Lck

S Wikipedije, slobodne enciklopedije
Lck
Dostupne strukture
PDBPretraga ortologa: E9PI33 PDBe E9PI33 RCSB
Spisak PDB ID kodova

1BHF, 1BHH, 1CWD, 1CWE, 1FBZ, 1H92, 1IJR, 1KIK, 1LCJ, 1LCK, 1LKK, 1LKL, 1Q68, 1Q69, 1QPC, 1QPD, 1QPE, 1QPJ, 1X27, 2IIM, 2OF2, 2OF4, 2OFU, 2OFV, 2OG8, 2PL0, 2ZM1, 2ZM4, 2ZYB, 3AC1, 3AC2, 3AC3, 3AC4, 3AC5, 3AC8, 3ACJ, 3ACK, 3AD4, 3AD5, 3AD6, 3B2W, 3BRH, 3BYM, 3BYO, 3BYS, 3BYU, 3KMM, 3KXZ, 3LCK, 3MPM, 4D8K, 4C3F

Identifikatori
AliasiLCK
Vanjski ID-jeviOMIM: 153390 MGI: 96756 HomoloGene: 3911 GeneCards: LCK
Lokacija gena (čovjek)
Hromosom 1 (čovjek)
Hrom.Hromosom 1 (čovjek)[1]
Hromosom 1 (čovjek)
Genomska lokacija za Lck
Genomska lokacija za Lck
Bend1p35.2Početak32,251,239 bp[1]
Kraj32,286,165 bp[1]
Lokacija gena (miš)
Hromosom 4 (miš)
Hrom.Hromosom 4 (miš)[2]
Hromosom 4 (miš)
Genomska lokacija za Lck
Genomska lokacija za Lck
Bend4 D2.2|4 63.26 cMPočetak129,442,137 bp[2]
Kraj129,467,434 bp[2]
Obrazac RNK ekspresije


Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija• aktivnost sa transferazom
• nucleotide binding
• protein kinase activity
• CD4 receptor binding
• ATPase binding
• SH2 domain binding
• CD8 receptor binding
• phosphatidylinositol 3-kinase binding
• protein C-terminus binding
• GO:0001948, GO:0016582 vezivanje za proteine
• vezivanje identičnih proteina
• protein phosphatase binding
• ATP binding
• protein kinase binding
• phosphatidylinositol-4,5-bisphosphate 3-kinase activity
• kinase activity
• protein serine/threonine phosphatase activity
• non-membrane spanning protein tyrosine kinase activity
• phosphotyrosine residue binding
• protein tyrosine kinase activity
• T cell receptor binding
• signaling receptor binding
Ćelijska komponenta• citoplazma
• citosol
• membrana
• extrinsic component of cytoplasmic side of plasma membrane
• immunological synapse
• Egzosom
• pericentriolar material
• Lipidni splav
• ćelijska membrana
Biološki proces• B cell receptor signaling pathway
• release of sequestered calcium ion into cytosol
• Hematopoeza
• Fosforilacija
• transmembrane receptor protein tyrosine kinase signaling pathway
• positive regulation of T cell receptor signaling pathway
• T cell costimulation
• GO:0019049, GO:0030683 mitigation of host defenses by virus
• platelet activation
• T cell differentiation
• regulation of cell population proliferation
• cellular zinc ion homeostasis
• regulation of lymphocyte activation
• peptidyl-tyrosine autophosphorylation
• T cell receptor signaling pathway
• positive regulation of intrinsic apoptotic signaling pathway
• leukocyte migration
• positive regulation of T cell activation
• GO:0016576 protein dephosphorylation
• Urođeni imunski sistem
• phosphatidylinositol phosphate biosynthetic process
• GO:0022415 viral process
• protein phosphorylation
• activation of cysteine-type endopeptidase activity involved in apoptotic process
• Ćelijska migracija
• peptidyl-tyrosine phosphorylation
• interleukin-7-mediated signaling pathway
• positive regulation of protein kinase B signaling
• Ćelijska diferencijacija
• positive regulation of heterotypic cell-cell adhesion
• positive regulation of leukocyte cell-cell adhesion
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez

3932

16818

Ensembl

ENSG00000182866

ENSMUSG00000000409

UniProt

P06239

P06240

RefSeq (mRNK)

NM_001042771
NM_005356
NM_001330468

NM_001162432
NM_001162433
NM_010693

RefSeq (bjelančevina)

NP_001036236
NP_001317397
NP_005347

NP_001155904
NP_001155905
NP_034823

Lokacija (UCSC)Chr 1: 32.25 – 32.29 MbChr 4: 129.44 – 129.47 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Lck ili limfocitno-specifična protein tirozin-kinaza jest 56-kDa enzim koji je kod ljudi kodiran genom sa hromosoma 1. Ovaj protein nalazi se unutar specijalizoiranih ćelija imunskog sistema zvanih limfociti. Lck je tirozin-kinaza, koja fosforilizira tirozinske ostatke određenih proteina uključenih u unutarćelijske signalne puteve ovih limfocita. Član je Src porodice tirozin-kinaza.

