LYN

V-yes-1 Yamaguchi sarcoma viral related oncogene homolog

PDB rendering based on 1wa7.
Identifiers
Symbols LYN; FLJ26625; JTK8
External IDs OMIM: 165120 MGI: 96892 HomoloGene: 55649 GeneCards: LYN Gene
EC number 2.7.10.2
Orthologs
Species Human Mouse
Entrez 4067 17096
Ensembl ENSG00000254087 ENSMUSG00000042228
UniProt P07948 P25911
RefSeq (mRNA) NM_001111097.1 NM_010747
RefSeq (protein) NP_001104567.1 NP_001104566
Location (UCSC) Chr 8:
56.79 – 56.92 Mb		 Chr 4:
3.61 – 3.74 Mb
PubMed search [1] [2]

Tyrosine-protein kinase Lyn is a protein that in humans is encoded in humans by the LYN gene.[1]

Lyn is a member of the Src family of protein tyrosine kinases, which is mainly expressed in hematopoietic cells,[2] in neural tissues[3] liver, and adipose tissue.[4] In various hematopoietic cells, Lyn has emerged as a key enzyme involved in the regulation of cell activation. In these cells, a small amount of LYN is associated with cell surface receptor proteins, including the B cell antigen receptor (BCR),[5][6] CD40,[7] or CD19.[8]

Contents

Function

Lyn has been described to have an inhibitory role in myeloid lineage proliferation.[9] Following engagement of the B cell receptors, Lyn undergoes rapid phosphorylation and activation. LYN activation triggers a cascade of signaling events mediated by Lyn phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the receptor proteins, and subsequent recruitment and activation of other kinases including Syk, phosholipase Cγ2 (PLCγ2) and phosphatidyl inositol-3 kinase.[8][10] These kinases provide activation signals, which play critical roles in proliferation, Ca2+ mobilization and cell differentiation. Lyn plays an essential role in the transmission of inhibitory signals through phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based inhibitory motifs (ITIM) in regulatory proteins such as CD22, PIR-B and FCγRIIb1. Their ITIM phosphorylation subsequently leads to recruitment and activation of phosphatases such as SHIP-1 and SHP-1,[11][12][13][14][15] which further downmodulate signaling pathways, attenuate cell activation and can mediate tolerance. In B cells, Lyn sets the threshold of cell signaling and maintains the balance between activation and inhibition. Lyn thus functions as a rheostat that modulates signaling rather than as a binary on-off switch.[16][17][18]

Lyn has also been implicated to have a role in the insulin signaling pathway. Activated Lyn phosphorylates insulin receptor substrate 1 (IRS1). This phosphorylation of IRS1 leads to an increase in translocation of Glut-4 to the cell membrane and increased glucose utilization.[19] In turn, activation of the insulin receptor has been shown to increase autophosphorylation of Lyn suggesting a possible feedback loop.[20] The insulin secretagogue, glimepiride (Amaryl®) activates Lyn in adipocytes via the disruption of lipid rafts [21]. This indirect Lyn activation may modulate the extrapancreatic glycemic control activity of glimepiride [21][22]

Pathology

Much of the current knowledge about Lyn has emerged from studies of genetically manipulated mice. Lyn deficient mice display a phenotype that includes splenomegaly, a dramatic increase in numbers of myeloid progenitors and moncyte/macrophage tumors. Biochemical analysis of cells from these mutants revealed that Lyn is essential in establishing ITIM-dependent inhibitory signaling and for activation of specific protein tyrosine phosphatases within myeloid cells.[9]

Mice that expressed a hyperactive Lyn allele were tumor free and displayed no propensity toward hematological malignancy. These mice have reduced numbers of conventional B lymphocytes, down-regulated surface immunoglobulin M and costimulatory molecules, and elevated numbers of B1a B cells. With age these animals developed a glomerulonephritis phenotype associated with a 30% reduction in life expectancy.[23]

Most recently LYN kinase inhibition with a novel small molecular inhibitor, bafetinib, appears to induce apoptosis in glioblastoma cells in preclinical models.

