oldberg A. Fibromodulin and lumican bind to the same region on collagen type I fibrils. FEBS Lett. 2000;470:178-82 pubmed
    ..Binding competition experiments and Scatchard plot analysis indicate that fibromodulin binds to collagen type I with higher affinity than lumican. ..
  7. Cohen R, Holland J, Redmond S, McNeal J, Dawkins H. Identification of the glycosaminoglycan keratan sulfate in the prostatic secretory cell. Prostate. 2000;44:204-9 pubmed
    ..corpora amylacea, a proposed by-product of PSG secretion, detected sulfated glycosaminoglycans (GAG) possibly keratan sulfate (KS), indicating a secretory mechanism for GAG in the human prostate surface epithelial cell...
  8. Hedlund H, Hedbom E, Heineg rd D, Mengarelli Widholm S, Reinholt F, Svensson O. Association of the aggrecan keratan sulfate-rich region with collagen in bovine articular cartilage. J Biol Chem. 1999;274:5777-81 pubmed
    ..One of the domains contains the majority of the keratan sulfate (KS) chain substituents and a protein segment with a proline-rich hexapeptide repeat sequence...
  9. Köninger J, Giese T, di Mola F, Wente M, Esposito I, Bachem M, et al. Pancreatic tumor cells influence the composition of the extracellular matrix. Biochem Biophys Res Commun. 2004;322:943-9 pubmed
    ..These findings indicate that malignant cells can actively influence the composition of the ECM through TGFbeta1 and other soluble factors, altering their microenvironment in a tumor-favorable way. ..
  10. Liles M, Palka B, Harris A, Kerr B, Hughes C, Young R, et al. Differential relative sulfation of Keratan sulfate glycosaminoglycan in the chick cornea during embryonic development. Invest Ophthalmol Vis Sci. 2010;51:1365-72 pubmed publisher
    ..structural remodeling of the developing corneal stroma concomitant with changing sulfation patterns of keratan sulfate (KS) glycosaminoglycan (GAG) epitopes during embryogenesis and the onset of corneal transparency...
  11. Zhang Y, Conrad A, Tasheva E, An K, Corpuz L, Kariya Y, et al. Detection and quantification of sulfated disaccharides from keratan sulfate and chondroitin/dermatan sulfate during chick corneal development by ESI-MS/MS. Invest Ophthalmol Vis Sci. 2005;46:1604-14 pubmed
    To identify and quantify changes in keratan sulfate (KS) and chondroitin/dermatan sulfate (CS/DS) sulfated disaccharides in the developing chick cornea using electrospray ionization tandem mass spectrometry (ESI-MS/MS)...
  12. Budsberg S, Lenz M, Thonar E. Serum and synovial fluid concentrations of keratan sulfate and hyaluronan in dogs with induced stifle joint osteoarthritis following cranial cruciate ligament transection. Am J Vet Res. 2006;67:429-32 pubmed
    To examine longitudinal changes in serum and synovial fluid concentrations of keratan sulfate (KS) and hyaluronan (HA) after cranial cruciate ligament (CCL) transection in dogs. 12 clinically normal adult mixed-breed dogs...
  13. Alowami S, Troup S, Al Haddad S, Kirkpatrick I, Watson P. Mammographic density is related to stroma and stromal proteoglycan expression. Breast Cancer Res. 2003;5:R129-35 pubmed
    ..Although epithelial changes define the eventual pathway for breast cancer development, mammographic density might correspond more directly to alterations in stromal composition. ..
  14. Ping Lu Y, Ishiwata T, Asano G. Lumican expression in alpha cells of islets in pancreas and pancreatic cancer cells. J Pathol. 2002;196:324-30 pubmed
  15. Qin H, Ishiwata T, Asano G. Effects of the extracellular matrix on lumican expression in rat aortic smooth muscle cells in vitro. J Pathol. 2001;195:604-8 pubmed
    ..The extracellular matrix (ECM) affected lumican protein production and restricted the lumican protein form to proteoglycan via the beta1 integrin receptor in SMCs. ..
