ZAP70

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ZAP70
Struktur yang tersedia
PDBPencarian Ortolog: PDBe RCSB
Pengidentifikasi
AliasZAP70, SRK, STCD, STD, TZK, ZAP-70, zeta chain of T cell receptor associated protein kinase 70kDa, zeta chain of T cell receptor associated protein kinase 70, zeta chain of T-cell receptor associated protein kinase 70, IMD48, ADMIO2
ID eksternalOMIM: 176947 MGI: 99613 HomoloGene: 839 GeneCards: ZAP70
Pola ekspresi RNA
Referensi data ekspresi selengkapnya
Ortolog
SpesiesManusiaTikus
Entrez

7535

22637

Ensembl

ENSG00000115085

ENSMUSG00000026117

UniProt

P43403

P43404

RefSeq (mRNA)

NM_001079
NM_207519
NM_001378594

NM_009539
NM_001289612
NM_001289765
NM_001289766

RefSeq (protein)

NP_001070
NP_997402
NP_001365523

NP_001276541
NP_001276694
NP_001276695
NP_033565

Lokasi (UCSC)n/aChr 1: 36.8 – 36.82 Mb
Pencarian PubMed[2][3]
Wikidata
Lihat/Sunting ManusiaLihat/Sunting Tikus

ZAP-70 (Zeta-chain-associated protein kinase 70) adalah protein yang secara normal diekspresikan dekat membran permukaan sel T dan sel pembunuh alami. Reseptor ini merupakan bagian dari reseptor sel T, dan memainkan peran penting dalam pensinyalan sel T. Berat molekul protein yaitu 70 kDa, dan merupakan anggota keluarga protein tirosin kinase.

Signifikansi klinis[sunting | sunting sumber]

ZAP-70 pada sel B digunakan sebagai penanda prognostik dalam mengidentifikasi berbagai bentuk leukemia limfositik kronis (CLL). Analisis DNA telah membedakan dua jenis utama CLL, dengan waktu bertahan hidup yang berbeda. CLL yang positif untuk marker ZAP-70 memiliki kelangsungan hidup rata-rata 8 tahun. CLL yang negatif untuk ZAP-70 memiliki kelangsungan hidup rata-rata lebih dari 25 tahun. Banyak pasien, terutama yang lebih tua, dengan penyakit yang berkembang lambat dapat dipertimbangkan tidak memerlukan perawatan apa pun selama hidup mereka.[4]

Pada lupus eritematosus sistemik, jalur reseptor Zap-70 hilang dan Syk menggantikan peran ini.[5]

Kekurangan ZAP70 menghasilkan suatu bentuk defisiensi imun. Pasien yang mempunyai kelainan pada tirosin kinase ZAP-70 menunjukkan gejala mirip SCID. Protein tirosin kinase ini merupakan protein sitosol dan berfungsi untuk meneruskan sinyal dari reseptor sel T. Pada pasien ini, jumlah sel T CD4 berada pada level normal, tetapi sel T CD8 tidak dapat berkembang. Meski demikian, sel T CD4 yang mengalami pematangan tidak dapat merespons stimuli yang normalnya dapat mengaktifkan sel melalui jalur reseptor sel T.[6]

Fungsi[sunting | sunting sumber]

Limfosit T diaktifkan oleh keterlibatan reseptor sel T dengan fragmen antigen yang diolah yang disajikan oleh sel penyaji antigen profesional (yaitu makrofag, sel dendritik, dan sel B) melalui MHC. Setelah aktivasi ini, ko-reseptor TCR CD4 atau CD8 berikatan dengan MHC, mengaktifkan ko-reseptor terkait tirosin kinase Lck. Lck memfosforilasi bagian intraseluler dari kompleks CD3 (disebut ITAM), membuat situs penempelan untuk ZAP-70. Anggota terpenting dari keluarga CD3 adalah CD3-zeta, yang diikat oleh ZAP-70. Tandem SH2-domain dari ZAP-70 digunakan oleh ITAM terfosforilasi ganda dari CD3-zeta, yang menempatkan ZAP-70 untuk memfosforilasi protein transmembran linker of activated T cells (LAT). LAT yang terfosforilasi, pada gilirannya, berfungsi sebagai tempat penemepelan sejumlah protein pemberi sinyal termasuk SLP-76. SLP-76 juga difosforilasi oleh ZAP-70, yang membutuhkan aktivasi oleh kinase famili Src.[7] Hasil akhir dari aktivasi sel T yaitu transkripsi dari beberapa produk gen yang memungkinkan sel T untuk berdiferensiasi, berkembang biak, dan mengeluarkan sejumlah sitokin.

