Tyrosine-protein kinase Lyn is a protein that in humans is encoded by the LYN gene.^[5]

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LYN
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1W1F, 1WA7, 3A4O
Identifiers
Aliases	LYN, LYN proto-oncogene, Src family tyrosine kinase, JTK8, p53Lyn, p56Lyn
External IDs	OMIM: 165120 MGI: 96892 HomoloGene: 55649 GeneCards: LYN
Gene location (Human) Chr. Chromosome 8 (human)[1] Band 8q12.1 Start 55,879,835 bp[1] End 56,014,169 bp[1]
Gene location (Mouse) Chr. Chromosome 4 (mouse)[2] Band 4 A1|4 2.05 cM Start 3,678,115 bp[2] End 3,813,122 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in monocyte blood palpebral conjunctiva bone marrow bone marrow cells appendix periodontal fiber trabecular bone pancreatic ductal cell spleen Top expressed in blood spleen right lung lobe left lung left lung lobe submandibular gland conjunctival fornix lacrimal gland jejunum epithelium of stomach More reference expression data BioGPS n/a
Gene ontology Molecular function transmembrane transporter binding SH3 domain binding protein-containing complex binding kinase activity gamma-tubulin binding signaling receptor binding ATP binding protein kinase activity non-membrane spanning protein tyrosine kinase activity enzyme binding transferase activity platelet-derived growth factor receptor binding integrin binding protein binding glycosphingolipid binding protein tyrosine kinase activity nucleotide binding phosphoprotein binding ubiquitin protein ligase binding ephrin receptor binding phosphorylation-dependent protein binding Cellular component cytoplasm cytosol membrane extrinsic component of cytoplasmic side of plasma membrane mitochondrial intermembrane space perinuclear region of cytoplasm nucleus mitochondrial membranes membrane raft extracellular exosome Golgi apparatus plasma membrane postsynaptic density mast cell granule integrin alpha2-beta1 complex mitochondrial crista intracellular membrane-bounded organelle glutamatergic synapse postsynaptic specialization, intracellular component Biological process regulation of protein phosphorylation cellular response to extracellular stimulus cellular response to retinoic acid positive regulation of B cell receptor signaling pathway tolerance induction to self antigen regulation of mast cell activation regulation of cell adhesion mediated by integrin cellular response to heat response to amino acid hemopoiesis adaptive immune response regulation of erythrocyte differentiation cellular response to DNA damage stimulus positive regulation of Fc receptor mediated stimulatory signaling pathway platelet activation Fc-epsilon receptor signaling pathway protein phosphorylation regulation of B cell apoptotic process positive regulation of dendritic cell apoptotic process positive regulation of glial cell proliferation response to carbohydrate regulation of platelet aggregation negative regulation of cell population proliferation B cell receptor signaling pathway negative regulation of myeloid leukocyte differentiation dendritic cell differentiation Fc receptor mediated inhibitory signaling pathway Fc-gamma receptor signaling pathway involved in phagocytosis transmembrane receptor protein tyrosine kinase signaling pathway regulation of B cell receptor signaling pathway stimulatory C-type lectin receptor signaling pathway response to sterol depletion positive regulation of stress-activated protein kinase signaling cascade regulation of cytokine production response to insulin positive regulation of mast cell proliferation negative regulation of MAP kinase activity regulation of ERK1 and ERK2 cascade positive regulation of peptidyl-tyrosine phosphorylation erythrocyte differentiation protein autophosphorylation oligodendrocyte development regulation of mast cell degranulation positive regulation of phosphorylation viral process response to toxic substance negative regulation of protein phosphorylation Fc receptor mediated stimulatory signaling pathway growth hormone receptor signaling pathway via JAK-STAT phosphorylation immune system process regulation of release of sequestered calcium ion into cytosol positive regulation of tyrosine phosphorylation of STAT protein B cell homeostasis immune response-regulating cell surface receptor signaling pathway response to axon injury negative regulation of mast cell proliferation regulation of inflammatory response peptidyl-tyrosine autophosphorylation response to hormone regulation of monocyte chemotaxis leukocyte migration lipopolysaccharide-mediated signaling pathway histamine secretion by mast cell intracellular signal transduction response to organic cyclic compound negative regulation of intracellular signal transduction positive regulation of cell migration ephrin receptor signaling pathway negative regulation of toll-like receptor 2 signaling pathway T cell costimulation response to peptide hormone platelet degranulation blood coagulation positive regulation of phosphatidylinositol 3-kinase activity positive regulation of oligodendrocyte progenitor proliferation negative regulation of immune response positive regulation of cell population proliferation positive regulation of neuron projection development negative regulation of ERK1 and ERK2 cascade peptidyl-tyrosine phosphorylation negative regulation of B cell proliferation negative regulation of toll-like receptor 4 signaling pathway signal transduction innate immune response neuron projection development central nervous system development inflammatory response positive regulation of protein phosphorylation positive regulation of phosphatidylinositol 3-kinase signaling cell differentiation positive regulation of Ras protein signal transduction positive regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 4067 17096 Ensembl ENSG00000254087 ENSMUSG00000042228 UniProt P07948 P25911 RefSeq (mRNA) NM_001111097 NM_002350 NM_001111096 NM_010747 RefSeq (protein) NP_001104567 NP_002341 NP_001104566 NP_034877 Location (UCSC) Chr 8: 55.88 – 56.01 Mb Chr 4: 3.68 – 3.81 Mb PubMed search [3] [4]
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Lyn is a member of the Src family of protein tyrosine kinases, which is mainly expressed in hematopoietic cells,^[6] in neural tissues^[7] liver, and adipose tissue.^[8] 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),^[9][10] CD40,^[11] or CD19.^[12] 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.^[13] 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.^[12][14] 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,^{[15][16][17][18][19]} 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.^[20][21][22] 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. ^[23]

LYN is reported to be a key signal mediator for estrogen-dependent suppression of human osteoclast differentiation, survival, and function.^[24] 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.^[25] In turn, activation of the insulin receptor has been shown to increase autophosphorylation of Lyn suggesting a possible feedback loop.^[26] The insulin secretagogue, glimepiride (Amaryl®) activates Lyn in adipocytes via the disruption of lipid rafts.^[27] This indirect Lyn activation may modulate the extrapancreatic glycemic control activity of glimepiride.^[27][28] Tolimidone (MLR-1023) is a small molecule allosteric activator of lyn kinase with an EC50 of 63 nM^[29][30] that is currently under Phase 2a investigation for Type II diabetes.^[31] In June, 2016, the sponsor of these studies, Melior Discovery, announced positive results from their Phase 2a study with tolimidone in diabetic patients,^[32][33] and the continuation of additional clinical studies.^[34]

Lyn has been shown to protect against hepatocellular apoptosis and promote liver regeneration through the preservation of hepatocellular mitochondrial integrity.^[35]

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.^[36][37] Additional evidence suggest that lyn activation in alveolar phagocytes improves phagocytosis of bacteria and reduces pulmonary infection. ^[38][39] Finally, other research has found that lyn activation reduces pulmonary hypersecretion of mucus. ^[40]

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.^[13]

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.^[41]

LYN has been shown to interact with:

• Lyn-CD22-SHP-1 pathway