Tyrosine-protein kinase Lyn is a protein that in humans is encoded in humans by the LYNgene.[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] The abbreviation Lyn is derived from Lck/Yes novel tyrosine kinase, Lck and Yes also being members of the Src kinase family.
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]Tolimidone (MLR-1023) is a small molecule lyn activator that is currently under Phase 2a investigation for Type II diabetes.[23] In June, 2016, the sponsor of these studies, Melior Discovery, announced positive results from their Phase 2a study with tolimidone in diabetic patients[24], and the continuation of additional clinical studies[25].
Lyn has been shown to protect against hepatcellular apoptosis and promote liver regeneration through the preservation of hepatocellular mitochondrial integrity.[26]
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 monocyte/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.[27]
↑Umemori H, Wanaka A, Kato H, Takeuchi M, Tohyama M, Yamamoto T (Dec 1992). "Specific expressions of Fyn and Lyn, lymphocyte antigen receptor-associated tyrosine kinases, in the central nervous system". Brain Research. Molecular Brain Research. 16 (3–4): 303–10. doi:10.1016/0169-328X(92)90239-8. PMID1337939.
↑ 9.09.1Harder KW, Parsons LM, Armes J, Evans N, Kountouri N, Clark R, Quilici C, Grail D, Hodgson GS, Dunn AR, Hibbs ML (Oct 2001). "Gain- and loss-of-function Lyn mutant mice define a critical inhibitory role for Lyn in the myeloid lineage". Immunity. 15 (4): 603–615. doi:10.1016/S1074-7613(01)00208-4. PMID11672542.
↑Saijo K, Schmedt C, Su IH, Karasuyama H, Lowell CA, Reth M, Adachi T, Patke A, Santana A, Tarakhovsky A (Mar 2003). "Essential role of Src-family protein tyrosine kinases in NF-kappaB activation during B cell development". Nature Immunology. 4 (3): 274–9. doi:10.1038/ni893. PMID12563261.
↑Xu Y, Harder KW, Huntington ND, Hibbs ML, Tarlinton DM (Jan 2005). "Lyn tyrosine kinase: accentuating the positive and the negative". Immunity. 22 (1): 9–18. doi:10.1016/j.immuni.2004.12.004. PMID15664155.
↑Müller G, Schulz A, Wied S, Frick W (Mar 2005). "Regulation of lipid raft proteins by glimepiride- and insulin-induced glycosylphosphatidylinositol-specific phospholipase C in rat adipocytes". Biochemical Pharmacology. 69 (5): 761–780. doi:10.1016/j.bcp.2004.11.014. PMID15710354.
↑Gringeri E, Carraro A, Tibaldi E, D'Amico FE, Mancon M, Toninello A, Pagano MA, Vio C, Cillo U, Brunati AM (December 2009). "Lyn-mediated mitochondrial tyrosine phosphorylation is required to preserve mitochondrial integrity in early liver regeneration". The Biochemical Journal. 425 (2): 401–12. doi:10.1042/BJ20090902. PMID19832701.
↑ 29.029.1Manié SN, Beck AR, Astier A, Law SF, Canty T, Hirai H, Druker BJ, Avraham H, Haghayeghi N, Sattler M, Salgia R, Griffin JD, Golemis EA, Freedman AS (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". The Journal of Biological Chemistry. 272 (7): 4230–6. doi:10.1074/jbc.272.7.4230. PMID9020138.
↑Qiu W, Cobb RR, Scholz W (May 1998). "Inhibition of p130cas tyrosine phosphorylation by calyculin A". Journal of Leukocyte Biology. 63 (5): 631–5. PMID9581808.
↑ 31.031.1Liang X, Wisniewski D, Strife A, Clarkson B, Resh MD (Apr 2002). "Phosphatidylinositol 3-kinase and Src family kinases are required for phosphorylation and membrane recruitment of Dok-1 in c-Kit signaling". The Journal of Biological Chemistry. 277 (16): 13732–8. doi:10.1074/jbc.M200277200. PMID11825908.
↑Linnekin D, DeBerry CS, 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". The Journal of Biological Chemistry. 272 (43): 27450–5. doi:10.1074/jbc.272.43.27450. PMID9341198.
↑Poe JC, Fujimoto M, Jansen PJ, Miller AS, Tedder TF (Jun 2000). "CD22 forms a quaternary complex with SHIP, Grb2, and Shc. A pathway for regulation of B lymphocyte antigen receptor-induced calcium flux". The Journal of Biological Chemistry. 275 (23): 17420–7. doi:10.1074/jbc.M001892200. PMID10748054.
↑Greer SF, Justement LB (May 1999). "CD45 regulates tyrosine phosphorylation of CD22 and its association with the protein tyrosine phosphatase SHP-1". Journal of Immunology. 162 (9): 5278–86. PMID10228003.
↑Kharbanda S, Yuan ZM, Rubin E, Weichselbaum R, Kufe D (Aug 1994). "Activation of Src-like p56/p53lyn tyrosine kinase by ionizing radiation". The Journal of Biological Chemistry. 269 (32): 20739–43. PMID8051175.
↑Pathan NI, Geahlen RL, Harrison ML (Nov 1996). "The protein-tyrosine kinase Lck associates with and is phosphorylated by Cdc2". The Journal of Biological Chemistry. 271 (44): 27517–23. doi:10.1074/jbc.271.44.27517. PMID8910336.
↑van Dijk TB, van Den Akker E, Amelsvoort MP, 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. 96 (10): 3406–13. PMID11071635.
↑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. 91 (10): 3734–45. PMID9573010.
↑Suzuki-Inoue K, Tulasne D, Shen Y, Bori-Sanz T, Inoue O, Jung SM, Moroi M, Andrews RK, Berndt MC, Watson SP (Jun 2002). "Association of Fyn and Lyn with the proline-rich domain of glycoprotein VI regulates intracellular signaling". The Journal of Biological Chemistry. 277 (24): 21561–6. doi:10.1074/jbc.M201012200. PMID11943772.
↑Baran CP, Tridandapani S, Helgason CD, Humphries RK, Krystal G, Marsh CB (Oct 2003). "The inositol 5'-phosphatase SHIP-1 and the Src kinase Lyn negatively regulate macrophage colony-stimulating factor-induced Akt activity". The Journal of Biological Chemistry. 278 (40): 38628–36. doi:10.1074/jbc.M305021200. PMID12882960.
↑Gross BS, Lee JR, Clements JL, Turner M, Tybulewicz VL, Findell PR, Koretzky GA, Watson SP (Feb 1999). "Tyrosine phosphorylation of SLP-76 is downstream of Syk following stimulation of the collagen receptor in platelets". The Journal of Biological Chemistry. 274 (9): 5963–71. doi:10.1074/jbc.274.9.5963. PMID10026222.
↑Brown VK, Ogle EW, Burkhardt AL, Rowley RB, Bolen JB, Justement LB (Jun 1994). "Multiple components of the B cell antigen receptor complex associate with the protein tyrosine phosphatase, CD45". The Journal of Biological Chemistry. 269 (25): 17238–44. PMID7516335.
↑Xu H, Zhao H, Tian W, Yoshida K, Roullet JB, Cohen DM (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". The Journal of Biological Chemistry. 278 (13): 11520–7. doi:10.1074/jbc.M211061200. PMID12538589.
↑Cen O, Gorska MM, Stafford SJ, Sur S, Alam R (Mar 2003). "Identification of UNC119 as a novel activator of SRC-type tyrosine kinases". The Journal of Biological Chemistry. 278 (10): 8837–45. doi:10.1074/jbc.M208261200. PMID12496276.
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