Interactions

LYN has been shown to interact with IRS1[24], PPP1R15A,[25] PLCG2,[26][27] Lymphocyte cytosolic protein 2,[28] MUC1,[29] CD117,[30][31] DOK1,[32][30] BCAR1,[33][34] TRPV4,[35] CD22,[36][37] INPP5D,[38] NEDD9,[33] GPVI,[39] Syk,[40] PTPRC,[41] Cdk1,[42][43] Erythropoietin receptor[44] and Protein unc-119 homolog.[45]

See also

References

  1. ^ Yamanashi Y, Fukushige S, Semba K, Sukegawa J, Miyajima N, Matsubara K, Yamamoto T, Toyoshima K (January 1987). "The yes-related cellular gene lyn encodes a possible tyrosine kinase similar to p56lck". Mol. Cell. Biol. 7 (1): 237–43. PMC 365062. PMID 3561390. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=365062. 
  2. ^ Yamanashi Y, Mori S, Yoshida M, et al. (September 1989). "Selective expression of a protein-tyrosine kinase, p56lyn, in hematopoietic cells and association with production of human T-cell lymphotropic virus type I". Proc. Natl. Acad. Sci. U.S.A. 86 (17): 6538–42. doi:10.1073/pnas.86.17.6538. PMC 297879. PMID 2505253. http://www.pnas.org/cgi/pmidlookup?view=long&pmid=2505253. 
  3. ^ Umemori H, Wanaka A, Kato H, Takeuchi M, Tohyama M, Yamamoto T (December 1992). "Specific expressions of Fyn and Lyn, lymphocyte antigen receptor-associated tyrosine kinases, in the central nervous system". Brain Res. Mol. Brain Res. 16 (3–4): 303–10. doi:10.1016/0169-328X(92)90239-8. PMID 1337939. 
  4. ^ Yamada E, Pessin J, Kurland I, Schwartz G, Bastie C (February 2010). "Fyn-dependent regulation of energy expediture and body weight is mediated by tyrosine phosphorylation of LKB1". Cell Metab. 11 (2): 113–124. doi:10.1016/j.cmet.2009.12.010. PMC 2830006. PMID 20142099. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2830006. 
  5. ^ Yamamoto T, Yamanashi Y, Toyoshima K (April 1993). "Association of Src-family kinase Lyn with B-cell antigen receptor". Immunol. Rev. 132: 187–206. doi:10.1111/j.1600-065X.1993.tb00843.x. PMID 8349296. 
  6. ^ Campbell MA, Sefton BM (May 1992). "Association between B-lymphocyte membrane immunoglobulin and multiple members of the Src family of protein tyrosine kinases". Mol. Cell. Biol. 12 (5): 2315–21. PMC 364403. PMID 1569953. http://mcb.asm.org/cgi/pmidlookup?view=long&pmid=1569953. 
  7. ^ Ren CL, Morio T, Fu SM, Geha RS (February 1994). "Signal transduction via CD40 involves activation of lyn kinase and phosphatidylinositol-3-kinase, and phosphorylation of phospholipase C gamma 2". J. Exp. Med. 179 (2): 673–80. doi:10.1084/jem.179.2.673. PMC 2191357. PMID 7507510. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2191357. 
  8. ^ a b Campbell 1999
  9. ^ a b Harder K, Parsons L, Ames J, Evans N, Kountouri N, Clark R, Quillici C, Grail D, Hodgson G, Dunn A, Hibbs M (October 2001). "Gain – and loss-of-function lyn mutant mice define a critical inhibitory role of lyn in the myeloid lineage". Immunity. 15 (4): 603–615. PMID 11672542. 
  10. ^ Yamanashi Y, Fukui Y, Wongsasant B, et al. (February 1992). "Activation of Src-like protein-tyrosine kinase Lyn and its association with phosphatidylinositol 3-kinase upon B-cell antigen receptor-mediated signaling". Proc. Natl. Acad. Sci. U.S.A. 89 (3): 1118–22. doi:10.1073/pnas.89.3.1118. PMC 48397. PMID 1371009. http://www.pnas.org/cgi/pmidlookup?view=long&pmid=1371009. 
  11. ^ Cornall RJ, Cyster JG, Hibbs ML, et al. (April 1998). "Polygenic autoimmune traits: Lyn, CD22, and SHP-1 are limiting elements of a biochemical pathway regulating BCR signaling and selection". Immunity 8 (4): 497–508. doi:10.1016/S1074-7613(00)80554-3. PMID 9586639. http://linkinghub.elsevier.com/retrieve/pii/S1074-7613(00)80554-3. 
