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CBL (gene)

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CBL (gene)

Cbl proto-oncogene, E3 ubiquitin protein ligase

PDB rendering based on 1b47.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols  ; C-CBL; CBL2; FRA11B; NSLL; RNF55
External IDs GeneCards:
RNA expression pattern
Species Human Mouse
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

Cbl (named after Casitas B-lineage Lymphoma) is a mammalian gene encoding the protein CBL which is an E3 ubiquitin-protein ligase involved in cell signalling and protein ubiquitination. Mutations to this gene have been implicated in a number of human cancers, particularly acute myeloid leukaemia.[1]


In 1989 a virally encoded portion of the chromosomal mouse Cbl gene was the first member of the Cbl family to be discovered[2] and was named v-Cbl to distinguish it from normal mouse c-Cbl. The virus used in the experiment was a retrovirus known as Cas-Br-M, and was found to have excised approximately a third of the original c-Cbl gene from mice it was injected into. Sequencing revealed that the portion carried by the retrovirus encoded a tyrosine kinase binding domain, and that this was the oncogenic form as retroviruses carrying full-length c-Cbl did not induce tumour formation. The resultant transformed retrovirus was found to consistently induce a type of pre-B lymphoma, known as Casitas B-lineage lymphoma, in infected mice.


Full length c-Cbl has been found to consist of several regions encoding for functionally distinct protein domains:

This domain structure and the tyrosine and serine-rich content of the protein product is typical of an "adaptor molecule" used in cell signalling pathways.[3]


Three mammalian homologues have been characterized, which all differ in their ability to function as adaptor proteins due to the differing lengths of their C-terminal UBA domains:

  1. c-Cbl: ubiquitously expressed, 906 and 913 amino acids in length in humans and mice respectively
  2. Cbl-b: ubiquitously expressed, 982 amino acids long in length.
  3. Cbl-c: lacks the UBA domain and is therefore only 474 amino acids in length. It is primarily expressed in epithelial cells however its function is poorly understood.

Interestingly, both c-Cbl and Cbl-b have orthologues in D. melanogaster (D-Cbl) and C. elegans (Sli-1), hinting at a long evolutionary path for these proteins.[3]


Ubiquitin ligase

Ubiquitination is the process of chemically attaching ubiquitin monomers to a protein, thereby targeting it for degradation. As this is a multi-step process, several different enzymes are involved, the final one being a member of the E3 family of ligases. Cbl functions as an E3 ligase, and therefore is able to catalyse the formation of a covalent bond between ubiquitin and Cbl's protein substrate - typically a receptor tyrosine kinase. The RING-finger domain mediates this transfer, however like other E3 ligases of the RING type no intermediate covalent bond is formed between ubiquitin and the RING-finger domain. The stepwise attachment of ubiquitin to the substrate receptor tyrosine kinase can lead to its removal from the plasma membrane and subsequent trafficking to the lysosome for degradation.


Cbl gene has been shown to interact with:


