Gene Symbol: HAPLN1
Description: hyaluronan and proteoglycan link protein 1
Alias: CRT1, CRTL1, hyaluronan and proteoglycan link protein 1, Cartilage link protein, cartilage-link protein, cartilage-linking protein 1, proteoglycan link protein
Species: human
Products:     HAPLN1

Top Publications

  1. Spicer A, Joo A, Bowling R. A hyaluronan binding link protein gene family whose members are physically linked adjacent to chondroitin sulfate proteoglycan core protein genes: the missing links. J Biol Chem. 2003;278:21083-91 pubmed
    ..hyaluronan and proteoglycan binding link protein gene family (HAPLN), consisting of four members including cartilage link protein. The encoded proteins share 45-52% overall amino acid identity...
  2. Dudhia J, Bayliss M, Hardingham T. Human link protein gene: structure and transcription pattern in chondrocytes. Biochem J. 1994;303 ( Pt 1):329-33 pubmed
    ..Equine and porcine mRNA contained this spliced form but the results suggested that this was expressed as a rare transcript. ..
  3. Lendvai D, Morawski M, Negyessy L, Gati G, Jäger C, Baksa G, et al. Neurochemical mapping of the human hippocampus reveals perisynaptic matrix around functional synapses in Alzheimer's disease. Acta Neuropathol. 2013;125:215-29 pubmed publisher
    ..We find that cartilage link protein-1 and brevican-containing matrices form isolated perisynaptic coats, engulfing both inhibitory and ..
  4. Kobayashi M, Nagashio R, Ryuge S, Murakami Y, Yanagita K, Nakashima H, et al. Acquisition of useful sero-diagnostic autoantibodies using the same patients'sera and tumor tissues. Biomed Res. 2014;35:133-43 pubmed
    ..Thirty-six proteins including Transforming growth factor-beta-induced protein ig-h3 (BIGH3) and Hyaluronan and proteoglycan link protein 1 (HAPLN1) were detected only from tissues, 32 proteins only from cell lines, and 9 proteins from ..
  5. Jones C, Bradford Y, Amos C, Blot W, Chanock S, Harris C, et al. Cross-Cancer Pleiotropic Associations with Lung Cancer Risk in African Americans. Cancer Epidemiol Biomarkers Prev. 2019;: pubmed publisher
    ..3, 16q22.2, and 17q12, which contain HNF1B, DHODH, and HAPLN1 genes, respectively. SNPs within these regions have been previously associated with multiple cancers...
  6. Ahn M, Kim B, Kim H, Jin J, Yoon H, Hwang J, et al. Anti-cancer effect of dung beetle glycosaminoglycans on melanoma. BMC Cancer. 2019;19:9 pubmed publisher
    ..genes were down-regulated, including nuclear RNA export factor (Nxf3) and hyaluronan proteoglycan link protein1 (Hapln1)...
  7. Szarvas D, Gaál B, Matesz C, Racz E. Distribution of the Extracellular Matrix in the Pararubral Area of the Rat. Neuroscience. 2018;394:177-188 pubmed publisher
    ..of major ECM components, the hyaluronan, aggrecan, versican, neurocan, brevican, tenascin-R (TN-R), and the HAPLN1 link protein in the pararubral area...
  8. Ecker B, Kaur A, Douglass S, Webster M, Almeida F, Marino G, et al. Age-Related Changes in HAPLN1 Increase Lymphatic Permeability and Affect Routes of Melanoma Metastasis. Cancer Discov. 2019;9:82-95 pubmed publisher
    ..We have implicated HAPLN1 in age-dependent ECM degradation in the dermis...
  9. Kaur A, Ecker B, Douglass S, Kugel C, Webster M, Almeida F, et al. Remodeling of the Collagen Matrix in Aging Skin Promotes Melanoma Metastasis and Affects Immune Cell Motility. Cancer Discov. 2019;9:64-81 pubmed publisher
    ..The most abundantly secreted was HAPLN1, a hyaluronic and proteoglycan link protein. HAPLN1 was lost in aged fibroblasts, resulting in a more aligned ECM that promoted metastasis of ..