  12. ^ Smith KG, Tarlinton DM, Doody GM, Hibbs ML, Fearon DT (March 1998). "Inhibition of the B cell by CD22: a requirement for Lyn". J. Exp. Med. 187 (5): 807–11. doi:10.1084/jem.187.5.807. PMC 2212179. PMID 9480991. http://www.jem.org/cgi/pmidlookup?view=long&pmid=9480991. 
  13. ^ Chan VW, Lowell CA, DeFranco AL (May 1998). "Defective negative regulation of antigen receptor signaling in Lyn-deficient B lymphocytes". Curr. Biol. 8 (10): 545–53. doi:10.1016/S0960-9822(98)70223-4. PMID 9601638. http://linkinghub.elsevier.com/retrieve/pii/S0960-9822(98)70223-4. 
  14. ^ Nishizumi H, Horikawa K, Mlinaric-Rascan I, Yamamoto T (April 1998). "A double-edged kinase Lyn: a positive and negative regulator for antigen receptor-mediated signals". J. Exp. Med. 187 (8): 1343–8. doi:10.1084/jem.187.8.1343. PMC 2212230. PMID 9547345. http://www.jem.org/cgi/pmidlookup?view=long&pmid=9547345. 
  15. ^ Maeda A, Scharenberg AM, Tsukada S, Bolen JB, Kinet JP, Kurosaki T (April 1999). "Paired immunoglobulin-like receptor B (PIR-B) inhibits BCR-induced activation of Syk and Btk by SHP-1". Oncogene 18 (14): 2291–7. doi:10.1038/sj.onc.1202552. PMID 10327049. 
  16. ^ Lowell CA (July 2004). "Src-family kinases: rheostats of immune cell signaling". Mol. Immunol. 41 (6–7): 631–43. doi:10.1016/j.molimm.2004.04.010. PMID 15220000. 
  17. ^ Saijo K, Schmedt C, Su IH, et al. (March 2003). "Essential role of Src-family protein tyrosine kinases in NF-kappaB activation during B cell development". Nat. Immunol. 4 (3): 274–9. doi:10.1038/ni893. PMID 12563261. 
  18. ^ Xu Y, Harder KW, Huntington ND, Hibbs ML, Tarlinton DM (January 2005). "Lyn tyrosine kinase: accentuating the positive and the negative". Immunity 22 (1): 9–18. doi:10.1016/j.immuni.2004.12.004. PMID 15664155. 
  19. ^ Müller G, Wied S, Frick W (July 2000). "Cross talk of pp125(FAK) and pp59(Lyn) non-receptor tyrosine kinases to insulin-mimetic signaling in adipocytes". Mol. Cell. Biol. 20 (13): 4708–4723. PMC 85892. PMID 10848597. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=85892. 
  20. ^ Anderwald C, Muller G, Koca G, Furnsinn C, Waldhausl W, Roden M (2002). "Short-term lpetin-dependent inhibition of hepatic gluconeogenesis is mediated by insulin receptor substrate-2". Mol. Endocrinol. 16 (7): 1612–1628. doi:10.1210/me.16.7.1612. PMID 12089355. 
  21. ^ a b Müller, G (2000). "The molecular mechanism of the insulin-mimetic sensitizing activity of the antidiabetic sulfonylurea drug Amaryl". Mol. Med. 6 (11): 907–933. PMC 1949923. PMID 11147570. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1949923. 
  22. ^ Müller G, Schulz A, Wied S, Frick W (2005). "Regulation of lipid raft proteins by glimepiride- and insulin-induced glycosylphospatidylinositol-specific phospholipase C in rat adipocytes". Biochem. Pharmacol. 69: 761–780. doi:10.1016/j.bcp.2004.11.014. PMID 15710354. 
  23. ^ Hibbs ML, Harder KW, Armes J, et al. (December 2002). "Sustained activation of Lyn tyrosine kinase in vivo leads to autoimmunity". J. Exp. Med. 196 (12): 1593–604. doi:10.1084/jem.20020515. PMC 2196073. PMID 12486102. http://www.jem.org/cgi/pmidlookup?view=long&pmid=12486102. 
  24. ^ Muller G, Wied S, Frick W (July 2000). "Cross talk of pp125(FAK) and pp59(Lyn) non-receptor tyrosine kinases to insulin-mimetic signaling in adipocytes". Mol. Cell. Biol. 20 (13): 4708–4723. PMC 85892. PMID 10848597. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=85892. 