  1. ^ Naramura, M.; Nadeau, S.; Mohapatra, B.; Ahmad, G.; Mukhopadhyay, C.; Sattler, M.; Raja, S. M.; Natarajan, A.; Band, V.; Band, H. (2011). "Mutant Cbl proteins as oncogenic drivers in myeloproliferative disorders". Oncotarget 2 (3): 245–250.  
  2. ^ Langdon WY, Hartley JW, Klinken SP, Ruscetti SK, Morse HC (1989). "v-cbl, an oncogene from a dual-recombinant murine retrovirus that induces early B-lineage lymphomas". Proc. Natl. Acad. Sci. U.S.A. 86 (4): 1168–72.  
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  4. ^ a b Miyoshi-Akiyama, T; Aleman L M; Smith J M; Adler C E; Mayer B J (July 2001). "Regulation of Cbl phosphorylation by the Abl tyrosine kinase and the Nck SH2/SH3 adaptor". Oncogene (England) 20 (30): 4058–69.  
  5. ^ a b Soubeyran P, Barac A, Szymkiewicz I, Dikic I (February 2003). "Cbl-ArgBP2 complex mediates ubiquitination and degradation of c-Abl". Biochem. J. 370 (Pt 1): 29–34.  
  6. ^ Flanders JA, Feng Q, Bagrodia S, Laux MT, Singavarapu A, Cerione RA (August 2003). "The Cbl proteins are binding partners for the Cool/Pix family of p21-activated kinase-binding proteins". FEBS Lett. 550 (1-3): 119–23.  
  7. ^ a b c d e Ng, Cherlyn; Jackson Rebecca A; Buschdorf Jan P; Sun Qingxiang; Guy Graeme R; Sivaraman J (March 2008). "Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates". EMBO J. (England) 27 (5): 804–16.  
  8. ^ a b Petrelli A, Gilestro GF, Lanzardo S, Comoglio PM, Migone N, Giordano S (March 2002). "The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met". Nature 416 (6877): 187–90.  
  9. ^ a b c d Haglund, Kaisa; Ivankovic-Dikic Inga, Shimokawa Noriaki, Kruh Gary D, Dikic Ivan (May 2004). "Recruitment of Pyk2 and Cbl to lipid rafts mediates signals important for actin reorganization in growing neurites". J. Cell. Sci. (England) 117 (Pt 12): 2557–68.  
  10. ^ Kirsch KH, Georgescu MM, Shishido T, Langdon WY, Birge RB, Hanafusa H (February 2001). "The adapter type protein CMS/CD2AP binds to the proto-oncogenic protein c-Cbl through a tyrosine phosphorylation-regulated Src homology 3 domain interaction". J. Biol. Chem. 276 (7): 4957–63.  
  11. ^ Cormont, Mireille; Metón Isidoro, Mari Muriel, Monzo Pascale, Keslair Frédérique, Gaskin Chantell, McGraw Timothy E, Le Marchand-Brustel Yannick (February 2003). "CD2AP/CMS regulates endosome morphology and traffic to the degradative pathway through its interaction with Rab4 and c-Cbl". Traffic (Denmark) 4 (2): 97–112.  
  12. ^ Mancini A, Koch A, Wilms R, Tamura T (April 2002). "c-Cbl associates directly with the C-terminal tail of the receptor for the macrophage colony-stimulating factor, c-Fms, and down-modulates this receptor but not the viral oncogene v-Fms". J. Biol. Chem. 277 (17): 14635–40.  
  13. ^ a b c d Gesbert, F; Garbay C; Bertoglio J (February 1998). "Interleukin-2 stimulation induces tyrosine phosphorylation of p120-Cbl and CrkL and formation of multimolecular signaling complexes in T lymphocytes and natural killer cells". J. Biol. Chem. (UNITED STATES) 273 (7): 3986–93.  
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  15. ^ a b c d Erdreich-Epstein, A; Liu M; Kant A M; Izadi K D; Nolta J A; Durden D L (April 1999). "Cbl functions downstream of Src kinases in Fc gamma RI signaling in primary human macrophages". J. Leukoc. Biol. (UNITED STATES) 65 (4): 523–34.  
  16. ^ Lin H, Martelli MP, Bierer BE (January 2001). "The involvement of the proto-oncogene p120 c-Cbl and ZAP-70 in CD2-mediated T cell activation". Int. Immunol. 13 (1): 13–22.  
  17. ^ Kyono WT, de Jong R, Park RK, Liu Y, Heisterkamp N, Groffen J, Durden DL (November 1998). "Differential interaction of Crkl with Cbl or C3G, Hef-1, and gamma subunit immunoreceptor tyrosine-based activation motif in signaling of myeloid high affinity Fc receptor for IgG (Fc gamma RI)". J. Immunol. 161 (10): 5555–63.  