Funkcija Lck je proučavana korištenjem nekoliko biokemijskih metoda, uključujući genski nokaut (nokaut-miševe), Jurkat-ćelije deficitarne Lck (JCaM1.6) i siRNK posredovane interferencije RNK.

Aminokiselinska sekvenca[uredi | uredi izvor]

Dužina polipeptidnog lanca je 509 aminokiselina, a molekulska težina 58.001 Da.[5]

1020304050
MGCGCSSHPEDDWMENIDVCENCHYPIVPLDGKGTLLIRNGSEVRDPLVT
YEGSNPPASPLQDNLVIALHSYEPSHDGDLGFEKGEQLRILEQSGEWWKA
QSLTTGQEGFIPFNFVAKANSLEPEPWFFKNLSRKDAERQLLAPGNTHGS
FLIRESESTAGSFSLSVRDFDQNQGEVVKHYKIRNLDNGGFYISPRITFP
GLHELVRHYTNASDGLCTRLSRPCQTQKPQKPWWEDEWEVPRETLKLVER
LGAGQFGEVWMGYYNGHTKVAVKSLKQGSMSPDAFLAEANLMKQLQHQRL
VRLYAVVTQEPIYIITEYMENGSLVDFLKTPSGIKLTINKLLDMAAQIAE
GMAFIEERNYIHRDLRAANILVSDTLSCKIADFGLARLIEDNEYTAREGA
KFPIKWTAPEAINYGTFTIKSDVWSFGILLTEIVTHGRIPYPGMTNPEVI
QNLERGYRMVRPDNCPEELYQLMRLCWKERPEDRPTFDYLRSVLEDFFTA
TEGQYQPQP

Struktura[uredi | uredi izvor]

Lck je 56-kD-ski protein. N-terminalni rep Lck je miristoiliran i palmitoiliran, koji vezuje protein za ćelijsku plazmamembranu. Protein dalje sadrži SH3-domen, SH2-domen i u C-terminalnom dijelu domen tirozin-kinaza. Dva glavna mjesta fosforilacije na Lck su tirozini 394 i 505. Prvo je autofosforilaciono mjesto i povezano je sa aktivacijom proteina. Potonje je fosforilirano pomoću Csk, koja inhibira Lck jer se protein savija i vezuje za sopstveni SH2-domen. Lck stoga služi kao poučan primjer da fosforilacija proteina može rezultirati i aktivacijom i inhibicijom.

T-ćelijska signalizacija[uredi | uredi izvor]

Lck se najčešće nalazi u T-ćelijaama. Povezuje se sa citoplazmatskim repovima CD4 i CD8 koreceptora na T-pomoćnim ćelijama i citotoksičnim T-ćelijama,[6][7] za pomoć pri prenosu signala iz kompleksa T-ćelijskih receptora (TCR). Kada je T-ćelijski receptor zahvaćen specifičnim antigenom predstavljenim MHC, Lck djeluje da fosforilira unutarćelijske lance CD3 i CD3-zeta (ζ-lanci) TCR kompleksa, omogućavajući još jednu citoplazmatsku tirozin-kinazu, zvanu ZAP-70, da se veže za njih. Lck zatim fosforilira i aktivira ZAP-70, koji zauzvrat fosforilira drugu molekulu u signalnoj kaskadi zvanoj LAT (skraćeno od Linker za aktivaciju T-ćelija), transmembranski protein koji služi kao mjesto vezanja brojnih drugih proteina, od kojih su najvažniji Shc-Grb2-SOS, PI3K i fosfolipaza C ( PLC). Dodatno, nakon aktivacije T-ćelija, dio aktivnog Lck kinaze, translocira se izvan lipidnog splava (LR) u unutrašnjih lipidnih splavova, gdje stupa u interakciju sa i aktivira LR-rezidentni Fyn, koji uključen je u dalju aktivaciju nizvodne signalizacije.[8][9]

