TYRP1 explained

Tyrosinase-related protein 1, also known as TYRP1, is an intermembrane enzyme which in humans is encoded by the TYRP1 gene.^[1]

Function

Tyrp1 is a melanocyte-specific gene product involved in melanin synthesis within melanosomes.^[2] Most Tyrp1 possess 5,6-dihydroxyindole-2-carboxylic acid (melanogenic intermediate) oxidase activity.^[3] The catalytic function of Tyrp1 in human melanocytes is less clear. Tyrp1 is involved in stabilizing of tyrosinase protein and modulating its catalytic activity. Tyrp1 is also involved in maintenance of melanosome structure and affects melanocyte proliferation and melanocyte cell death.^[4] Melanocytes are derived from the neural crest and migrate into the overlying epidermal ectoderm of a developing organism which forms skin and hair.^[5] Therefore, Tyrp1 influences the expression of melanin notably in the skin and hair of an organism.

The Tyrp1 gene also has a non-coding function which indirectly promotes melanoma tumor cell proliferation, especially when highly expressed in a cell.^[6] Tyrp1 mRNA interacts with miR-16 and affects its ability to repress genes involved in melanoma cell production.

Clinical significance

Mutations in the mouse Tyrp1 gene are associated with brown pelage and in the human TYRP1 gene with oculocutaneous albinism type 3 (OCA3).^[4] An allele of TYRP1 common in Solomon Islanders results in blond hair. Although the phenotype is similar to Northern European blond hair, this allele is not found in Europeans.^{[7] [8]} More recent study, Ju et al. 2020 found TYRP1 allele was selected in European population.^[9]

Norton et al. 2016 study found TYRP1 is not associated with blond hair color in Melanesians as many populations in Oceania did not carry TYRP1 alleles but still displayed blondism, study indicates that additional unknown alleles contribute to the blondism phenotype in Melanesians.^[10]

Alterations of the Tyrp1 gene is responsible for some of the differing phenotypes of skin and coat appearance in various animals. In Dalmatians, black versus "liver" spot color is due to genetic variation of the TYRP1 gene.^[11] A particular deletion in the Tyrp1 gene of domestic Chinese-Tibetan swine results in a "brown coloration" of the swine's skin and hair as opposed to the wild-type "black" phenotype.^[12] In Oujiang-color carp, mutations of the Tyrp1 gene influenced the expression of "grey" or "brown" phenotypic color of scales.^[13]

Elevated levels of Tyrp1 gene expression is also associated with unfavorable patient outcome of those affected by melanoma. The role of Tyrp1 in melanoma progression was determined by comparing "knockout" cell lines which have inactive Tyrp1 to cells with normal and highly expressed Tyrp1. Such studies provide insight to possible clinical usage and treatment of melanoma via regulation of Tyrp1 expression in cells.

Regulation

The expression of TYRP1 is regulated by the microphthalmia-associated transcription factor (MITF).^{[14] [15]}

Interactions

TYRP1 has been shown to interact with GIPC1.^[16]

See also

• Dopachrome tautomerase (DCT; also known as TYRP2)