  18. ^ Park RK, Kyono WT, Liu Y, Durden DL (May 1998). "CBL-GRB2 interaction in myeloid immunoreceptor tyrosine activation motif signaling". J. Immunol. 160 (10): 5018–27.  
  19. ^ a b Taher TE, Tjin EP, Beuling EA, Borst J, Spaargaren M, Pals ST (October 2002). "c-Cbl is involved in Met signaling in B cells and mediates hepatocyte growth factor-induced receptor ubiquitination". J. Immunol. 169 (7): 3793–800.  
  20. ^ Sattler M, Salgia R, Shrikhande G, Verma S, Pisick E, Prasad KV, Griffin JD (April 1997). "Steel factor induces tyrosine phosphorylation of CRKL and binding of CRKL to a complex containing c-kit, phosphatidylinositol 3-kinase, and p120(CBL)". J. Biol. Chem. 272 (15): 10248–53.  
  21. ^ Sattler M, Salgia R, Shrikhande G, Verma S, Uemura N, Law SF, Golemis EA, Griffin JD (May 1997). "Differential signaling after beta1 integrin ligation is mediated through binding of CRKL to p120(CBL) and p110(HEF1)". J. Biol. Chem. 272 (22): 14320–6.  
  22. ^ Chin H, Saito T, Arai A, Yamamoto K, Kamiyama R, Miyasaka N, Miura O (October 1997). "Erythropoietin and IL-3 induce tyrosine phosphorylation of CrkL and its association with Shc, SHP-2, and Cbl in hematopoietic cells". Biochem. Biophys. Res. Commun. 239 (2): 412–7.  
  23. ^ Tvorogov D, Carpenter G (July 2002). "EGF-dependent association of phospholipase C-gamma1 with c-Cbl". Exp. Cell Res. 277 (1): 86–94.  
  24. ^ Umebayashi K, Stenmark H, Yoshimori T (August 2008). "Ubc4/5 and c-Cbl continue to ubiquitinate EGF receptor after internalization to facilitate polyubiquitination and degradation". Mol. Biol. Cell 19 (8): 3454–62.  
  25. ^ a b Wong, Andy; Lamothe Betty; Lee Arnold; Schlessinger Joseph; Lax Irit; Li Arnold (May 2002). "FRS2 alpha attenuates FGF receptor signaling by Grb2-mediated recruitment of the ubiquitin ligase Cbl".  
  26. ^ Deckert M, Elly C, Altman A, Liu YC (April 1998). "Coordinated regulation of the tyrosine phosphorylation of Cbl by Fyn and Syk tyrosine kinases". J. Biol. Chem. 273 (15): 8867–74.  
  27. ^ a b Park, R K; Erdreich-Epstein A; Liu M; Izadi K D; Durden D L (December 1999). "High affinity IgG receptor activation of Src family kinases is required for modulation of the Shc-Grb2-Sos complex and the downstream activation of the nicotinamide adenine dinucleotide phosphate (reduced) oxidase". J. Immunol. (UNITED STATES) 163 (11): 6023–34.  
  28. ^ Jain, S K; Langdon W Y; Varticovski L (May 1997). "Tyrosine phosphorylation of p120cbl in BCR/abl transformed hematopoietic cells mediates enhanced association with phosphatidylinositol 3-kinase". Oncogene (ENGLAND) 14 (18): 2217–28.  
  29. ^ Liu, S K; McGlade C J (December 1998). "Gads is a novel SH2 and SH3 domain-containing adaptor protein that binds to tyrosine-phosphorylated Shc". Oncogene (ENGLAND) 17 (24): 3073–82.  
  30. ^ Ettenberg, S A; Keane M M; Nau M M; Frankel M; Wang L M; Pierce J H; Lipkowitz S (March 1999). "cbl-b inhibits epidermal growth factor receptor signaling". Oncogene (ENGLAND) 18 (10): 1855–66.  
  31. ^ a b Robertson, H; Langdon W Y; Thien C B; Bowtell D D (November 1997). "A c-Cbl yeast two hybrid screen reveals interactions with 14-3-3 isoforms and cytoskeletal components". Biochem. Biophys. Res. Commun. (UNITED STATES) 240 (1): 46–50.  
  32. ^ Donovan, J A; Wange R L; Langdon W Y; Samelson L E (September 1994). "The protein product of the c-cbl protooncogene is the 120-kDa tyrosine-phosphorylated protein in Jurkat cells activated via the T cell antigen receptor". J. Biol. Chem. (UNITED STATES) 269 (37): 22921–4.  
  33. ^ Saci, Abdelhafid; Liu Wang-Qing, Vidal Michel, Garbay Christiane, Rendu Francine, Bachelot-Loza Christilla (May 2002). "Differential effect of the inhibition of Grb2-SH3 interactions in platelet activation induced by thrombin and by Fc receptor engagement". Biochem. J. (England) 363 (Pt 3): 717–25.  
