| Structural highlights
Function
LYN_MOUSE Non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors and plays an important role in the regulation of innate and adaptive immune responses, hematopoiesis, responses to growth factors and cytokines, integrin signaling, but also responses to DNA damage and genotoxic agents. Functions primarily as negative regulator, but can also function as activator, depending on the context. Required for the initiation of the B-cell response, but also for its down-regulation and termination. Plays an important role in the regulation of B-cell differentiation, proliferation, survival and apoptosis, and is important for immune self-tolerance. Acts downstream of several immune receptors, including the B-cell receptor, CD79A, CD79B, CD5, CD19, CD22, FCER1, FCGR2, FCGR1A, TLR2 and TLR4. Plays a role in the inflammatory response to bacterial lipopolysaccharide. Mediates the responses to cytokines and growth factors in hematopoietic progenitors, platelets, erythrocytes, and in mature myeloid cells, such as dendritic cells, neutrophils and eosinophils. Acts downstream of EPOR, KIT, MPL, the chemokine receptor CXCR4, as well as the receptors for IL3, IL5 and CSF2. Plays an important role in integrin signaling. Regulates cell proliferation, survival, differentiation, migration, adhesion, degranulation, and cytokine release. Down-regulates signaling pathways by phosphorylation of immunoreceptor tyrosine-based inhibitory motifs (ITIM), that then serve as binding sites for phosphatases, such as PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1, that modulate signaling by dephosphorylation of kinases and their substrates. Phosphorylates LIME1 in response to CD22 activation. Phosphorylates BTK, CBL, CD5, CD19, CD72, CD79A, CD79B, CSF2RB, DOK1, HCLS1, LILRB3/PIR-B, MS4A2/FCER1B, PTK2B/PYK2, SYK and TEC. Promotes phosphorylation of SIRPA, PTPN6/SHP-1, PTPN11/SHP-2 and INPP5D/SHIP-1. Required for rapid phosphorylation of FER in response to FCER1 activation. Mediates KIT phosphorylation. Acts as an effector of EPOR (erythropoietin receptor) in controlling KIT expression and may play a role in erythroid differentiation during the switch between proliferation and maturation. Depending on the context, activates or inhibits several signaling cascades. Regulates phosphatidylinositol 3-kinase activity and AKT1 activation. Regulates activation of the MAP kinase signaling cascade, including activation of MAP2K1/MEK1, MAPK1/ERK2, MAPK3/ERK1, MAPK8/JNK1 and MAPK9/JNK2. Mediates activation of STAT5A and/or STAT5B. Phosphorylates LPXN on 'Tyr-72'.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The Src-family protein-tyrosine kinase (PTK) Lyn is the most important Src-family kinase in B cells, having both inhibitory and stimulatory activity that is dependent on the receptor, ligand, and developmental context of the B cell. An important role for Lyn has been reported in acute myeloid leukemia and chronic myeloid leukemia, as well as certain solid tumors. Although several Src-family inhibitors are available, the development of Lyn-specific inhibitors, or inhibitors with reduced off-target activity to Lyn, has been hampered by the lack of structural data on the Lyn kinase. Here we report the crystal structure of the non-liganded form of Lyn kinase domain, as well as in complex with three different inhibitors: the ATP analogue AMP-PNP; the pan Src kinase inhibitor PP2; and the BCR-Abl/Src-family inhibitor Dasatinib. The Lyn kinase domain was determined in its "active" conformation, but in the unphosphorylated state. All three inhibitors are bound at the ATP-binding site, with PP2 and Dasatinib extending into a hydrophobic pocket deep in the substrate cleft, thereby providing a basis for the Src-specific inhibition. Analysis of sequence and structural differences around the active site region of the Src-family PTKs were evident. Accordingly, our data provide valuable information for the further development of therapeutics targeting Lyn and the important Src-family of kinases.