Interaksi[sunting | sunting sumber]

ZAP-70 telah terbukti berinteraksi dengan:

Lihat juga[sunting | sunting sumber]

  • Lck
  • Syk

Bacaan lebih lanjut[sunting | sunting sumber]

  • Chan AC, Iwashima M, Turck CW, Weiss A (November 1992). "ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain". Cell. 71 (4): 649–62. doi:10.1016/0092-8674(92)90598-7. PMID 1423621. 
  • Deindl S, Kadlecek TA, Brdicka T, Cao X, Weiss A, Kuriyan J (May 2007). "Structural basis for the inhibition of tyrosine kinase activity of ZAP-70". Cell. 129 (4): 735–46. doi:10.1016/j.cell.2007.03.039. PMID 17512407. 
  • Orchard J, Ibbotson R, Best G, Parker A, Oscier D (December 2005). "ZAP-70 in B cell malignancies". Leukemia & Lymphoma. 46 (12): 1689–98. doi:10.1080/09638280500260079. PMID 16263570. 
  • Hamblin AD, Hamblin TJ (December 2005). "Functional and prognostic role of ZAP-70 in chronic lymphocytic leukaemia". Expert Opinion on Therapeutic Targets. 9 (6): 1165–78. doi:10.1517/14728222.9.6.1165. PMID 16300468. 
  • Chan AC, Iwashima M, Turck CW, Weiss A (November 1992). "ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR zeta chain". Cell. 71 (4): 649–62. doi:10.1016/0092-8674(92)90598-7. PMID 1423621. 
  • Goldman F, Jensen WA, Johnson GL, Heasley L, Cambier JC (October 1994). "gp120 ligation of CD4 induces p56lck activation and TCR desensitization independent of TCR tyrosine phosphorylation". Journal of Immunology. 153 (7): 2905–17. PMID 7522245. 
  • Isakov N, Wange RL, Burgess WH, Watts JD, Aebersold R, Samelson LE (January 1995). "ZAP-70 binding specificity to T cell receptor tyrosine-based activation motifs: the tandem SH2 domains of ZAP-70 bind distinct tyrosine-based activation motifs with varying affinity". The Journal of Experimental Medicine. 181 (1): 375–80. doi:10.1084/jem.181.1.375. PMC 2191847 alt=Dapat diakses gratis. PMID 7528772. 
  • Nel AE, Gupta S, Lee L, Ledbetter JA, Kanner SB (August 1995). "Ligation of the T-cell antigen receptor (TCR) induces association of hSos1, ZAP-70, phospholipase C-gamma 1, and other phosphoproteins with Grb2 and the zeta-chain of the TCR". The Journal of Biological Chemistry. 270 (31): 18428–36. doi:10.1074/jbc.270.31.18428. PMID 7629168. 
  • Negishi I, Motoyama N, Nakayama K, Nakayama K, Senju S, Hatakeyama S, Zhang Q, Chan AC, Loh DY (August 1995). "Essential role for ZAP-70 in both positive and negative selection of thymocytes". Nature. 376 (6539): 435–8. doi:10.1038/376435a0. PMID 7630421. 
  • Mustelin T, Williams S, Tailor P, Couture C, Zenner G, Burn P, Ashwell JD, Altman A (April 1995). "Regulation of the p70zap tyrosine protein kinase in T cells by the CD45 phosphotyrosine phosphatase". European Journal of Immunology. 25 (4): 942–6. doi:10.1002/eji.1830250413. PMID 7737297. 
  • Neumeister EN, Zhu Y, Richard S, Terhorst C, Chan AC, Shaw AS (June 1995). "Binding of ZAP-70 to phosphorylated T-cell receptor zeta and eta enhances its autophosphorylation and generates specific binding sites for SH2 domain-containing proteins". Molecular and Cellular Biology. 15 (6): 3171–8. doi:10.1128/mcb.15.6.3171. PMC 230549 alt=Dapat diakses gratis. PMID 7760813. 