  34. ^ Odai, H; Sasaki K; Iwamatsu A; Nakamoto T; Ueno H; Yamagata T; Mitani K; Yazaki Y; Hirai H (April 1997). "Purification and molecular cloning of SH2- and SH3-containing inositol polyphosphate-5-phosphatase, which is involved in the signaling pathway of granulocyte-macrophage colony-stimulating factor, erythropoietin, and Bcr-Abl". Blood (UNITED STATES) 89 (8): 2745–56.  
  35. ^ Howlett, Christopher J; Robbins Stephen M (March 2002). "Membrane-anchored Cbl suppresses Hck protein-tyrosine kinase mediated cellular transformation". Oncogene (England) 21 (11): 1707–16.  
  36. ^ Howlett, C J; Bisson S A; Resek M E; Tigley A W; Robbins S M (April 1999). "The proto-oncogene p120(Cbl) is a downstream substrate of the Hck protein-tyrosine kinase". Biochem. Biophys. Res. Commun. (UNITED STATES) 257 (1): 129–38.  
  37. ^ Sehat, Bita; Andersson Sandra; Girnita Leonard; Larsson Olle (July 2008). "Identification of c-Cbl as a new ligase for insulin-like growth factor-I receptor with distinct roles from Mdm2 in receptor ubiquitination and endocytosis". Cancer Res. (United States) 68 (14): 5669–77.  
  38. ^ Park, R K; Izadi K D; Deo Y M; Durden D L (September 1999). "Role of Src in the modulation of multiple adaptor proteins in FcalphaRI oxidant signaling". Blood (UNITED STATES) 94 (6): 2112–20.  
  39. ^ Bonita, D P; Miyake S; Lupher M L; Langdon W Y; Band H (August 1997). "Phosphotyrosine binding domain-dependent upregulation of the platelet-derived growth factor receptor alpha signaling cascade by transforming mutants of Cbl: implications for Cbl's function and oncogenicity". Mol. Cell. Biol. (UNITED STATES) 17 (8): 4597–610.  
  40. ^ Zhang, S; Broxmeyer H E (January 1999). "p85 subunit of PI3 kinase does not bind to human Flt3 receptor, but associates with SHP2, SHIP, and a tyrosine-phosphorylated 100-kDa protein in Flt3 ligand-stimulated hematopoietic cells". Biochem. Biophys. Res. Commun. (UNITED STATES) 254 (2): 440–5.  
  41. ^ Dufour, Cécilie; Guenou Hind; Kaabeche Karim; Bouvard Daniel; Sanjay Archana; Marie Pierre J (June 2008). "FGFR2-Cbl interaction in lipid rafts triggers attenuation of PI3K/Akt signaling and osteoblast survival". Bone (United States) 42 (6): 1032–9.  
  42. ^ Lin, H; Martelli M P; Bierer B E (January 2001). "The involvement of the proto-oncogene p120 c-Cbl and ZAP-70 in CD2-mediated T cell activation". Int. Immunol. (England) 13 (1): 13–22.  
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  44. ^ Tvorogov, Denis; Carpenter Graham (July 2002). "EGF-dependent association of phospholipase C-gamma1 with c-Cbl". Exp. Cell Res. (United States) 277 (1): 86–94.  
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  46. ^ Sanjay, A; Houghton A, Neff L, DiDomenico E, Bardelay C, Antoine E, Levy J, Gailit J, Bowtell D, Horne W C, Baron R (January 2001). "Cbl associates with Pyk2 and Src to regulate Src kinase activity, alpha(v)beta(3) integrin-mediated signaling, cell adhesion, and osteoclast motility". J. Cell Biol. (United States) 152 (1): 181–95.  
  47. ^ Tanaka, Yoshinori; Tanaka Nobuyuki; Saeki Yasushi; Tanaka Keiji; Murakami Masaaki; Hirano Toshio; Ishii Naoto; Sugamura Kazuo (August 2008). "c-Cbl-dependent monoubiquitination and lysosomal degradation of gp130". Mol. Cell. Biol. (United States) 28 (15): 4805–18.  
  48. ^ Wakioka, T; Sasaki A; Mitsui K; Yokouchi M; Inoue A; Komiya S; Yoshimura A (May 1999). "APS, an adaptor protein containing Pleckstrin homology (PH) and Src homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration with c-Cbl". Leukemia (ENGLAND) 13 (5): 760–7.  
  49. ^ Watanabe, S; Take H; Takeda K; Yu Z X; Iwata N; Kajigaya S (November 2000). "Characterization of the CIN85 adaptor protein and identification of components involved in CIN85 complexes". Biochem. Biophys. Res. Commun. (UNITED STATES) 278 (1): 167–74.  