  25. ^ Grishin, A V; Azhipa O, Semenov I, Corey S J (Aug. 2001). "Interaction between growth arrest-DNA damage protein 34 and Src kinase Lyn negatively regulates genotoxic apoptosis". Proc. Natl. Acad. Sci. U.S.A. (United States) 98 (18): 10172–7. doi:10.1073/pnas.191130798. ISSN 0027-8424. PMC 56934. PMID 11517336. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=56934. 
  26. ^ Pleiman, C M; Clark M R, Gauen L K, Winitz S, Coggeshall K M, Johnson G L, Shaw A S, Cambier J C (Sep. 1993). "Mapping of sites on the Src family protein tyrosine kinases p55blk, p59fyn, and p56lyn which interact with the effector molecules phospholipase C-gamma 2, microtubule-associated protein kinase, GTPase-activating protein, and phosphatidylinositol 3-kinase". Mol. Cell. Biol. (UNITED STATES) 13 (9): 5877–87. ISSN 0270-7306. PMC 360336. PMID 8395016. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=360336. 
  27. ^ Guo, B; Kato R M, Garcia-Lloret M, Wahl M I, Rawlings D J (Aug. 2000). "Engagement of the human pre-B cell receptor generates a lipid raft-dependent calcium signaling complex". Immunity (UNITED STATES) 13 (2): 243–53. doi:10.1016/S1074-7613(00)00024-8. ISSN 1074-7613. PMID 10981967. 
  28. ^ Gross, B S; Lee J R, Clements J L, Turner M, Tybulewicz V L, Findell P R, Koretzky G A, Watson S P (Feb. 1999). "Tyrosine phosphorylation of SLP-76 is downstream of Syk following stimulation of the collagen receptor in platelets". J. Biol. Chem. (UNITED STATES) 274 (9): 5963–71. doi:10.1074/jbc.274.9.5963. ISSN 0021-9258. PMID 10026222. 
  29. ^ Li, Yongqing; Chen Wen, Ren Jian, Yu Wei-Hsuan, Li Quan, Yoshida Kiyotsugu, Kufe Donald (2003). "DF3/MUC1 signaling in multiple myeloma cells is regulated by interleukin-7". Cancer Biol. Ther. (United States) 2 (2): 187–93. ISSN 1538-4047. PMID 12750561. 
  30. ^ a b Liang, Xiquan; Wisniewski David, Strife Annabel, Shivakrupa , Clarkson Bayard, Resh Marilyn D (Apr. 2002). "Phosphatidylinositol 3-kinase and Src family kinases are required for phosphorylation and membrane recruitment of Dok-1 in c-Kit signaling". J. Biol. Chem. (United States) 277 (16): 13732–8. doi:10.1074/jbc.M200277200. ISSN 0021-9258. PMID 11825908. 
  31. ^ Linnekin, D; DeBerry C S, Mou S (Oct. 1997). "Lyn associates with the juxtamembrane region of c-Kit and is activated by stem cell factor in hematopoietic cell lines and normal progenitor cells". J. Biol. Chem. (UNITED STATES) 272 (43): 27450–5. doi:10.1074/jbc.272.43.27450. ISSN 0021-9258. PMID 9341198. 
  32. ^ van Dijk, T B; van Den Akker E, Amelsvoort M P, Mano H, Löwenberg B, von Lindern M (Nov. 2000). "Stem cell factor induces phosphatidylinositol 3'-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells". Blood (UNITED STATES) 96 (10): 3406–13. ISSN 0006-4971. PMID 11071635. 
  33. ^ a b Manié, S N; Beck A R, Astier A, Law S F, Canty T, Hirai H, Druker B J, Avraham H, Haghayeghi N, Sattler M, Salgia R, Griffin J D, Golemis E A, Freedman A S (Feb. 1997). "Involvement of p130(Cas) and p105(HEF1), a novel Cas-like docking protein, in a cytoskeleton-dependent signaling pathway initiated by ligation of integrin or antigen receptor on human B cells". J. Biol. Chem. (UNITED STATES) 272 (7): 4230–6. doi:10.1074/jbc.272.7.4230. ISSN 0021-9258. PMID 9020138. 
  34. ^ Qiu, W; Cobb R R, Scholz W (May. 1998). "Inhibition of p130cas tyrosine phosphorylation by calyculin A". J. Leukoc. Biol. (UNITED STATES) 63 (5): 631–5. ISSN 0741-5400. PMID 9581808. 