Crystal structures of the Lyn protein tyrosine kinase domain in its Apo- and inhibitor-bound state.,Williams NK, Lucet IS, Klinken SP, Ingley E, Rossjohn J J Biol Chem. 2009 Jan 2;284(1):284-91. Epub 2008 Nov 4. PMID:18984583[37]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Law DA, Chan VW, Datta SK, DeFranco AL. B-cell antigen receptor motifs have redundant signalling capabilities and bind the tyrosine kinases PTK72, Lyn and Fyn. Curr Biol. 1993 Oct 1;3(10):645-57. PMID:15335855
- ↑ Kurosaki T, Takata M, Yamanashi Y, Inazu T, Taniguchi T, Yamamoto T, Yamamura H. Syk activation by the Src-family tyrosine kinase in the B cell receptor signaling. J Exp Med. 1994 May 1;179(5):1725-9. PMID:7513017
- ↑ Pleiman CM, Hertz WM, Cambier JC. Activation of phosphatidylinositol-3' kinase by Src-family kinase SH3 binding to the p85 subunit. Science. 1994 Mar 18;263(5153):1609-12. PMID:8128248
- ↑ Hibbs ML, Tarlinton DM, Armes J, Grail D, Hodgson G, Maglitto R, Stacker SA, Dunn AR. Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease. Cell. 1995 Oct 20;83(2):301-11. PMID:7585947
- ↑ Nishizumi H, Taniuchi I, Yamanashi Y, Kitamura D, Ilic D, Mori S, Watanabe T, Yamamoto T. Impaired proliferation of peripheral B cells and indication of autoimmune disease in lyn-deficient mice. Immunity. 1995 Nov;3(5):549-60. PMID:7584145
- ↑ Mano H, Yamashita Y, Miyazato A, Miura Y, Ozawa K. Tec protein-tyrosine kinase is an effector molecule of Lyn protein-tyrosine kinase. FASEB J. 1996 Apr;10(5):637-42. PMID:8621063
- ↑ Wang J, Koizumi T, Watanabe T. Altered antigen receptor signaling and impaired Fas-mediated apoptosis of B cells in Lyn-deficient mice. J Exp Med. 1996 Sep 1;184(3):831-8. PMID:9064343
- ↑ Rawlings DJ, Scharenberg AM, Park H, Wahl MI, Lin S, Kato RM, Fluckiger AC, Witte ON, Kinet JP. Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases. Science. 1996 Feb 9;271(5250):822-5. PMID:8629002
- ↑ Chan VW, Meng F, Soriano P, DeFranco AL, Lowell CA. Characterization of the B lymphocyte populations in Lyn-deficient mice and the role of Lyn in signal initiation and down-regulation. Immunity. 1997 Jul;7(1):69-81. PMID:9252121
- ↑ Nishizumi H, Yamamoto T. Impaired tyrosine phosphorylation and Ca2+ mobilization, but not degranulation, in lyn-deficient bone marrow-derived mast cells. J Immunol. 1997 Mar 1;158(5):2350-5. PMID:9036984
- ↑ Chin H, Arai A, Wakao H, Kamiyama R, Miyasaka N, Miura O. Lyn physically associates with the erythropoietin receptor and may play a role in activation of the Stat5 pathway. Blood. 1998 May 15;91(10):3734-45. PMID:9573010
- ↑ Chan VW, Lowell CA, DeFranco AL. Defective negative regulation of antigen receptor signaling in Lyn-deficient B lymphocytes. Curr Biol. 1998 May 7;8(10):545-53. PMID:9601638
- ↑ Smith KG, Tarlinton DM, Doody GM, Hibbs ML, Fearon DT. Inhibition of the B cell by CD22: a requirement for Lyn. J Exp Med. 1998 Mar 2;187(5):807-11. PMID:9480991