  16. Gill M, Oldberg A, Reinholt F. Fibromodulin-null murine knee joints display increased incidences of osteoarthritis and alterations in tissue biochemistry. Osteoarthritis Cartilage. 2002;10:751-7 pubmed
    ..We conclude that alterations in ligaments, and possibly other tissues within the knee, are of considerable importance in the pathogenesis of the observed articular cartilage degeneration. ..
  17. Nakayama Y, Shirai Y, Yoshihara K, Uesaka S. Evaluation of glycosaminoglycans levels in normal joint fluid of the knee. J Nippon Med Sch. 2000;67:92-5 pubmed
    ..The mean HA concentration was 3.4+/-0.6 mg/ml. The mean concentration of C4S and C6S, and C6S/C4S ratio were 19.0+/-4.9 nmol/ml, 125.5+/-44.4 nmol/ml and 6.5+/-1.1 respectively. ..
  18. Zhang H, Muramatsu T, Murase A, Yuasa S, Uchimura K, Kadomatsu K. N-Acetylglucosamine 6-O-sulfotransferase-1 is required for brain keratan sulfate biosynthesis and glial scar formation after brain injury. Glycobiology. 2006;16:702-10 pubmed
    b>Keratan sulfate (KS) is a glycosaminoglycan composed of repeating disaccharide units with sulfate residues at the C6 positions of galactose and N-acetylglucosamine (GlcNAc)...
  19. Tomatsu S, Okamura K, Maeda H, Taketani T, Castrillon S, Gutierrez M, et al. Keratan sulphate levels in mucopolysaccharidoses and mucolipidoses. J Inherit Metab Dis. 2005;28:187-202 pubmed
    ..This finding suggests that measurement of KS level provides a new diagnostic biomarker in a wide variety of mucopolysaccharidoses and mucolipidoses in addition to MPS IV...
  20. Torii T, Fukuta M, Habuchi O. Sulfation of sialyl N-acetyllactosamine oligosaccharides and fetuin oligosaccharides by keratan sulfate Gal-6-sulfotransferase. Glycobiology. 2000;10:203-11 pubmed
    We have previously cloned keratan sulfate Gal-6-sulfotransferase (KSGal6ST), which transfers sulfate from 3'-phosphoadenosine 5'-phosphosulfate to position 6 of Gal residue of keratan sulfate...
  21. Carlson E, Liu C, Chikama T, Hayashi Y, Kao C, Birk D, et al. Keratocan, a cornea-specific keratan sulfate proteoglycan, is regulated by lumican. J Biol Chem. 2005;280:25541-7 pubmed
    ..Corneal lumican modified with keratan sulfate constitutes one of the major proteoglycans of the stroma...
  22. Vij N, Roberts L, Joyce S, Chakravarti S. Lumican regulates corneal inflammatory responses by modulating Fas-Fas ligand signaling. Invest Ophthalmol Vis Sci. 2005;46:88-95 pubmed
    ..The data suggest that lumican binds FasL and facilitates induction of Fas. Poor signaling through Fas-FasL in lumican deficiency leads to impaired induction of inflammatory cytokines and corneal healing. ..
  23. Yoon J, Brooks R, Halper J. Immunoblotting assays for keratan sulfate. Anal Biochem. 2002;306:298-304 pubmed
    ..used uronic acid assay in terms of its sensitivity and ability to detect all classes of GAGs, including keratan sulfate (KS)...
  24. Hayes A, Benjamin M, Ralphs J. Extracellular matrix in development of the intervertebral disc. Matrix Biol. 2001;20:107-21 pubmed
    ..and of other proteoglycans that may be present - thus differential distribution of aggrecan and keratan sulfate label suggested the presence of fibromodulin and/or lumican...