Fosforilacija tirozinske kaskade koju su pokrenuli Lck i Fyn kulminira unutarćelijskom mobilizacijom kalcijevih (Ca2+) iona i aktivacijom važne signalizacije kaskade unutar limfocita. To uključuje Ras-MEK-ERK puta, koji dalje aktivira određene transkripcijski faktor, kao što su NFAT, NF-κB i AP-1. Ovi faktori transkripcije regulišu proizvodnju pletora genskih proizvoda, najistaknutijih, citokina, kao što je interleukin-2 koji promoviraju dugotrajnu proliferaciju i diferencijaciju aktiviranih limfocita. Pored značaja Lck i Fyn u signalizaciji receptora T-ćelija, pokazalo se da su ove dvije src kinaze važne u TLR-posredovanoj signalizaciji u T-ćelijama.[10]

Podloge[uredi | uredi izvor]

Lck tirozin fosforilira brojne proteine, od kojih su najvažniji CD3-receptor, CEACAM1, ZAP-70, SLP-76, IL-2 receptor, Protein kinaza C, ITK, PLC, Src dvodomenska homologija (SHC), RasGAP , Cbl, Vav1 i PI3K.

Inhibicija[uredi | uredi izvor]

U T-ćelijama u mirovanju, Lck je konstitutivno inhibiran fosforilacijom Csk na tirozinu 505. Lck je također inhibiran defosforilacijom SHP-1 na tirozinu 394. Lck također može biti inhibiran pomoću Cbl ubikvitin-ligaze, koja je dio ubikvitinom-posredovanog puta.[11]

Saraktinib, specifični inhibitor LCK, narušava održavanje ljudskih T-ALL ćelija in vitro kao i in vivo ciljajući ovu tirozin-kinazu u ćelije koje pokazuju visok nivo lipidnih splavova.[12]

Masitinib također inhibira Lck, što može imati određeni uticaj na njegove terapeutske efekte kod mastocitoma.[13]

Opisano je da inhibitor HSP90 NVP-BEP800 utiče na stabilnost LCK kinaze i rast T-ćelija akutne limfoblastne leukemije.[14]

Interakcije[uredi | uredi izvor]

Pokazalo se da Lck interraguje sa:

Također pogledajte[uredi | uredi izvor]