- ↑ Nishizumi H, Horikawa K, Mlinaric-Rascan I, Yamamoto T. A double-edged kinase Lyn: a positive and negative regulator for antigen receptor-mediated signals. J Exp Med. 1998 Apr 20;187(8):1343-8. PMID:9547345
- ↑ Malbec O, Fong DC, Turner M, Tybulewicz VL, Cambier JC, Fridman WH, Daeron M. Fc epsilon receptor I-associated lyn-dependent phosphorylation of Fc gamma receptor IIB during negative regulation of mast cell activation. J Immunol. 1998 Feb 15;160(4):1647-58. PMID:9469421
- ↑ Adachi T, Flaswinkel H, Yakura H, Reth M, Tsubata T. The B cell surface protein CD72 recruits the tyrosine phosphatase SHP-1 upon tyrosine phosphorylation. J Immunol. 1998 May 15;160(10):4662-5. PMID:9590210
- ↑ Ochi H, Takeshita H, Suda T, Nisitani S, Honjo T, Watanabe T. Regulation of B-1 cell activation and its autoantibody production by Lyn kinase-regulated signallings. Immunology. 1999 Dec;98(4):595-603. PMID:10594694
- ↑ Maeda A, Scharenberg AM, Tsukada S, Bolen JB, Kinet JP, Kurosaki T. Paired immunoglobulin-like receptor B (PIR-B) inhibits BCR-induced activation of Syk and Btk by SHP-1. Oncogene. 1999 Apr 8;18(14):2291-7. PMID:10327049 doi:http://dx.doi.org/10.1038/sj.onc.1202552
- ↑ Dahl ME, Arai KI, Watanabe S. Association of Lyn tyrosine kinase to the GM-CSF and IL-3 receptor common betac subunit and role of Src tyrosine kinases in DNA synthesis and anti-apoptosis. Genes Cells. 2000 Feb;5(2):143-53. PMID:10672044
- ↑ Yamanashi Y, Tamura T, Kanamori T, Yamane H, Nariuchi H, Yamamoto T, Baltimore D. Role of the rasGAP-associated docking protein p62(dok) in negative regulation of B cell receptor-mediated signaling. Genes Dev. 2000 Jan 1;14(1):11-6. PMID:10640270
- ↑ Ochi H, Watanabe T. Negative regulation of B cell receptor-mediated signaling in B-1 cells through CD5 and Ly49 co-receptors via Lyn kinase activity. Int Immunol. 2000 Oct;12(10):1417-23. PMID:11007759
- ↑ O'Laughlin-Bunner B, Radosevic N, Taylor ML, Shivakrupa, DeBerry C, Metcalfe DD, Zhou M, Lowell C, Linnekin D. Lyn is required for normal stem cell factor-induced proliferation and chemotaxis of primary hematopoietic cells. Blood. 2001 Jul 15;98(2):343-50. PMID:11435302
- ↑ Harder KW, Parsons LM, Armes J, Evans N, Kountouri N, Clark R, Quilici C, Grail D, Hodgson GS, Dunn AR, Hibbs ML. Gain- and loss-of-function Lyn mutant mice define a critical inhibitory role for Lyn in the myeloid lineage. Immunity. 2001 Oct;15(4):603-15. PMID:11672542
- ↑ Hong JJ, Yankee TM, Harrison ML, Geahlen RL. Regulation of signaling in B cells through the phosphorylation of Syk on linker region tyrosines. A mechanism for negative signaling by the Lyn tyrosine kinase. J Biol Chem. 2002 Aug 30;277(35):31703-14. Epub 2002 Jun 20. PMID:12077122 doi:http://dx.doi.org/10.1074/jbc.M201362200
- ↑ Pereira S, Lowell C. The Lyn tyrosine kinase negatively regulates neutrophil integrin signaling. J Immunol. 2003 Aug 1;171(3):1319-27. PMID:12874221
- ↑ Lannutti BJ, Drachman JG. Lyn tyrosine kinase regulates thrombopoietin-induced proliferation of hematopoietic cell lines and primary megakaryocytic progenitors. Blood. 2004 May 15;103(10):3736-43. Epub 2004 Jan 15. PMID:14726379 doi:http://dx.doi.org/10.1182/blood-2003-10-3566