More Information


  1. Bebek G, Patel V, Chance M. PETALS: Proteomic Evaluation and Topological Analysis of a mutated Locus' Signaling. BMC Bioinformatics. 2010;11:596 pubmed publisher
    ..The predicted pathways linking Apc and Hapln1 exhibited the highest amount of bimodal coexpression with the proteomic targets, prioritizing the Apc-Hapln1 petal ..
  2. Romberg C, Yang S, Melani R, Andrews M, Horner A, Spillantini M, et al. Depletion of perineuronal nets enhances recognition memory and long-term depression in the perirhinal cortex. J Neurosci. 2013;33:7057-65 pubmed publisher
    ..Expression of the link protein Crtl1/Hapln1 in neurons has recently been identified as the key event triggering the formation of PNNs...
  3. Gaál B, Kecskes S, Matesz C, Birinyi A, Hunyadi A, Rácz Ã. Molecular composition and expression pattern of the extracellular matrix in a mossy fiber-generating precerebellar nucleus of rat, the prepositus hypoglossi. Neurosci Lett. 2015;594:122-6 pubmed publisher
    ..followed by the hyaluronan, then least with reactions for chondroitin sulfate-based proteoglycan components and HAPLN1 link protein reactions, but PNNs were not observed with the versican, neurocan, and brevican staining...
  4. Gao R, Cao C, Zhang M, Lopez M, Yan Y, Chen Z, et al. A unifying gene signature for adenoid cystic cancer identifies parallel MYB-dependent and MYB-independent therapeutic targets. Oncotarget. 2014;5:12528-42 pubmed
    ..analyses suggests that NOTCH1 and RUNX1 participate with MYB to activate ECM elements including the VCAN/HAPLN1 complex...
  5. Forostyak S, Homola A, Turnovcova K, Svitil P, Jendelova P, Sykova E. Intrathecal delivery of mesenchymal stromal cells protects the structure of altered perineuronal nets in SOD1 rats and amends the course of ALS. Stem Cells. 2014;32:3163-72 pubmed publisher
    ..Additionally, SOD1 rats had different profiles for CSPG gene expression (Versican, Hapln1, Neurocan, and Tenascin-R), whereas Aggrecan and Brevican profiles remained unchanged...
  6. Fawcett J. The extracellular matrix in plasticity and regeneration after CNS injury and neurodegenerative disease. Prog Brain Res. 2015;218:213-26 pubmed publisher
    ..Knockout of the PNN-organizing protein Crtl1 link protein attenuates PNNs and leads to continued plasticity into adulthood, demonstrating that the CSPGs in ..
  7. Long K, Newland B, Florio M, Kalebic N, Langen B, Kolterer A, et al. Extracellular Matrix Components HAPLN1, Lumican, and Collagen I Cause Hyaluronic Acid-Dependent Folding of the Developing Human Neocortex. Neuron. 2018;99:702-719.e6 pubmed publisher
    ..We focus on three specific ECM components localized in the human fetal cortical plate (CP): hyaluronan and proteoglycan link protein 1 (HAPLN1), lumican and collagen I (collectively, HLC)...
  8. Wianny F, Kennedy H, Dehay C. Bridging the Gap between Mechanics and Genetics in Cortical Folding: ECM as a Major Driving Force. Neuron. 2018;99:625-627 pubmed publisher
    ..In this issue, Long et al. identify the key roles of HAPLN1, lumican, collagen I, and HA in relationship with changes in tissue stiffness.
  9. Bano F, Tammi M, Kang D, Harris E, Richter R. Single-Molecule Unbinding Forces between the Polysaccharide Hyaluronan and Its Binding Proteins. Biophys J. 2018;114:2910-2922 pubmed publisher
    ..of hyaladherins from the Link module superfamily, namely the complex of the proteoglycan aggrecan and cartilage link protein, the proteoglycan versican, the inflammation-associated protein TSG-6, the HA receptor for endocytosis (..