  25. Chakravarti S. Functions of lumican and fibromodulin: lessons from knockout mice. Glycoconj J. 2002;19:287-93 pubmed
    ..both proteoglycans are present, fibromodulin may be required early in collagen fibrillogenesis to stabilize small-diameter fibril-intermediates and lumican may be needed at a later stage, primarily to limit lateral growth of fibrils ..
  26. D Onofrio M, Brezillon S, Baranek T, Perreau C, Roughley P, Maquart F, et al. Identification of beta1 integrin as mediator of melanoma cell adhesion to lumican. Biochem Biophys Res Commun. 2008;365:266-72 pubmed
    ..The increased beta1 integrin-mediated adhesion of melanoma cells to lumican might explain, at least in part, the anti-invasive effect of this SLRP. ..
  27. Souza A, Kozlowski E, Cerqueira V, Castelo Branco M, Costa M, Pavão M. Chondroitin sulfate and keratan sulfate are the major glycosaminoglycans present in the adult zebrafish Danio rerio (Chordata-Cyprinidae). Glycoconj J. 2007;24:521-30 pubmed
    ..Two GAGs were identified: a low-molecular-weight chondroitin sulfate (CS) and keratan sulfate (KS), corresponding to approximately 80% and 20% of the total GAGs, respectively...
  28. Kato Y, Hayatsu N, Kaneko M, Ogasawara S, Hamano T, Takahashi S, et al. Increased expression of highly sulfated keratan sulfate synthesized in malignant astrocytic tumors. Biochem Biophys Res Commun. 2008;369:1041-6 pubmed publisher
    b>Keratan sulfate (KS) proteoglycans are expressed on a subpopulation of microglia in normal adult brain. We previously showed the up-regulated expression of KS in one of glioblastoma cell lines using anti-KS antibody (5D4)...
  29. Sifaki M, Assouti M, Nikitovic D, Krasagakis K, Karamanos N, Tzanakakis G. Lumican, a small leucine-rich proteoglycan substituted with keratan sulfate chains is expressed and secreted by human melanoma cells and not normal melanocytes. IUBMB Life. 2006;58:606-10 pubmed
    ..human melanocytes (HEMN) using real time PCR, western blotting with antibodies against the protein core and keratan sulfate, and treatments with specific enzymes...
  30. Troup S, Njue C, Kliewer E, Parisien M, Roskelley C, Chakravarti S, et al. Reduced expression of the small leucine-rich proteoglycans, lumican, and decorin is associated with poor outcome in node-negative invasive breast cancer. Clin Cancer Res. 2003;9:207-14 pubmed
    ..These results suggest that low levels of small leucine-rich proteoglycans in breast tumors may be associated with a worse prognosis in lymph node-negative invasive breast carcinomas and warrant further study with larger patient cohorts. ..
  31. Liu C, Birk D, Hassell J, Kane B, Kao W. Keratocan-deficient mice display alterations in corneal structure. J Biol Chem. 2003;278:21672-7 pubmed
    Keratocan (Kera) is a cornea-specific keratan sulfate proteoglycan (KSPG) in the adult vertebrate eye...
  32. Chakravarti S, Petroll W, Hassell J, Jester J, Lass J, Paul J, et al. Corneal opacity in lumican-null mice: defects in collagen fibril structure and packing in the posterior stroma. Invest Ophthalmol Vis Sci. 2000;41:3365-73 pubmed
    ..The purpose of the present study was to analyze the loss of transparency quantitatively and to define the associated corneal collagen fibril and stromal defects...
  33. Soriano E, Campos M, Aguiar J, Michelacci Y. Effect of epithelial debridement on human cornea proteoglycans. Braz J Med Biol Res. 2001;34:325-31 pubmed
    ..Decorin was identified as the main dermatan sulfate proteoglycan and keratan sulfate proteoglycans were also prominent components...
  34. Philipp W, Speicher L, Gottinger W. Histological and immunohistochemical findings after laser in situ keratomileusis in human corneas. J Cataract Refract Surg. 2003;29:808-20 pubmed
    ..After LASIK in patients with high hyperopia, compensatory epithelial thickening in the annular midperipheral ablation zone might be partly responsible for regression. ..