  • Katzav S, Sutherland M, Packham G, Yi T, Weiss A (December 1994). "The protein tyrosine kinase ZAP-70 can associate with the SH2 domain of proto-Vav". The Journal of Biological Chemistry. 269 (51): 32579–85. PMID 7798261. 
  • Schumann G, Dasgupta JD (September 1994). "Specificity of signal transduction through CD16, TCR-CD3 and BCR receptor chains containing the tyrosine-associated activation motif". International Immunology. 6 (9): 1383–92. doi:10.1093/intimm/6.9.1383. PMID 7819147. 
  • Watts JD, Affolter M, Krebs DL, Wange RL, Samelson LE, Aebersold R (November 1994). "Identification by electrospray ionization mass spectrometry of the sites of tyrosine phosphorylation induced in activated Jurkat T cells on the protein tyrosine kinase ZAP-70". The Journal of Biological Chemistry. 269 (47): 29520–9. PMID 7961936. 
  • Ku G, Malissen B, Mattei MG (1994). "Chromosomal location of the Syk and ZAP-70 tyrosine kinase genes in mice and humans". Immunogenetics. 40 (4): 300–2. doi:10.1007/BF00189976. PMID 8082894. 
  • Chan AC, van Oers NS, Tran A, Turka L, Law CL, Ryan JC, Clark EA, Weiss A (May 1994). "Differential expression of ZAP-70 and Syk protein tyrosine kinases, and the role of this family of protein tyrosine kinases in TCR signaling". Journal of Immunology. 152 (10): 4758–66. PMID 8176201. 
  • Elder ME, Lin D, Clever J, Chan AC, Hope TJ, Weiss A, Parslow TG (June 1994). "Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase". Science. 264 (5165): 1596–9. doi:10.1126/science.8202712. PMID 8202712. 
  • Chan AC, Kadlecek TA, Elder ME, Filipovich AH, Kuo WL, Iwashima M, Parslow TG, Weiss A (June 1994). "ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency". Science. 264 (5165): 1599–601. doi:10.1126/science.8202713. PMID 8202713. 
  • Wange RL, Malek SN, Desiderio S, Samelson LE (September 1993). "Tandem SH2 domains of ZAP-70 bind to T cell antigen receptor zeta and CD3 epsilon from activated Jurkat T cells". The Journal of Biological Chemistry. 268 (26): 19797–801. PMID 8366117. 
  • Huby RD, Carlile GW, Ley SC (December 1995). "Interactions between the protein-tyrosine kinase ZAP-70, the proto-oncoprotein Vav, and tubulin in Jurkat T cells". The Journal of Biological Chemistry. 270 (51): 30241–4. doi:10.1074/jbc.270.51.30241. PMID 8530437. 
  • Plas DR, Johnson R, Pingel JT, Matthews RJ, Dalton M, Roy G, Chan AC, Thomas ML (May 1996). "Direct regulation of ZAP-70 by SHP-1 in T cell antigen receptor signaling". Science. 272 (5265): 1173–6. doi:10.1126/science.272.5265.1173. PMID 8638162. 
  • Bubeck Wardenburg J, Fu C, Jackman JK, Flotow H, Wilkinson SE, Williams DH, Johnson R, Kong G, Chan AC, Findell PR (August 1996). "Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function". The Journal of Biological Chemistry. 271 (33): 19641–4. doi:10.1074/jbc.271.33.19641. PMID 8702662. 