  50. ^ Soubeyran, Philippe; Kowanetz Katarzyna; Szymkiewicz Iwona; Langdon Wallace Y; Dikic Ivan (March 2002). "Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors".  
  51. ^ Szymkiewicz, Iwona; Kowanetz Katarzyna; Soubeyran Philippe; Dinarina Ana; Lipkowitz Stanley; Dikic Ivan (October 2002). "CIN85 participates in Cbl-b-mediated down-regulation of receptor tyrosine kinases". J. Biol. Chem. (United States) 277 (42): 39666–72.  
  52. ^ Borinstein, S C; Hyatt M A; Sykes V W; Straub R E; Lipkowitz S; Boulter J; Bogler O (December 2000). "SETA is a multifunctional adapter protein with three SH3 domains that binds Grb2, Cbl, and the novel SB1 proteins". Cell. Signal. (ENGLAND) 12 (11-12): 769–79.  
  53. ^ Pandey, Akhilesh; Ibarrola Nieves; Kratchmarova Irina; Fernandez Minerva M; Constantinescu Stefan N; Ohara Osamu; Sawasdikosol Sansana; Lodish Harvey F; Mann Matthias (May 2002). "A novel Src homology 2 domain-containing molecule, Src-like adapter protein-2 (SLAP-2), which negatively regulates T cell receptor signaling". J. Biol. Chem. (United States) 277 (21): 19131–8.  
  54. ^ Vandenbroere, Isabelle; Paternotte Nathalie; Dumont Jacques E; Erneux Christophe; Pirson Isabelle (January 2003). "The c-Cbl-associated protein and c-Cbl are two new partners of the SH2-containing inositol polyphosphate 5-phosphatase SHIP2". Biochem. Biophys. Res. Commun. (United States) 300 (2): 494–500.  
  55. ^ a b Wong, Esther Sook Miin; Fong Chee Wai; Lim Jormay; Yusoff Permeen; Low Boon Chuan; Langdon Wallace Y; Guy Graeme R (September 2002). "Sprouty2 attenuates epidermal growth factor receptor ubiquitylation and endocytosis, and consequently enhances Ras/ERK signalling". EMBO J. (England) 21 (18): 4796–808.  
  56. ^ Wong, E S; Lim J; Low B C; Chen Q; Guy G R (February 2001). "Evidence for direct interaction between Sprouty and Cbl". J. Biol. Chem. (United States) 276 (8): 5866–75.  
  57. ^ Lupher, M L; Rao N; Lill N L; Andoniou C E; Miyake S; Clark E A; Druker B; Band H (December 1998). "Cbl-mediated negative regulation of the Syk tyrosine kinase. A critical role for Cbl phosphotyrosine-binding domain binding to Syk phosphotyrosine 323". J. Biol. Chem. (UNITED STATES) 273 (52): 35273–81.  
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  59. ^ Melander, Fredrik; Andersson Tommy; Dib Karim (March 2003). "Fgr but not Syk tyrosine kinase is a target for beta 2 integrin-induced c-Cbl-mediated ubiquitination in adherent human neutrophils". Biochem. J. (England) 370 (Pt 2): 687–94.  
  60. ^ Yokouchi, M; Kondo T; Houghton A; Bartkiewicz M; Horne W C; Zhang H; Yoshimura A; Baron R (October 1999). "Ligand-induced ubiquitination of the epidermal growth factor receptor involves the interaction of the c-Cbl RING finger and UbcH7". J. Biol. Chem. (UNITED STATES) 274 (44): 31707–12.  
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  62. ^ Marengère, L E; Mirtsos C; Kozieradzki I; Veillette A; Mak T W; Penninger J M (July 1997). "Proto-oncoprotein Vav interacts with c-Cbl in activated thymocytes and peripheral T cells". J. Immunol. (UNITED STATES) 159 (1): 70–6.  
  63. ^ Pedraza-Alva, G; Sawasdikosol S; Liu Y C; Mérida L B; Cruz-Muñoz M E; Oceguera-Yañez F; Burakoff S J; Rosenstein Y (January 2001). "Regulation of Cbl molecular interactions by the co-receptor molecule CD43 in human T cells". J. Biol. Chem. (UNITED STATES) 276 (1): 729–37.  
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  66. ^ Meng, W; Sawasdikosol S; Burakoff S J; Eck M J (March 1999). "Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase".  

Further reading

External links

  • Quips article describing CBL function at PDBe
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