  35. Ito Z, Sakamoto K, Imagama S, Matsuyama Y, Zhang H, Hirano K, et al. N-acetylglucosamine 6-O-sulfotransferase-1-deficient mice show better functional recovery after spinal cord injury. J Neurosci. 2010;30:5937-47 pubmed publisher
    Neurons in the adult CNS do not spontaneously regenerate after injuries. The glycosaminoglycan keratan sulfate is induced after spinal cord injury, but its biological significance is not well understood...
  36. Raouf A, Ganss B, McMahon C, Vary C, Roughley P, Seth A. Lumican is a major proteoglycan component of the bone matrix. Matrix Biol. 2002;21:361-7 pubmed
  37. Sanches J, Jones C, Aplin J, Iozzo R, Zorn T, Oliveira S. Collagen fibril organization in the pregnant endometrium of decorin-deficient mice. J Anat. 2010;216:144-55 pubmed publisher
    ..Our data further suggest that decorin, biglycan and lumican might play an interactive role in collagen fibrillogenesis in the mouse endometrium, a process modulated according to the stage of pregnancy. ..
  38. Zeltz C, Brezillon S, Perreau C, Ramont L, Maquart F, Wegrowski Y. Lumcorin: a leucine-rich repeat 9-derived peptide from human lumican inhibiting melanoma cell migration. FEBS Lett. 2009;583:3027-32 pubmed publisher
    ..We propose the name lumcorin (fragment of lumican core protein) for the active peptide derived from this site. Lumcorin was able to inhibit melanoma cell migration in vitro. ..
  39. Yin J, Sakamoto K, Zhang H, Ito Z, Imagama S, Kishida S, et al. Transforming growth factor-beta1 upregulates keratan sulfate and chondroitin sulfate biosynthesis in microglias after brain injury. Brain Res. 2009;1263:10-22 pubmed publisher
    ..We have recently reported that keratan sulfate-deficient mice show better axonal regeneration after injury...
  40. Du Y, Carlson E, Funderburgh M, Birk D, Pearlman E, Guo N, et al. Stem cell therapy restores transparency to defective murine corneas. Stem Cells. 2009;27:1635-42 pubmed publisher
    ..The results suggest that cell-based therapy can be an effective approach to treatment of human corneal blindness. ..
  41. Monfort J, Tardif G, Reboul P, Mineau F, Roughley P, Pelletier J, et al. Degradation of small leucine-rich repeat proteoglycans by matrix metalloprotease-13: identification of a new biglycan cleavage site. Arthritis Res Ther. 2006;8:R26 pubmed
    ..Awareness of SLRP degradation products, especially those of biglycan and fibromodulin, may assist in early detection of OA cartilage degradation. ..
  42. Markiewicz M, Asano Y, Znoyko S, Gong Y, Watson D, Trojanowska M. Distinct effects of gonadectomy in male and female mice on collagen fibrillogenesis in the skin. J Dermatol Sci. 2007;47:217-26 pubmed
    ..Androgens play a positive role in the regulation of collagen biosynthesis. In summary, our data demonstrate that androgens and estrogens regulate distinct aspects of collagen fibrillogenesis in mouse skin. ..
  43. Young R, Akama T, Liskova P, Ebenezer N, Allan B, Kerr B, et al. Differential immunogold localisation of sulphated and unsulphated keratan sulphate proteoglycans in normal and macular dystrophy cornea using sulphation motif-specific antibodies. Histochem Cell Biol. 2007;127:115-20 pubmed
    ..These antibodies will thus facilitate high-resolution investigations of phenotypic heterogeneity in support of genetic studies in this disease...
  44. Alini M, Roughley P. Changes in leucine-rich repeat proteoglycans during maturation of the bovine growth plate. Matrix Biol. 2001;19:805-13 pubmed
    ..In the case of both biglycan and fibromodulin, message expression continued at a similar level throughout the growth plate. Thus, the leucine-rich repeat proteoglycans are different in the way they behave during growth plate maturation. ..