  10. Galtrey C, Kwok J, Carulli D, Rhodes K, Fawcett J. Distribution and synthesis of extracellular matrix proteoglycans, hyaluronan, link proteins and tenascin-R in the rat spinal cord. Eur J Neurosci. 2008;27:1373-90 pubmed publisher
    ..In situ hybridization showed that aggrecan and cartilage link protein (CRTL 1) and brain link protein-2 (BRAL 2) are produced by neurons...
  11. Huh J, Koh P, Seo B, Park Y, Baek Y, Lee J, et al. Mangiferin reduces the inhibition of chondrogenic differentiation by IL-1β in mesenchymal stem cells from subchondral bone and targets multiple aspects of the Smad and SOX9 pathways. Int J Mol Sci. 2014;15:16025-42 pubmed publisher
    ..sex-determining region Y-box (SRY-box) containing gene 9 (SOX9), type 2α1 collagen (Col2α1), cartilage link protein, and aggrecan...
  12. Kecskes S, Gaál B, Rácz Ã, Birinyi A, Hunyadi A, Matesz C. Extracellular matrix molecules exhibit unique expression pattern in the climbing fiber-generating precerebellar nucleus, the inferior olive. Neuroscience. 2015;284:412-21 pubmed publisher
    ..We have observed positive ECM reaction for the hyaluronan, tenascin-R, hyaluronan and proteoglycan link protein 1 (HAPLN1) and various chondroitin sulfate proteoglycans...
  13. Erwin W, DeSouza L, Funabashi M, Kawchuk G, Karim M, Kim S, et al. The biological basis of degenerative disc disease: proteomic and biomechanical analysis of the canine intervertebral disc. Arthritis Res Ther. 2015;17:240 pubmed publisher
    ..fibronectin, as well as of other important extracellular matrix (ECM)-related proteins, such as fibromodulin and HAPLN1 in the IVD NP obtained from CD canines compared with NCD canines...
  14. Suttkus A, Holzer M, Morawski M, Arendt T. The neuronal extracellular matrix restricts distribution and internalization of aggregated Tau-protein. Neuroscience. 2016;313:225-35 pubmed publisher
    ..by using organotypic slice cultures of wildtype mice as well as mice lacking the ECM-components aggrecan, HAPLN1 or tenascin-R. We could demonstrate that PNs restrict both distribution and internalization of Tau...
  15. Dunn S, Soul J, Anand S, Schwartz J, Boot Handford R, Hardingham T. Gene expression changes in damaged osteoarthritic cartilage identify a signature of non-chondrogenic and mechanical responses. Osteoarthritis Cartilage. 2016;24:1431-40 pubmed publisher
    ..OA cartilage, there was decreased expression of chondrogenic genes SOX9, SOX6, COL11A2, COL9A1/2/3, ACAN and HAPLN1; increases in non-chondrogenic genes COL1A1, COMP and FN1; an altered pattern of secreted proteinase expression; ..
  16. Rácz Ã, Gaál B, Matesz C. Heterogeneous expression of extracellular matrix molecules in the red nucleus of the rat. Neuroscience. 2016;322:1-17 pubmed publisher
    ..The two parts were clearly distinguished on the basis of neurocan and HAPLN1 expression as they have lower intensity in the perineuronal nets of large cells and in the neuropil of the ..
  17. Huynh M, Pak C, Markovina S, Callander N, Chng K, Wuerzberger Davis S, et al. Hyaluronan and proteoglycan link protein 1 (HAPLN1) activates bortezomib-resistant NF-κB activity and increases drug resistance in multiple myeloma. J Biol Chem. 2018;293:2452-2465 pubmed publisher
    ..Here, we report that hyaluronan and proteoglycan link protein 1 (HAPLN1) is produced in bone marrow stromal cells from MM patients, is detected in patients' ..