Further reading

• Sarangarajan R, Boissy RE . Tyrp1 and oculocutaneous albinism type 3 . Pigment Cell Research . 14 . 6 . 437–444 . December 2001 . 11775055 . 10.1034/j.1600-0749.2001.140603.x . free .
• Lowings P, Yavuzer U, Goding CR . Positive and negative elements regulate a melanocyte-specific promoter . Molecular and Cellular Biology . 12 . 8 . 3653–3662 . August 1992 . 1321344 . 364632 . 10.1128/MCB.12.8.3653 .
• Shibata K, Takeda K, Tomita Y, Tagami H, Shibahara S . Downstream region of the human tyrosinase-related protein gene enhances its promoter activity . Biochemical and Biophysical Research Communications . 184 . 2 . 568–575 . April 1992 . 1575733 . 10.1016/0006-291X(92)90627-W .
• Murty VV, Bouchard B, Mathew S, Vijayasaradhi S, Houghton AN . Assignment of the human TYRP (brown) locus to chromosome region 9p23 by nonradioactive in situ hybridization . Genomics . 13 . 1 . 227–229 . May 1992 . 1577487 . 10.1016/0888-7543(92)90228-K .
• Colman MA, Shibahara S, Kwon B, Jenkins T, Ramsay M . A two allele XbaI RFLP at the catalase 2 locus . Nucleic Acids Research . 19 . 4 . 960 . February 1991 . 1673236 . 333744 . 10.1093/nar/19.4.960-a .
• Halaban R, Moellmann G . Murine and human b locus pigmentation genes encode a glycoprotein (gp75) with catalase activity . Proceedings of the National Academy of Sciences of the United States of America . 87 . 12 . 4809–4813 . June 1990 . 1693779 . 54207 . 10.1073/pnas.87.12.4809 . free . 1990PNAS...87.4809H .
• Abbott C, Jackson IJ, Carritt B, Povey S . The human homolog of the mouse brown gene maps to the short arm of chromosome 9 and extends the known region of homology with mouse chromosome 4 . Genomics . 11 . 2 . 471–473 . October 1991 . 1769662 . 10.1016/0888-7543(91)90160-G .
• Chintamaneni CD, Ramsay M, Colman MA, Fox MF, Pickard RT, Kwon BS . Mapping the human CAS2 gene, the homologue of the mouse brown (b) locus, to human chromosome 9p22-pter . Biochemical and Biophysical Research Communications . 178 . 1 . 227–235 . July 1991 . 1906272 . 10.1016/0006-291X(91)91803-K .
• Urquhart A . Human tyrosinase-like protein (TYRL) carboxy terminus: closer homology with the mouse protein than previously reported . Nucleic Acids Research . 19 . 20 . 5803 . October 1991 . 1945866 . 329017 . 10.1093/nar/19.20.5803 .
• Cohen T, Muller RM, Tomita Y, Shibahara S . Nucleotide sequence of the cDNA encoding human tyrosinase-related protein . Nucleic Acids Research . 18 . 9 . 2807–2808 . May 1990 . 2111010 . 330768 . 10.1093/nar/18.9.2807 .
• Vijayasaradhi S, Bouchard B, Houghton AN . The melanoma antigen gp75 is the human homologue of the mouse b (brown) locus gene product . The Journal of Experimental Medicine . 171 . 4 . 1375–1380 . April 1990 . 2324688 . 2187848 . 10.1084/jem.171.4.1375 .
• Box NF, Sturm RA . Dinucleotide repeat polymorphism at the human TYRP1 locus . Human Molecular Genetics . 3 . 12 . 2270 . December 1994 . 7881448 . 10.1093/hmg/3.12.2270 .
• Orlow SJ, Zhou BK, Chakraborty AK, Drucker M, Pifko-Hirst S, Pawelek JM . High-molecular-weight forms of tyrosinase and the tyrosinase-related proteins: evidence for a melanogenic complex . The Journal of Investigative Dermatology . 103 . 2 . 196–201 . August 1994 . 8040609 . 10.1111/1523-1747.ep12392743 . free .
• Sturm RA, O'Sullivan BJ, Box NF, Smith AG, Smit SE, Puttick ER, Parsons PG, Dunn IS . 6 . Chromosomal structure of the human TYRP1 and TYRP2 loci and comparison of the tyrosinase-related protein gene family . Genomics . 29 . 1 . 24–34 . September 1995 . 8530077 . 10.1006/geno.1995.1211 .
• Boissy RE, Zhao H, Oetting WS, Austin LM, Wildenberg SC, Boissy YL, Zhao Y, Sturm RA, Hearing VJ, King RA, Nordlund JJ . 6 . Mutation in and lack of expression of tyrosinase-related protein-1 (TRP-1) in melanocytes from an individual with brown oculocutaneous albinism: a new subtype of albinism classified as "OCA3" . American Journal of Human Genetics . 58 . 6 . 1145–1156 . June 1996 . 8651291 . 1915069 .
• Manga P, Kromberg JG, Box NF, Sturm RA, Jenkins T, Ramsay M . Rufous oculocutaneous albinism in southern African Blacks is caused by mutations in the TYRP1 gene . American Journal of Human Genetics . 61 . 5 . 1095–1101 . November 1997 . 9345097 . 1716031 . 10.1086/301603 .
• Box NF, Wyeth JR, Mayne CJ, O'Gorman LE, Martin NG, Sturm RA . Complete sequence and polymorphism study of the human TYRP1 gene encoding tyrosinase-related protein 1 . Mammalian Genome . 9 . 1 . 50–53 . January 1998 . 9434945 . 10.1007/s003359900678 . 10020827 .
• Bertolotto C, Buscà R, Abbe P, Bille K, Aberdam E, Ortonne JP, Ballotti R . Different cis-acting elements are involved in the regulation of TRP1 and TRP2 promoter activities by cyclic AMP: pivotal role of M boxes (GTCATGTGCT) and of microphthalmia . Molecular and Cellular Biology . 18 . 2 . 694–702 . February 1998 . 9447965 . 108780 . 10.1128/mcb.18.2.694 .
• Abe T, Sato M, Tamai M . Dedifferentiation of the retinal pigment epithelium compared to the proliferative membranes of proliferative vitreoretinopathy . Current Eye Research . 17 . 12 . 1103–1109 . December 1998 . 9872531 . 10.1076/ceyr.17.12.1103.5126 .
• Commo S, Bernard BA . Melanocyte subpopulation turnover during the human hair cycle: an immunohistochemical study . Pigment Cell Research . 13 . 4 . 253–259 . August 2000 . 10952393 . 10.1034/j.1600-0749.2000.130407.x .