  45. Vuillermoz B, Khoruzhenko A, D Onofrio M, Ramont L, Venteo L, Perreau C, et al. The small leucine-rich proteoglycan lumican inhibits melanoma progression. Exp Cell Res. 2004;296:294-306 pubmed
    ..The results suggest that lumican is involved in the control of melanoma growth and invasion and may be considered, like decorin, as an anti-tumor factor from the extracellular matrix. ..
  46. Tomatsu S, Okamura K, Taketani T, Orii K, Nishioka T, Gutierrez M, et al. Development and testing of new screening method for keratan sulfate in mucopolysaccharidosis IVA. Pediatr Res. 2004;55:592-7 pubmed
    ..MPS IVA), a progressive lysosomal storage disease, causes skeletal dysplasia through excessive storage of keratan sulfate (KS). We developed an ELISA-sandwich assay that used a MAb specific to KS...
  47. Iida Hasegawa N, Furuhata A, Hayatsu H, Murakami A, Fujiki K, Nakayasu K, et al. Mutations in the CHST6 gene in patients with macular corneal dystrophy: immunohistochemical evidence of heterogeneity. Invest Ophthalmol Vis Sci. 2003;44:3272-7 pubmed
    ..Immunohistochemistry with a monoclonal anti-keratan sulfate (KS) antibody was performed on corneas of four patients from three families...
  48. Brezillon S, Venteo L, Ramont L, D Onofrio M, Perreau C, Pluot M, et al. Expression of lumican, a small leucine-rich proteoglycan with antitumour activity, in human malignant melanoma. Clin Exp Dermatol. 2007;32:405-16 pubmed
    ..CONCLUSIONS. Lumican may regulate vertical progression of human malignant melanoma, but further study is necessary to clarify the antitumour mechanism and the downstream signal transduction pathways involved. ..
  49. Chen J, Guerriero E, Sado Y, SundarRaj N. Rho-mediated regulation of TGF-beta1- and FGF-2-induced activation of corneal stromal keratocytes. Invest Ophthalmol Vis Sci. 2009;50:3662-70 pubmed publisher
  50. Akama T, Nishida K, Nakayama J, Watanabe H, Ozaki K, Nakamura T, et al. Macular corneal dystrophy type I and type II are caused by distinct mutations in a new sulphotransferase gene. Nat Genet. 2000;26:237-41 pubmed
    ..In situ hybridization analysis did not detect CHST6 transcripts in corneal epithelium in an MCD type II patient, suggesting that the mutations found in type II lead to loss of cornea-specific expression of CHST6. ..
  51. Tomatsu S, Dieter T, Schwartz I, Sarmient P, Giugliani R, Barrera L, et al. Identification of a common mutation in mucopolysaccharidosis IVA: correlation among genotype, phenotype, and keratan sulfate. J Hum Genet. 2004;49:490-4 pubmed
    ..R380S, was associated with an attenuated form. MPS IVA patients had an elevation of urine and plasma keratan sulfate (KS) concentrations compared with those of the age-matched control...
  52. Zeltz C, Brezillon S, Kapyla J, Eble J, Bobichon H, Terryn C, et al. Lumican inhibits cell migration through ?2?1 integrin. Exp Cell Res. 2010;316:2922-31 pubmed publisher
    ..In conclusion, we demonstrated for the first time that the inhibition of cell migration by lumican depends on a direct binding between the core protein of lumican and the ?2?1 integrin. ..
  53. Badcock G, Pigott C, Goepel J, Andrews P. The human embryonal carcinoma marker antigen TRA-1-60 is a sialylated keratan sulfate proteoglycan. Cancer Res. 1999;59:4715-9 pubmed
    ..Our results indicate that human EC cells generally express a cell surface sialylated keratan sulfate proteoglycan that is subject to modification to yield a variety of epitopes, one of which is recognized by ..