  18. Layh Schmitt G, Lu S, Navid F, Brooks S, Lazowick E, Davis K, et al. Generation and differentiation of induced pluripotent stem cells reveal ankylosing spondylitis risk gene expression in bone progenitors. Clin Rheumatol. 2017;36:143-154 pubmed publisher
    ..We show for the first time, that expression levels of several AS susceptibility genes (EDIL3, ANO6, HAPLN1, ANTXR2) involved in bone formation are significantly elevated in MSCs (2-15-fold; p ? 0...
  19. Naba A, Clauser K, Hoersch S, Liu H, Carr S, Hynes R. The matrisome: in silico definition and in vivo characterization by proteomics of normal and tumor extracellular matrices. Mol Cell Proteomics. 2012;11:M111.014647 pubmed publisher
  20. Cénit M, Blanco Kelly F, De Las Heras V, Bartolome M, de la Concha E, Urcelay E, et al. Glypican 5 is an interferon-beta response gene: a replication study. Mult Scler. 2009;15:913-7 pubmed publisher
    ..the results obtained at the two loci most strongly implicated in the response to interferon-beta treatment, HAPLN1 and GPC5...
  21. Urano T, Narusawa K, Shiraki M, Sasaki N, Hosoi T, Ouchi Y, et al. Single-nucleotide polymorphism in the hyaluronan and proteoglycan link protein 1 (HAPLN1) gene is associated with spinal osteophyte formation and disc degeneration in Japanese women. Eur Spine J. 2011;20:572-7 pubmed publisher
    ..b>HAPLN1 is a key component of the cartilage extracellular matrix; thus, variations in this gene may affect the ..
  22. Dudhia J, Hardingham T. The primary structure of human cartilage link protein. Nucleic Acids Res. 1990;18:1292 pubmed
  23. Perkins S, Nealis A, Dudhia J, Hardingham T. Immunoglobulin fold and tandem repeat structures in proteoglycan N-terminal domains and link protein. J Mol Biol. 1989;206:737-53 pubmed
    ..These analyses show that both the proteoglycan G1 domain and link protein are constructed from two distinct globular components, which may provide the two functional roles of these proteins in proteoglycan aggregation. ..
  24. Mebarki S, Désert R, Sulpice L, Sicard M, Desille M, Canal F, et al. De novo HAPLN1 expression hallmarks Wnt-induced stem cell and fibrogenic networks leading to aggressive human hepatocellular carcinomas. Oncotarget. 2016;7:39026-39043 pubmed publisher
    ..Both networks were linked by Hyaluronan And Proteoglycan Link Protein 1 (HAPLN1), that appeared de novo in aggressive HCCs expressing cytoplasmic ?-catenin and stem ..
  25. Sun G, Kobayashi H, Suzuki M, Kanayama N, Terao T. Production of cartilage link protein by human granulosa-lutein cells. J Endocrinol. 2002;175:505-15 pubmed
    ..Collectively, the present results raise the possibility that cartilage LP forms extracellular structures that may have a regulatory function in the developing follicle in the human ovary. ..
  26. Lin Y, Lewallen E, Camilleri E, Bonin C, Jones D, Dudakovic A, et al. RNA-seq analysis of clinical-grade osteochondral allografts reveals activation of early response genes. J Orthop Res. 2016;34:1950-1959 pubmed publisher
    ..e., COL1A1, COL2A1, COL10A1, ACAN, DCN, HAPLN1, TNC, and COMP) in stored cartilage...
  27. Rhodes C, Savagner P, Line S, Sasaki M, Chirigos M, Doege K, et al. Characterization of the promoter for the rat and human link protein gene. Nucleic Acids Res. 1991;19:1933-9 pubmed
    ..These results indicate the presence of positive cisacting regulatory elements in both the promoter and first intron of the rat gene for link protein. ..
  28. Milz S, Schlüter T, Putz R, Moriggl B, Ralphs J, Benjamin M. Fibrocartilage in the transverse ligament of the human atlas. Spine (Phila Pa 1976). 2001;26:1765-71 pubmed
    ..In some rheumatoid patients there can be an autoimmune response to cartilage link protein, aggrecan, and Type II collagen...
