V-yes-1 Yamaguchi sarcoma viral related oncogene homolog, also known as LYN, is a human gene.

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Lyn is a member of the Src family of protein tyrosine kinases, which is mainly expressed in hematopoietic cells (Yamanashi, Mori et al. 1989) and in neural tissues (Umemori, Wanaka et al. 1992). 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) (Yamamoto, Yamanashi et al. 1993; Campbell and Sefton 1992), CD40 (Ren, Morio et al. 1994) or CD19 (Campbell 1999).

Following engagement of the 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 (Yamanashi, Fukui et al. 1992; Campbell 1999). These kinases provide activation signals, which play critical roles in proliferation, Ca2+ mobilization and cell differentiation.

Intriguingly, Lyn also 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, (Cornall, Cyster et al. 1998; Smith, Tarlinton et al. 1998; Chan, Lowell et al. 1998; Nishizumi, Horikawa et al. 1998; Maeda, Scharenberg et al. 1999), which further downmodulate signaling pathways, attenuate cell activation and can mediate tolerance.

By acting as a key regulator of both positive and negative signals, Lyn plays an important role in B cells. In these, 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 (Lowell, 2004; Saijo et al., 2003; Xu et al., 2005).

Much of the current knowledge about Lyn has emerged from studies of genetically manipulated mice. Lyn deficient mice display a phenotype that includes reduced numbers of mature B cells, B cell hyper-responsiveness to BCR stimulation, elevated serum IgM levels and accumulation of autoimmune antibodies, and development of autoimmune Glomerulonephritis in aging mice (Nishizumi, Taniuchi et al. 1995; Hibbs, Tarlinton et al. 1995; Chan, Meng et al. 1997). Intriguingly, mice expressing a hyperactive Lyn allele also develop severe autoimmune Glomerulonephritis and have a reduced life expectancy (Hibbs, Harder et al. 2002). Deregulation of the balance between positive vs. negative signaling is thought to underlie the paradoxical observation of B cell hyperactivity and lethal autoimmune glomerulonephritis in mice with reduced or elevated Lyn activity.

These observations very impressively demonstrate the importance of balancing positive and negative signaling appropriately to maintain proper cell function. In B cells, this balance is maintained through the function of one key regulator, Lyn. Deregulation of the balance can result in such severe pathological consequences as autoimmune disease, Glomerulonephritis (a model for human systemic lupus erythematosus, SLE) in the case of Lyn. Detailed studies of the functions of important signaling regulators like Lyn in mice therefore are key to understand and ultimately treat severe human diseases.

Further reading

citations =
*cite journal | author=Jouvin MH, Numerof RP, Kinet JP |title=Signal transduction through the conserved motifs of the high affinity IgE receptor Fc epsilon RI. |journal=Semin. Immunol. |volume=7 |issue= 1 |pages= 29–35 |year= 1995 |pmid= 7612892 |doi=
*cite journal | author=Hibbs ML, Dunn AR |title=Lyn, a src-like tyrosine kinase. |journal=Int. J. Biochem. Cell Biol. |volume=29 |issue= 3 |pages= 397–400 |year= 1997 |pmid= 9202419 |doi=
*cite journal | author=Blasioli J, Goodnow CC |title=Lyn/CD22/SHP-1 and their importance in autoimmunity. |journal=Curr. Dir. Autoimmun. |volume=5 |issue= |pages= 151–60 |year= 2002 |pmid= 11826756 |doi=
*cite journal | author=Greenway AL, Holloway G, McPhee DA, "et al." |title=HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication. |journal=J. Biosci. |volume=28 |issue= 3 |pages= 323–35 |year= 2004 |pmid= 12734410 |doi=
*cite journal | author=Tolstrup M, Ostergaard L, Laursen AL, "et al." |title=HIV/SIV escape from immune surveillance: focus on Nef. |journal=Curr. HIV Res. |volume=2 |issue= 2 |pages= 141–51 |year= 2004 |pmid= 15078178 |doi=
*cite journal | author=Joseph AM, Kumar M, Mitra D |title=Nef: "necessary and enforcing factor" in HIV infection. |journal=Curr. HIV Res. |volume=3 |issue= 1 |pages= 87–94 |year= 2005 |pmid= 15638726 |doi=
*cite journal | author=Stove V, Verhasselt B |title=Modelling thymic HIV-1 Nef effects. |journal=Curr. HIV Res. |volume=4 |issue= 1 |pages= 57–64 |year= 2006 |pmid= 16454711 |doi=

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