LYN explained

Tyrosine-protein kinase Lyn is a protein that in humans is encoded 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] The abbreviation Lyn is derived from Lck/Yes novel tyrosine kinase, Lck and Yes also being members of the Src kinase family.

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.^[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]} HSP90 inhibitor NVP-BEP800 has been described to affect stability of LYN kinase and growth of B-cell acute lymphoblastic leukemias through inhibition of the NF-kappaB signaling. ^[19]

LYN is reported to be a key signal mediator for estrogen-dependent suppression of human osteoclast differentiation, survival, and function.^[20] 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.^[21] In turn, activation of the insulin receptor has been shown to increase autophosphorylation of Lyn suggesting a possible feedback loop.^[22] The insulin secretagogue, glimepiride (Amaryl®) activates Lyn in adipocytes via the disruption of lipid rafts.^[23] This indirect Lyn activation may modulate the extrapancreatic glycemic control activity of glimepiride.^[24] Tolimidone (MLR-1023) is a small molecule allosteric activator of lyn kinase with an EC50 of 63 nM^{[25] [26]} that is currently under Phase 2a investigation for Type II diabetes.^[27] In June, 2016, the sponsor of these studies, Melior Discovery, announced positive results from their Phase 2a study with tolimidone in diabetic patients,^{[28] [29]} and the continuation of additional clinical studies.^[30]

Lyn has been shown to protect against hepatocellular apoptosis and promote liver regeneration through the preservation of hepatocellular mitochondrial integrity.^[31]

Several investigators have shown the role of lyn kinase in different aspects of pulmonary function. Lyn activation in pulmonary epithelium has been shown to be important in improving pulmonary barrier integrity and to reduce edema.^{[32] [33]} Additional evidence suggest that lyn activation in alveolar phagocytes improves phagocytosis of bacteria and reduces pulmonary infection. ^{[34] [35]} Finally, other research has found that lyn activation reduces pulmonary hypersecretion of mucus. ^[36]

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 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.

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.^[37]

Interactions

LYN has been shown to interact with:

• BCAR1,^{[38] [39]}
• CD117,^{[40] [41]}
• CD22,^{[42] [43]}
• Cdk1,^{[44] [45]}
• DOK1,^{[40] [46]}
• EPOR^[47]
• GPVI,^[48]
• INPP5D,^[49]
• IRS1,^[50]
• LCP2,^[51]
• MUC1,^[52]
• NEDD9,^[38]
• PLCG2,^{[53] [54]}
• PPP1R15A,^[55]
• PTPRC,^[56]
• Syk,^[57]
• TRPV4,^[58]
• UNC119,^[59]

See also

• Lyn-CD22-SHP-1 pathway

Further reading

• Jouvin MH, Numerof RP, Kinet JP . Signal transduction through the conserved motifs of the high affinity IgE receptor Fc epsilon RI . Seminars in Immunology . 7 . 1 . 29–35 . Feb 1995 . 7612892 . 10.1016/1044-5323(95)90005-5 .
• Hibbs ML, Dunn AR . Lyn, a src-like tyrosine kinase . The International Journal of Biochemistry & Cell Biology . 29 . 3 . 397–400 . Mar 1997 . 9202419 . 10.1016/S1357-2725(96)00104-5 .
• Book: Blasioli . J.. Goodnow . C. C. . Lyn/CD22/SHP-1 and Their Importance in Autoimmunity . Current Directions in Autoimmunity . 5 . 151–60 . 2002 . 11826756 . 10.1159/000060551 . 978-3-8055-7308-5 .
• Greenway AL, Holloway G, McPhee DA, Ellis P, Cornall A, Lidman M . HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication . Journal of Biosciences . 28 . 3 . 323–35 . Apr 2003 . 12734410 . 10.1007/BF02970151 . 33749514 .
• Tolstrup M, Ostergaard L, Laursen AL, Pedersen SF, Duch M . HIV/SIV escape from immune surveillance: focus on Nef . Current HIV Research . 2 . 2 . 141–51 . Apr 2004 . 15078178 . 10.2174/1570162043484924 .
• Joseph AM, Kumar M, Mitra D . Nef: "necessary and enforcing factor" in HIV infection . Current HIV Research . 3 . 1 . 87–94 . Jan 2005 . 15638726 . 10.2174/1570162052773013 .
• Stove V, Verhasselt B . Modelling thymic HIV-1 Nef effects . Current HIV Research . 4 . 1 . 57–64 . Jan 2006 . 16454711 . 10.2174/157016206775197583 .