- ↑ Hernandez-Hansen V, Mackay GA, Lowell CA, Wilson BS, Oliver JM. The Src kinase Lyn is a negative regulator of mast cell proliferation. J Leukoc Biol. 2004 Jan;75(1):143-51. Epub 2003 Oct 2. PMID:14525964 doi:http://dx.doi.org/10.1189/jlb.0503224
- ↑ Chu CL, Lowell CA. The Lyn tyrosine kinase differentially regulates dendritic cell generation and maturation. J Immunol. 2005 Sep 1;175(5):2880-9. PMID:16116174
- ↑ Beavitt SJ, Harder KW, Kemp JM, Jones J, Quilici C, Casagranda F, Lam E, Turner D, Brennan S, Sly PD, Tarlinton DM, Anderson GP, Hibbs ML. Lyn-deficient mice develop severe, persistent asthma: Lyn is a critical negative regulator of Th2 immunity. J Immunol. 2005 Aug 1;175(3):1867-75. PMID:16034130
- ↑ Xiao W, Nishimoto H, Hong H, Kitaura J, Nunomura S, Maeda-Yamamoto M, Kawakami Y, Lowell CA, Ra C, Kawakami T. Positive and negative regulation of mast cell activation by Lyn via the FcepsilonRI. J Immunol. 2005 Nov 15;175(10):6885-92. PMID:16272347
- ↑ Ahn E, Lee H, Yun Y. LIME acts as a transmembrane adapter mediating BCR-dependent B-cell activation. Blood. 2006 Feb 15;107(4):1521-7. Epub 2005 Oct 25. PMID:16249387 doi:http://dx.doi.org/2005-05-1859
- ↑ Udell CM, Samayawardhena LA, Kawakami Y, Kawakami T, Craig AW. Fer and Fps/Fes participate in a Lyn-dependent pathway from FcepsilonRI to platelet-endothelial cell adhesion molecule 1 to limit mast cell activation. J Biol Chem. 2006 Jul 28;281(30):20949-57. Epub 2006 May 26. PMID:16731527 doi:http://dx.doi.org/10.1074/jbc.M604252200
- ↑ Chew V, Lam KP. Leupaxin negatively regulates B cell receptor signaling. J Biol Chem. 2007 Sep 14;282(37):27181-91. Epub 2007 Jul 19. PMID:17640867 doi:http://dx.doi.org/10.1074/jbc.M704625200
- ↑ Kosmider O, Buet D, Gallais I, Denis N, Moreau-Gachelin F. Erythropoietin down-regulates stem cell factor receptor (Kit) expression in the leukemic proerythroblast: role of Lyn kinase. PLoS One. 2009 May 28;4(5):e5721. doi: 10.1371/journal.pone.0005721. PMID:19492092 doi:http://dx.doi.org/10.1371/journal.pone.0005721
- ↑ Li Z, Zhang G, Liu J, Stojanovic A, Ruan C, Lowell CA, Du X. An important role of the SRC family kinase Lyn in stimulating platelet granule secretion. J Biol Chem. 2010 Apr 23;285(17):12559-70. doi: 10.1074/jbc.M109.098756. Epub, 2010 Feb 26. PMID:20189992 doi:http://dx.doi.org/10.1074/jbc.M109.098756
- ↑ Keck S, Freudenberg M, Huber M. Activation of murine macrophages via TLR2 and TLR4 is negatively regulated by a Lyn/PI3K module and promoted by SHIP1. J Immunol. 2010 May 15;184(10):5809-18. doi: 10.4049/jimmunol.0901423. Epub 2010 , Apr 12. PMID:20385881 doi:http://dx.doi.org/10.4049/jimmunol.0901423
- ↑ Williams NK, Lucet IS, Klinken SP, Ingley E, Rossjohn J. Crystal structures of the Lyn protein tyrosine kinase domain in its Apo- and inhibitor-bound state. J Biol Chem. 2009 Jan 2;284(1):284-91. Epub 2008 Nov 4. PMID:18984583 doi:10.1074/jbc.M807850200
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