Notes and References

1. Box NF, Wyeth JR, Mayne CJ, O'Gorman LE, Martin NG, Sturm RA . Complete sequence and polymorphism study of the human TYRP1 gene encoding tyrosinase-related protein 1 . Mammalian Genome . 9 . 1 . 50–53 . January 1998 . 9434945 . 10.1007/s003359900678 . 10020827 .
2. Kobayashi T, Imokawa G, Bennett DC, Hearing VJ . Tyrosinase stabilization by Tyrp1 (the brown locus protein) . The Journal of Biological Chemistry . 273 . 48 . 31801–31805 . November 1998 . 9822646 . 10.1074/jbc.273.48.31801 . free .
3. Jiménez-Cervantes C, Solano F, Kobayashi T, Urabe K, Hearing VJ, Lozano JA, García-Borrón JC . A new enzymatic function in the melanogenic pathway. The 5,6-dihydroxyindole-2-carboxylic acid oxidase activity of tyrosinase-related protein-1 (TRP1) . The Journal of Biological Chemistry . 269 . 27 . 17993–18000 . July 1994 . 10.1016/S0021-9258(17)32408-0 . 8027058 . free .
4. Sarangarajan R, Boissy RE . Tyrp1 and oculocutaneous albinism type 3 . Pigment Cell Research . 14 . 6 . 437–444 . December 2001 . 11775055 . 10.1034/j.1600-0749.2001.140603.x . free .
5. Mayer TC . The migratory pathway of neural crest cells into the skin of mouse embryos . Developmental Biology . 34 . 1 . 39–46 . September 1973 . 4595498 . 10.1016/0012-1606(73)90337-0 .
6. Gilot D, Migault M, Bachelot L, Journé F, Rogiers A, Donnou-Fournet E, Mogha A, Mouchet N, Pinel-Marie ML, Mari B, Montier T, Corre S, Gautron A, Rambow F, El Hajj P, Ben Jouira R, Tartare-Deckert S, Marine JC, Felden B, Ghanem G, Galibert MD . 6 . A non-coding function of TYRP1 mRNA promotes melanoma growth . Nature Cell Biology . 19 . 11 . 1348–1357 . November 2017 . 28991221 . 10.1038/ncb3623 . 23539385 .
7. News: Another Genetic Quirk of the Solomon Islands: Blond Hair . Bhanoo SN . The New York Times . 3 May 2012 . 3 May 2012.
8. Kenny EE, Timpson NJ, Sikora M, Yee MC, Moreno-Estrada A, Eng C, Huntsman S, Burchard EG, Stoneking M, Bustamante CD, Myles S . 6 . Melanesian blond hair is caused by an amino acid change in TYRP1 . Science . 336 . 6081 . 554 . May 2012 . 22556244 . 3481182 . 10.1126/science.1217849 . 2012Sci...336..554K .
9. Ju . Dan . Mathieson . Iain . The evolution of skin pigmentation-associated variation in West Eurasia . Proceedings of the National Academy of Sciences of the United States of America . December 21, 2020 . 118 . 1 . 10.1073/pnas.2009227118 . 33443182 . 7817156 . free .
10. Norton HL, Hanna M, Werren E, Friedlaender J . The rs387907171 SNP in TYRP1 is not associated with blond hair color on the Island of Bougainville . American Journal of Human Biology . 28 . 3 . 431–435 . May 2016 . 26450459 . 10.1002/ajhb.22795 . 13727757 .
11. Cargill EJ, Famula TR, Schnabel RD, Strain GM, Murphy KE . The color of a Dalmatian's spots: linkage evidence to support the TYRP1 gene . BMC Veterinary Research . 1 . 1 . 1 . July 2005 . 16045797 . 1192828 . 10.1186/1746-6148-1-1 . free .
12. Ren J, Mao H, Zhang Z, Xiao S, Ding N, Huang L . A 6-bp deletion in the TYRP1 gene causes the brown colouration phenotype in Chinese indigenous pigs . Heredity . 106 . 5 . 862–868 . May 2011 . 20978532 . 3186233 . 10.1038/hdy.2010.129 .
13. Chen H, Wang J, Du J, Mandal BK, Si Z, Xu X, Yang H, Wang C . 6 . Analysis of recently duplicated TYRP1 genes and their effect on the formation of black patches in Oujiang-color common carp (Cyprinus carpio var. color) . Animal Genetics . 52 . 4 . 451–460 . August 2021 . 33939849 . 10.1111/age.13071 . 233720032 .
14. Fang D, Tsuji Y, Setaluri V . Selective down-regulation of tyrosinase family gene TYRP1 by inhibition of the activity of melanocyte transcription factor, MITF . Nucleic Acids Research . 30 . 14 . 3096–3106 . July 2002 . 12136092 . 135745 . 10.1093/nar/gkf424 .
15. Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E . 6 . Novel MITF targets identified using a two-step DNA microarray strategy . Pigment Cell & Melanoma Research . 21 . 6 . 665–676 . December 2008 . 19067971 . 10.1111/j.1755-148X.2008.00505.x . free .
16. Liu TF, Kandala G, Setaluri V . PDZ domain protein GIPC interacts with the cytoplasmic tail of melanosomal membrane protein gp75 (tyrosinase-related protein-1) . The Journal of Biological Chemistry . 276 . 38 . 35768–35777 . September 2001 . 11441007 . 10.1074/jbc.M103585200 . free .