  29. Matsumoto K, Shionyu M, Go M, Shimizu K, Shinomura T, Kimata K, et al. Distinct interaction of versican/PG-M with hyaluronan and link protein. J Biol Chem. 2003;278:41205-12 pubmed
    ..These results provide important insights into the mechanisms of formation of the proteoglycan aggregate and HA binding of molecules containing the link module. ..
  30. Seyfried N, McVey G, Almond A, Mahoney D, Dudhia J, Day A. Expression and purification of functionally active hyaluronan-binding domains from human cartilage link protein, aggrecan and versican: formation of ternary complexes with defined hyaluronan oligosaccharides. J Biol Chem. 2005;280:5435-48 pubmed
    ..In this study, cartilage link protein (cLP) and the G1-domains of aggrecan (AG1) and versican (VG1) were expressed in Drosophila S2 cells...
  31. Kwok J, Carulli D, Fawcett J. In vitro modeling of perineuronal nets: hyaluronan synthase and link protein are necessary for their formation and integrity. J Neurochem. 2010;114:1447-59 pubmed publisher
    ..all perineuronal nets (PNNs) bearing neurons express a hyaluronan synthase (HAS), a link protein (usually cartilage link protein-1; Crtl1) and a chondroitin sulfate proteoglycan (usually aggrecan)...
  32. Kähler A, Djurovic S, Rimol L, Brown A, Athanasiu L, Jonsson E, et al. Candidate gene analysis of the human natural killer-1 carbohydrate pathway and perineuronal nets in schizophrenia: B3GAT2 is associated with disease risk and cortical surface area. Biol Psychiatry. 2011;69:90-6 pubmed publisher
    ..for HNK-1 biosynthesis (B3GAT1, B3GAT2, and CHST10) or for the formation of perineuronal nets (TNR, BCAN, NCAN, HAPLN1, HAPLN2, HAPLN3, and HAPLN4) were investigated for potential involvement in schizophrenia (SCZ) susceptibility, by ..
  33. Shi S, Grothe S, Zhang Y, O Connor McCourt M, Poole A, Roughley P, et al. Link protein has greater affinity for versican than aggrecan. J Biol Chem. 2004;279:12060-6 pubmed
    ..These observations suggest that link protein may function as a stabilizer of the interaction, not only between aggrecan and hyaluronan in cartilage, but also between versican and hyaluronan in many tissues. ..
  34. Murabito J, Rosenberg C, Finger D, Kreger B, Levy D, Splansky G, et al. A genome-wide association study of breast and prostate cancer in the NHLBI's Framingham Heart Study. BMC Med Genet. 2007;8 Suppl 1:S6 pubmed
    ..These findings can serve as a resource for replication in other populations to identify novel biologic pathways contributing to cancer susceptibility. ..
  35. Mundlos S, Meyer R, Yamada Y, Zabel B. Distribution of cartilage proteoglycan (aggrecan) core protein and link protein gene expression during human skeletal development. Matrix. 1991;11:339-46 pubmed
    The distribution of cartilage proteoglycan core protein (aggrecan) and cartilage proteoglycan link protein was investigated by in situ hybridization during different stages of human skeletal development...
  36. Ivanova A, Goparaju C, Ivanov S, Nonaka D, Cruz C, Beck A, et al. Protumorigenic role of HAPLN1 and its IgV domain in malignant pleural mesothelioma. Clin Cancer Res. 2009;15:2602-11 pubmed publisher
    ..We find that one of the ECM proteins, HAPLN1, is overexpressed in the majority of mesotheliomas...
  37. Wang W, Yu Y, Hao J, Wen Y, Han J, Hou W, et al. Genome-wide DNA methylation profiling of articular cartilage reveals significant epigenetic alterations in Kashin-Beck disease and osteoarthritis. Osteoarthritis Cartilage. 2017;25:2127-2133 pubmed publisher
    ..MS and IHC confirmed the hypermethylation status and decreased protein expression of HAPLN1 gene in KBD cartilage. Our data implicate epigenetic dysregulation of a host of genes in KBD and OA...