Notes and References

1. Yamanashi Y, Fukushige S, Semba K, Sukegawa J, Miyajima N, Matsubara K, Yamamoto T, Toyoshima K . The yes-related cellular gene lyn encodes a possible tyrosine kinase similar to p56lck . Molecular and Cellular Biology . 7 . 1 . 237–43 . Jan 1987 . 3561390 . 365062 . 10.1128/MCB.7.1.237.
2. Yamanashi Y, Mori S, Yoshida M, Kishimoto T, Inoue K, Yamamoto T, Toyoshima K . Selective expression of a protein-tyrosine kinase, p56lyn, in hematopoietic cells and association with production of human T-cell lymphotropic virus type I . Proceedings of the National Academy of Sciences of the United States of America . 86 . 17 . 6538–42 . Sep 1989 . 2505253 . 297879 . 10.1073/pnas.86.17.6538 . 1989PNAS...86.6538Y . free .
3. Umemori H, Wanaka A, Kato H, Takeuchi M, Tohyama M, Yamamoto T . 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 . Dec 1992 . 1337939 . 10.1016/0169-328X(92)90239-8 .
4. Yamada E, Pessin JE, Kurland IJ, Schwartz GJ, Bastie CC . Fyn-dependent regulation of energy expenditure and body weight is mediated by tyrosine phosphorylation of LKB1 . Cell Metabolism . 11 . 2 . 113–124 . Feb 2010 . 20142099 . 2830006 . 10.1016/j.cmet.2009.12.010 .
5. Yamamoto T, Yamanashi Y, Toyoshima K . Association of Src-family kinase Lyn with B-cell antigen receptor . Immunological Reviews . 132 . 187–206 . Apr 1993 . 8349296 . 10.1111/j.1600-065X.1993.tb00843.x . 10782326 .
6. Campbell MA, Sefton BM . Association between B-lymphocyte membrane immunoglobulin and multiple members of the Src family of protein tyrosine kinases . Molecular and Cellular Biology . 12 . 5 . 2315–21 . May 1992 . 1569953 . 364403 . 10.1128/MCB.12.5.2315.
7. Ren CL, Morio T, Fu SM, Geha RS . Signal transduction via CD40 involves activation of lyn kinase and phosphatidylinositol-3-kinase, and phosphorylation of phospholipase C gamma 2 . The Journal of Experimental Medicine . 179 . 2 . 673–80 . Feb 1994 . 7507510 . 2191357 . 10.1084/jem.179.2.673 .
8. Campbell 1999
9. 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 . 15 . 4 . 603–615 . Oct 2001 . 11672542 . 10.1016/S1074-7613(01)00208-4 . free .
10. Yamanashi Y, Fukui Y, Wongsasant B, Kinoshita Y, Ichimori Y, Toyoshima K, Yamamoto T . Activation of Src-like protein-tyrosine kinase Lyn and its association with phosphatidylinositol 3-kinase upon B-cell antigen receptor-mediated signaling . Proceedings of the National Academy of Sciences of the United States of America . 89 . 3 . 1118–22 . Feb 1992 . 1371009 . 48397 . 10.1073/pnas.89.3.1118 . 1992PNAS...89.1118Y . free .
11. Cornall RJ, Cyster JG, Hibbs ML, Dunn AR, Otipoby KL, Clark EA, Goodnow CC . 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 . Apr 1998 . 9586639 . 10.1016/S1074-7613(00)80554-3 . free .
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13. Chan VW, Lowell CA, DeFranco AL . Defective negative regulation of antigen receptor signaling in Lyn-deficient B lymphocytes . Current Biology . 8 . 10 . 545–53 . May 1998 . 9601638 . 10.1016/S0960-9822(98)70223-4 . 12195731 . free . 1998CBio....8..545C .
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19. 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 . HSP90 inhibitor NVP-BEP800 affects stability of SRC kinases and growth of T-cell and B-cell acute lymphoblastic leukemia . Blood Cancer J. . 3 . 11 . 61 . March 2021 . 33737511 . 10.1038/s41408-021-00450-2 . 7973815 . free .
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