LYN
Mammalian protein found in Homo sapiens
From Wikipedia, the free encyclopedia
Tyrosine-protein kinase Lyn is a protein that in humans is encoded by the LYN gene.[5]
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.
Function
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. This activation initiates a cascade of signaling events mediated by Lyn phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based activation motifs (ITAMs) of receptor proteins. This cascade leads to the recruitment and activation of other kinases, including Syk, phospholipase Cγ2 (PLCγ2), and phosphatidyl inositol-3 kinase.[12][14] These kinases generate activation signals critical for proliferation, Ca2+ mobilization, and cell differentiation.
Lyn also plays an essential role in transmitting inhibitory signals by phosphorylating tyrosine residues within the immunoreceptor tyrosine-based inhibitory motifs (ITIMs) of regulatory proteins such as CD22, PIR-B, and FCγRIIb1. ITIM phosphorylation subsequently recruits and activates phosphatases including SHIP-1 and SHP-1,[15][16][17][18][19] leading to the attenuation of signaling pathways, downregulation of cell activation, and promotion of tolerance. In B cells, Lyn sets the threshold of signaling and maintains the balance between activation and inhibition, effectively functioning as a rheostat rather than a binary switch.[20][21][22]
LYN is reported to be a key mediator of estrogen-dependent suppression of human osteoclast differentiation, survival, and function.[23] It has also been implicated in the insulin signaling pathway, where activated Lyn phosphorylates insulin receptor substrate 1 (IRS1), promoting Glut-4 translocation to the membrane and enhancing glucose utilization.[24] Insulin receptor activation has been shown to increase Lyn autophosphorylation, suggesting a feedback loop.[25]
Lyn has been shown to protect against hepatocellular apoptosis and promote liver regeneration by preserving mitochondrial integrity.[26]
In pulmonary function, Lyn activation in pulmonary epithelium has been linked to improved barrier integrity and reduced edema.[27][28] Lyn activation in alveolar phagocytes enhances bacterial phagocytosis and reduces pulmonary infections.[29][30] Furthermore, Lyn activation has been shown to reduce pulmonary mucus hypersecretion.[31]
Clinical significance
As a drug target
HSP90 inhibitor NVP-BEP800 has been reported to affect Lyn kinase stability and inhibit the growth of B-cell acute lymphoblastic leukemias by interfering with NF-kappaB signaling.[32]
The allosteric activator of Lyn kinase Tolimidone (MLR-1023) is currently under Phase 2a clinical investigation for Type II diabetes, with promising results reported from studies conducted by Melior Discovery.[33][34][35][36]
The insulin secretagogue glimepiride (Amaryl®) activates Lyn in adipocytes by disrupting lipid rafts,[37] potentially contributing to its extrapancreatic glycemic control effects.[37][38] Tolimidone (MLR-1023), a small-molecule allosteric activator of Lyn kinase with an EC50 of 63 nM,[39][40] is under Phase 2a investigation for Type II diabetes.[33]
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.[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]
Interactions
See also
- Lyn-CD22-SHP-1 pathway