  35. ^ Xu, Hongshi; Zhao Hongyu, Tian Wei, Yoshida Kiyotsugu, Roullet Jean-Baptiste, Cohen David M (Mar. 2003). "Regulation of a transient receptor potential (TRP) channel by tyrosine phosphorylation. SRC family kinase-dependent tyrosine phosphorylation of TRPV4 on TYR-253 mediates its response to hypotonic stress". J. Biol. Chem. (United States) 278 (13): 11520–7. doi:10.1074/jbc.M211061200. ISSN 0021-9258. PMID 12538589. 
  36. ^ Poe, J C; Fujimoto M, Jansen P J, Miller A S, Tedder T F (Jun. 2000). "CD22 forms a quaternary complex with SHIP, Grb2, and Shc. A pathway for regulation of B lymphocyte antigen receptor-induced calcium flux". J. Biol. Chem. (UNITED STATES) 275 (23): 17420–7. doi:10.1074/jbc.M001892200. ISSN 0021-9258. PMID 10748054. 
  37. ^ Greer, S F; Justement L B (May. 1999). "CD45 regulates tyrosine phosphorylation of CD22 and its association with the protein tyrosine phosphatase SHP-1". J. Immunol. (UNITED STATES) 162 (9): 5278–86. ISSN 0022-1767. PMID 10228003. 
  38. ^ Baran, Christopher P; Tridandapani Susheela, Helgason Cheryl D, Humphries R Keith, Krystal Gerald, Marsh Clay B (Oct. 2003). "The inositol 5'-phosphatase SHIP-1 and the Src kinase Lyn negatively regulate macrophage colony-stimulating factor-induced Akt activity". J. Biol. Chem. (United States) 278 (40): 38628–36. doi:10.1074/jbc.M305021200. ISSN 0021-9258. PMID 12882960. 
  39. ^ Suzuki-Inoue, Katsue; Tulasne David, Shen Yang, Bori-Sanz Teresa, Inoue Osamu, Jung Stephanie M, Moroi Masaaki, Andrews Robert K, Berndt Michael C, Watson Steve P (Jun. 2002). "Association of Fyn and Lyn with the proline-rich domain of glycoprotein VI regulates intracellular signaling". J. Biol. Chem. (United States) 277 (24): 21561–6. doi:10.1074/jbc.M201012200. ISSN 0021-9258. PMID 11943772. 
  40. ^ Sidorenko, S P; Law C L, Chandran K A, Clark E A (Jan. 1995). "Human spleen tyrosine kinase p72Syk associates with the Src-family kinase p53/56Lyn and a 120-kDa phosphoprotein". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 92 (2): 359–63. doi:10.1073/pnas.92.2.359. ISSN 0027-8424. PMC 42739. PMID 7831290. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=42739. 
  41. ^ Brown, V K; Ogle E W, Burkhardt A L, Rowley R B, Bolen J B, Justement L B (Jun. 1994). "Multiple components of the B cell antigen receptor complex associate with the protein tyrosine phosphatase, CD45". J. Biol. Chem. (UNITED STATES) 269 (25): 17238–44. ISSN 0021-9258. PMID 7516335. 
  42. ^ Kharbanda, S; Yuan Z M, Rubin E, Weichselbaum R, Kufe D (Aug. 1994). "Activation of Src-like p56/p53lyn tyrosine kinase by ionizing radiation". J. Biol. Chem. (UNITED STATES) 269 (32): 20739–43. ISSN 0021-9258. PMID 8051175. 
  43. ^ Pathan, N I; Geahlen R L, Harrison M L (Nov. 1996). "The protein-tyrosine kinase Lck associates with and is phosphorylated by Cdc2". J. Biol. Chem. (UNITED STATES) 271 (44): 27517–23. doi:10.1074/jbc.271.44.27517. ISSN 0021-9258. PMID 8910336. 
  44. ^ Chin, H; Arai A, Wakao H, Kamiyama R, Miyasaka N, Miura O (May. 1998). "Lyn physically associates with the erythropoietin receptor and may play a role in activation of the Stat5 pathway". Blood (UNITED STATES) 91 (10): 3734–45. ISSN 0006-4971. PMID 9573010. 
  45. ^ Cen, Osman; Gorska Magdalena M, Stafford Susan J, Sur Sanjiv, Alam Rafeul (Mar. 2003). "Identification of UNC119 as a novel activator of SRC-type tyrosine kinases". J. Biol. Chem. (United States) 278 (10): 8837–45. doi:10.1074/jbc.M208261200. ISSN 0021-9258. PMID 12496276. 