  38. Hirakawa S, Oohashi T, Su W, Yoshioka H, Murakami T, Arata J, et al. The brain link protein-1 (BRAL1): cDNA cloning, genomic structure, and characterization as a novel link protein expressed in adult brain. Biochem Biophys Res Commun. 2000;276:982-9 pubmed
    ..The deduced amino acid sequence of human brain link protein-1 exhibited 45% identity with human cartilage link protein-1 (CRTL1), previously reported as link protein to stabilize aggregates of aggrecan and hyaluronan in ..
  39. Osborne Lawrence S, Sinclair A, Hicks R, Lacey S, Eddy R, Byers M, et al. Complete amino acid sequence of human cartilage link protein (CRTL1) deduced from cDNA clones and chromosomal assignment of the gene. Genomics. 1990;8:562-7 pubmed
    Little is known about the primary amino acid structure of human cartilage link protein (CRTL1). We screened a human genomic library with a cDNA encoding the 3' untranslated region and the adjoining B1 domain of chicken link protein...
  40. Zheng J, Wu C, Ma W, Zhang Y, Hou T, Xu H, et al. Abnormal expression of chondroitin sulphate N-acetylgalactosaminyltransferase 1 and Hapln-1 in cartilage with Kashin-Beck disease and primary osteoarthritis. Int Orthop. 2013;37:2051-9 pubmed publisher
    ..It was indicated that CSGalNAcT-1 and Hapln-1 may play important roles in the pathogenesis of KBD and OA. ..
  41. Dudhia J, Hardingham T. The primary structure of human cartilage link protein. Nucleic Acids Res. 1990;18:2214 pubmed
  42. Nguyen Q, Murphy G, Hughes C, Mort J, Roughley P. Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Biochem J. 1993;295 ( Pt 2):595-8 pubmed
  43. Pokharna H, Pottenger L. Glycation induced crosslinking of link proteins, in vivo and in vitro. J Surg Res. 2000;94:35-42 pubmed
    ..These studies suggest that human link proteins tend to become crosslinked to aggrecan in adult cartilage. A likely cause of the crosslinking is formation of AGE due to reducing sugars. ..
  44. Guerassimov A, Zhang Y, Banerjee S, Cartman A, Webber C, Esdaile J, et al. Autoimmunity to cartilage link protein in patients with rheumatoid arthritis and ankylosing spondylitis. J Rheumatol. 1998;25:1480-4 pubmed
    ..patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) express cellular immunity to cartilage link protein (LP). LP was purified from human fetal epiphyseal and bovine adult nasal cartilage...
  45. Perveen R, Hart Holden N, Dixon M, Wiszniewski W, Fryer A, Brunner H, et al. Refined genetic and physical localization of the Wagner disease (WGN1) locus and the genes CRTL1 and CSPG2 to a 2- to 2.5-cM region of chromosome 5q14.3. Genomics. 1999;57:219-26 pubmed
    ..Within the critical region lie genes encoding two extracellular macromolecules, link protein (CRTL1) and versican (CSPG2), which are important in binding hyaluronan, a significant component of the mammalian ..
  46. Kou I, Ikegawa S. SOX9-dependent and -independent transcriptional regulation of human cartilage link protein. J Biol Chem. 2004;279:50942-8 pubmed
    b>Cartilage link protein is a key component of the cartilage extracellular matrix. The transcriptional regulation of the gene encoding cartilage link protein (CRTL1) is largely unknown, however...
  47. Lin Z, Bei J, Shen M, Li Q, Liao Z, Zhang Y, et al. A genome-wide association study in Han Chinese identifies new susceptibility loci for ankylosing spondylitis. Nat Genet. 2011;44:73-7 pubmed publisher
    ..We identified two new susceptibility loci between EDIL3 and HAPLN1 at 5q14.3 (rs4552569; P = 8.77 × 10(-10)) and within ANO6 at 12q12 (rs17095830; P = 1.63 × 10(-8))...