Reference[uredi | uredi izvor]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000182866 - Ensembl, maj 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000000409 - Ensembl, maj 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "UniProt, P06239" (jezik: eng.). Pristupljeno 29. 11. 2021.CS1 održavanje: nepoznati jezik (link)
  6. ^ Rudd CE, Trevillyan JM, Dasgupta JD, Wong LL, Schlossman SF (juli 1988). "The CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes". Proceedings of the National Academy of Sciences of the United States of America. 85 (14): 5190–4. Bibcode:1988PNAS...85.5190R. doi:10.1073/pnas.85.14.5190. PMC 281714. PMID 2455897.
  7. ^ Barber EK, Dasgupta JD, Schlossman SF, Trevillyan JM, Rudd CE (maj 1989). "The CD4 and CD8 antigens are coupled to a protein-tyrosine kinase (p56lck) that phosphorylates the CD3 complex". Proceedings of the National Academy of Sciences of the United States of America. 86 (9): 3277–81. Bibcode:1989PNAS...86.3277B. doi:10.1073/pnas.86.9.3277. PMC 287114. PMID 2470098.
  8. ^ Filipp D, Zhang J, Leung BL, Shaw A, Levin SD, Veillette A, Julius M (maj 2003). "Regulation of Fyn through translocation of activated Lck into lipid rafts". The Journal of Experimental Medicine. 197 (9): 1221–7. doi:10.1084/jem.20022112. PMC 2193969. PMID 12732664.
  9. ^ Filipp D, Moemeni B, Ferzoco A, Kathirkamathamby K, Zhang J, Ballek O, Davidson D, Veillette A, Julius M (septembar 2008). "Lck-dependent Fyn activation requires C terminus-dependent targeting of kinase-active Lck to lipid rafts". The Journal of Biological Chemistry. 283 (39): 26409–22. doi:10.1074/jbc.M710372200. PMC 3258908. PMID 18660530.
  10. ^ Sharma N, Akhade AS, Qadri A (april 2016). "Src kinases central to T-cell receptor signaling regulate TLR-activated innate immune responses from human T cells". Innate Immunity. 22 (3): 238–244. doi:10.1177/1753425916632305. PMID 26888964.
  11. ^ Rao N, Miyake S, Reddi AL, Douillard P, Ghosh AK, Dodge IL, Zhou P, Fernandes ND, Band H (mart 2002). "Negative regulation of Lck by Cbl ubiquitin ligase". Proceedings of the National Academy of Sciences of the United States of America. 99 (6): 3794–9. Bibcode:2002PNAS...99.3794R. doi:10.1073/pnas.062055999. PMC 122603. PMID 11904433.
  12. ^ Buffière A, Accogli T, Saint-Paul L, Lucchi G, Uzan B, Ballerini P, Bastie JN, Delva L, Pflumio F, Quéré R (februar 2018). "Saracatinib impairs maintenance of human T-ALL by targeting the LCK tyrosine kinase in cells displaying high level of lipid rafts". Leukemia. 32 (9): 2062–2065. doi:10.1038/s41375-018-0081-5. PMID 29535432. S2CID 3833020.
  13. ^ Gil da Costa RM (juli 2015). "C-kit as a prognostic and therapeutic marker in canine cutaneous mast cell tumours: From laboratory to clinic" (PDF). Veterinary Journal. 205 (1): 5–10. doi:10.1016/j.tvjl.2015.05.002. hdl:10216/103345. PMID 26021891. Arhivirano s originala (PDF), 29. 11. 2021. Pristupljeno 29. 11. 2021.
  14. ^ Mshaik R, Simonet J, Georgievski A, Jamal L, Bechoua S, Ballerini P, Bellaye PS, Mlamla Z, Pais de Barros JP, Geissler A, Francin PJ, Girodon F, Garrido C, Quéré R (mart 2021). "HSP90 inhibitor NVP-BEP800 affects stability of SRC kinases and growth of T-cell and B-cell acute lymphoblastic leukemias". Blood Cancer J. 3 (11): 61. doi:10.1038/s41408-021-00450-2. PMC 7973815. PMID 33737511.
  15. ^ Poghosyan Z, Robbins SM, Houslay MD, Webster A, Murphy G, Edwards DR (februar 2002). "Phosphorylation-dependent interactions between ADAM15 cytoplasmic domain and Src family protein-tyrosine kinases". The Journal of Biological Chemistry. 277 (7): 4999–5007. doi:10.1074/jbc.M107430200. PMID 11741929.
  16. ^ Bell GM, Fargnoli J, Bolen JB, Kish L, Imboden JB (januar 1996). "The SH3 domain of p56lck binds to proline-rich sequences in the cytoplasmic domain of CD2". The Journal of Experimental Medicine. 183 (1): 169–78. doi:10.1084/jem.183.1.169. PMC 2192399. PMID 8551220.
  17. ^ Taher TE, Smit L, Griffioen AW, Schilder-Tol EJ, Borst J, Pals ST (februar 1996). "Signaling through CD44 is mediated by tyrosine kinases. Association with p56lck in T lymphocytes". The Journal of Biological Chemistry. 271 (5): 2863–7. doi:10.1074/jbc.271.5.2863. PMID 8576267.
  18. ^ Ilangumaran S, Briol A, Hoessli DC (maj 1998). "CD44 selectively associates with active Src family protein tyrosine kinases Lck and Fyn in glycosphingolipid-rich plasma membrane domains of human peripheral blood lymphocytes". Blood. 91 (10): 3901–8. doi:10.1182/blood.V91.10.3901. PMID 9573028.