Pranala luar[sunting | sunting sumber]

  1. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000026117 - Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine. 
  3. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine. 
  4. ^ "Chronic lymphocytic leukemia". The New England Journal of Medicine. 352 (8): 804–15. February 2005. doi:10.1056/NEJMra041720. PMID 15728813. 
  5. ^ Tsokos, George C. (2011-12-01). "Systemic Lupus Erythematosus". New England Journal of Medicine. 365 (22): 2110–2121. doi:10.1056/NEJMra1100359. ISSN 0028-4793. PMID 22129255. 
  6. ^ Shlomchik, Mark J.; Walport, Mark; Travers, Paul; Charles A Janeway, Jr (2001). "Inherited immunodeficiency diseases". Immunobiology: The Immune System in Health and Disease. 5th edition (dalam bahasa Inggris). 
  7. ^ "Differential Requirements for Src-Family Kinases in SYK or ZAP70-Mediated SLP-76 Phosphorylation in Lymphocytes". Frontiers in Immunology. 8: 789. 2017-07-07. doi:10.3389/fimmu.2017.00789. PMC 5500614 alt=Dapat diakses gratis. PMID 28736554. 
  8. ^ Lupher ML, Reedquist KA, Miyake S, Langdon WY, Band H (September 1996). "A novel phosphotyrosine-binding domain in the N-terminal transforming region of Cbl interacts directly and selectively with ZAP-70 in T cells". The Journal of Biological Chemistry. 271 (39): 24063–8. doi:10.1074/jbc.271.39.24063. PMID 8798643. 
  9. ^ Meng W, Sawasdikosol S, Burakoff SJ, Eck MJ (March 1999). "Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase". Nature. 398 (6722): 84–90. doi:10.1038/18050. PMID 10078535. 
  10. ^ Han J, Kori R, Shui JW, Chen YR, Yao Z, Tan TH (December 2003). "The SH3 domain-containing adaptor HIP-55 mediates c-Jun N-terminal kinase activation in T cell receptor signaling". The Journal of Biological Chemistry. 278 (52): 52195–202. doi:10.1074/jbc.M305026200. PMID 14557276. 
  11. ^ Neumeister EN, Zhu Y, Richard S, Terhorst C, Chan AC, Shaw AS (June 1995). "Binding of ZAP-70 to phosphorylated T-cell receptor zeta and eta enhances its autophosphorylation and generates specific binding sites for SH2 domain-containing proteins". Molecular and Cellular Biology. 15 (6): 3171–8. doi:10.1128/mcb.15.6.3171. PMC 230549 alt=Dapat diakses gratis. PMID 7760813. 
  12. ^ Pelosi M, Di Bartolo V, Mounier V, Mège D, Pascussi JM, Dufour E, Blondel A, Acuto O (May 1999). "Tyrosine 319 in the interdomain B of ZAP-70 is a binding site for the Src homology 2 domain of Lck". The Journal of Biological Chemistry. 274 (20): 14229–37. doi:10.1074/jbc.274.20.14229. PMID 10318843. 
  13. ^ Thome M, Duplay P, Guttinger M, Acuto O (June 1995). "Syk and ZAP-70 mediate recruitment of p56lck/CD4 to the activated T cell receptor/CD3/zeta complex". The Journal of Experimental Medicine. 181 (6): 1997–2006. doi:10.1084/jem.181.6.1997. PMC 2192070 alt=Dapat diakses gratis. PMID 7539035. 
  14. ^ Paz PE, Wang S, Clarke H, Lu X, Stokoe D, Abo A (June 2001). "Mapping the Zap-70 phosphorylation sites on LAT (linker for activation of T cells) required for recruitment and activation of signalling proteins in T cells". The Biochemical Journal. 356 (Pt 2): 461–71. doi:10.1042/bj3560461. PMC 1221857 alt=Dapat diakses gratis. PMID 11368773. 
  15. ^ Perez-Villar JJ, Whitney GS, Sitnick MT, Dunn RJ, Venkatesan S, O'Day K, Schieven GL, Lin TA, Kanner SB (August 2002). "Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav". Biochemistry. 41 (34): 10732–40. doi:10.1021/bi025554o. PMID 12186560. 
  16. ^ Lindholm CK, Henriksson ML, Hallberg B, Welsh M (July 2002). "Shb links SLP-76 and Vav with the CD3 complex in Jurkat T cells". European Journal of Biochemistry. 269 (13): 3279–88. doi:10.1046/j.1432-1033.2002.03008.x. PMID 12084069. 
  17. ^ Pacini S, Ulivieri C, Di Somma MM, Isacchi A, Lanfrancone L, Pelicci PG, Telford JL, Baldari CT (August 1998). "Tyrosine 474 of ZAP-70 is required for association with the Shc adaptor and for T-cell antigen receptor-dependent gene activation". The Journal of Biological Chemistry. 273 (32): 20487–93. doi:10.1074/jbc.273.32.20487. PMID 9685404. 
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