Further reading

  • Jouvin MH, Numerof RP, Kinet JP (1995). "Signal transduction through the conserved motifs of the high affinity IgE receptor Fc epsilon RI". Semin. Immunol. 7 (1): 29–35. doi:10.1016/1044-5323(95)90005-5. PMID 7612892. 
  • Hibbs ML, Dunn AR (1997). "Lyn, a src-like tyrosine kinase". Int. J. Biochem. Cell Biol. 29 (3): 397–400. doi:10.1016/S1357-2725(96)00104-5. PMID 9202419. 
  • Blasioli J, Goodnow CC (2002). Lyn/CD22/SHP-1 and Their Importance in Autoimmunity. "Signal Transduction Pathways in Autoimmunity". Curr. Dir. Autoimmun.. Current Directions in Autoimmunity 5: 151–60. doi:10.1159/000060551. ISBN 3-8055-7308-1. PMID 11826756. 
  • Greenway AL, Holloway G, McPhee DA, et al. (2004). "HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication". J. Biosci. 28 (3): 323–35. doi:10.1007/BF02970151. PMID 12734410. 
  • Tolstrup M, Ostergaard L, Laursen AL, et al. (2004). "HIV/SIV escape from immune surveillance: focus on Nef". Curr. HIV Res. 2 (2): 141–51. doi:10.2174/1570162043484924. PMID 15078178. 
  • Joseph AM, Kumar M, Mitra D (2005). "Nef: "necessary and enforcing factor" in HIV infection". Curr. HIV Res. 3 (1): 87–94. doi:10.2174/1570162052773013. PMID 15638726. 
  • Stove V, Verhasselt B (2006). "Modelling thymic HIV-1 Nef effects". Curr. HIV Res. 4 (1): 57–64. doi:10.2174/157016206775197583. PMID 16454711.