  19. ^ Hawash IY, Hu XE, Adal A, Cassady JM, Geahlen RL, Harrison ML (april 2002). "The oxygen-substituted palmitic acid analogue, 13-oxypalmitic acid, inhibits Lck localization to lipid rafts and T cell signaling". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1589 (2): 140–50. doi:10.1016/s0167-4889(02)00165-9. PMID 12007789.
  20. ^ Foti M, Phelouzat MA, Holm A, Rasmusson BJ, Carpentier JL (februar 2002). "p56Lck anchors CD4 to distinct microdomains on microvilli". Proceedings of the National Academy of Sciences of the United States of America. 99 (4): 2008–13. Bibcode:2002PNAS...99.2008F. doi:10.1073/pnas.042689099. PMC 122310. PMID 11854499.
  21. ^ Marcus SL, Winrow CJ, Capone JP, Rachubinski RA (novembar 1996). "A p56(lck) ligand serves as a coactivator of an orphan nuclear hormone receptor". The Journal of Biological Chemistry. 271 (44): 27197–200. doi:10.1074/jbc.271.44.27197. PMID 8910285.
  22. ^ Hanada T, Lin L, Chandy KG, Oh SS, Chishti AH (oktobar 1997). "Human homologue of the Drosophila discs large tumor suppressor binds to p56lck tyrosine kinase and Shaker type Kv1.3 potassium channel in T lymphocytes". The Journal of Biological Chemistry. 272 (43): 26899–904. doi:10.1074/jbc.272.43.26899. PMID 9341123.
  23. ^ a b Sade H, Krishna S, Sarin A (januar 2004). "The anti-apoptotic effect of Notch-1 requires p56lck-dependent, Akt/PKB-mediated signaling in T cells". The Journal of Biological Chemistry. 279 (4): 2937–44. doi:10.1074/jbc.M309924200. PMID 14583609.
  24. ^ Prasad KV, Kapeller R, Janssen O, Repke H, Duke-Cohan JS, Cantley LC, Rudd CE (decembar 1993). "Phosphatidylinositol (PI) 3-kinase and PI 4-kinase binding to the CD4-p56lck complex: the p56lck SH3 domain binds to PI 3-kinase but not PI 4-kinase". Molecular and Cellular Biology. 13 (12): 7708–17. doi:10.1128/mcb.13.12.7708. PMC 364842. PMID 8246987.
  25. ^ Yu CL, Jin YJ, Burakoff SJ (januar 2000). "Cytosolic tyrosine dephosphorylation of STAT5. Potential role of SHP-2 in STAT5 regulation". The Journal of Biological Chemistry. 275 (1): 599–604. doi:10.1074/jbc.275.1.599. PMID 10617656.
  26. ^ Chiang GG, Sefton BM (juni 2001). "Specific dephosphorylation of the Lck tyrosine protein kinase at Tyr-394 by the SHP-1 protein-tyrosine phosphatase". The Journal of Biological Chemistry. 276 (25): 23173–8. doi:10.1074/jbc.M101219200. PMID 11294838.
  27. ^ Lorenz U, Ravichandran KS, Pei D, Walsh CT, Burakoff SJ, Neel BG (mart 1994). "Lck-dependent tyrosyl phosphorylation of the phosphotyrosine phosphatase SH-PTP1 in murine T cells". Molecular and Cellular Biology. 14 (3): 1824–34. doi:10.1128/mcb.14.3.1824. PMC 358540. PMID 8114715.
  28. ^ Koretzky GA, Kohmetscher M, Ross S (april 1993). "CD45-associated kinase activity requires lck but not T cell receptor expression in the Jurkat T cell line". The Journal of Biological Chemistry. 268 (12): 8958–64. doi:10.1016/S0021-9258(18)52965-3. PMID 8473339.
  29. ^ Ng DH, Watts JD, Aebersold R, Johnson P (januar 1996). "Demonstration of a direct interaction between p56lck and the cytoplasmic domain of CD45 in vitro". The Journal of Biological Chemistry. 271 (3): 1295–300. doi:10.1074/jbc.271.3.1295. PMID 8576115.
  30. ^ Gorska MM, Stafford SJ, Cen O, Sur S, Alam R (februar 2004). "Unc119, a novel activator of Lck/Fyn, is essential for T cell activation". The Journal of Experimental Medicine. 199 (3): 369–79. doi:10.1084/jem.20030589. PMC 2211793. PMID 14757743.
  31. ^ a b Thome M, Duplay P, Guttinger M, Acuto O (juni 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. PMID 7539035.
  32. ^ Oda H, Kumar S, Howley PM (august 1999). "Regulation of the Src family tyrosine kinase Blk through E6AP-mediated ubiquitination". Proceedings of the National Academy of Sciences of the United States of America. 96 (17): 9557–62. Bibcode:1999PNAS...96.9557O. doi:10.1073/pnas.96.17.9557. PMC 22247. PMID 10449731.
  33. ^ Pelosi M, Di Bartolo V, Mounier V, Mège D, Pascussi JM, Dufour E, Blondel A, Acuto O (maj 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.

Dopunska literatura[uredi | uredi izvor]

Vanjski linkovi[uredi | uredi izvor]

Portal iconPortal Biologija
Preuzeto iz "https://bs.wikipedia.org/w/index.php?title=Lck&oldid=3504702"