LYN

Function

Lyn has been described to have an inhibitory role in myeloid lineage proliferation. 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. 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, 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.

LYN is reported to be a key mediator of estrogen-dependent suppression of human osteoclast differentiation, survival, and function. 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. Insulin receptor activation has been shown to increase Lyn autophosphorylation, suggesting a feedback loop.

Lyn has been shown to protect against hepatocellular apoptosis and promote liver regeneration by preserving mitochondrial integrity.

In pulmonary function, Lyn activation in pulmonary epithelium has been linked to improved barrier integrity and reduced edema. Lyn activation in alveolar phagocytes enhances bacterial phagocytosis and reduces pulmonary infections. Furthermore, Lyn activation has been shown to reduce pulmonary mucus hypersecretion.

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.

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.

The insulin secretagogue glimepiride (Amaryl®) activates Lyn in adipocytes by disrupting lipid rafts, potentially contributing to its extrapancreatic glycemic control effects. Tolimidone (MLR-1023), a small-molecule allosteric activator of Lyn kinase with an EC50 of 63 nM, is under Phase 2a investigation for Type II diabetes.

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.

Interactions

LYN has been shown to interact with:

• BCAR1,
• CD117,
• CD22,
• Cdk1,
• DOK1,
• EPOR
• GPVI,
• INPP5D,
• IRS1,
• LCP2,
• MUC1,
• NEDD9,
• PLCG2,
• PPP1R15A,
• PTPRC,
• Syk,
• TRPV4,
• UNC119,

References

References

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3. (Jul 2002). "Short-term leptin-dependent inhibition of hepatic gluconeogenesis is mediated by insulin receptor substrate-2". Molecular Endocrinology.
4. (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.
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10. (May 1998). "Lyn physically associates with the erythropoietin receptor and may play a role in activation of the Stat5 pathway". Blood.
11. (Dec 2013). "Shockingly: the loss of Lyn leads to leakiness". Blood.
12. (Apr 1998). "Polygenic autoimmune traits: Lyn, CD22, and SHP-1 are limiting elements of a biochemical pathway regulating BCR signaling and selection". Immunity.
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14. (March 2019). "LYN, a key mediator in estrogen-dependent suppression of osteoclast differentiation, survival, and function". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.
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16. (December 2009). "Lyn-mediated mitochondrial tyrosine phosphorylation is required to preserve mitochondrial integrity in early liver regeneration". The Biochemical Journal.
17. (Aug 2001). "Interaction between growth arrest-DNA damage protein 34 and Src kinase Lyn negatively regulates genotoxic apoptosis". Proceedings of the National Academy of Sciences of the United States of America.
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48. (Mar 1998). "Inhibition of the B cell by CD22: a requirement for Lyn". The Journal of Experimental Medicine.
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50. (Dec 1992). "Specific expressions of Fyn and Lyn, lymphocyte antigen receptor-associated tyrosine kinases, in the central nervous system". Brain Research. Molecular Brain Research.
51. (Feb 2016). "Lyn regulates mucus secretion and MUC5AC via the STAT6 signaling pathway during allergic airway inflammation". Scientific Reports.
52. (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.
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55. (Apr 1993). "Association of Src-family kinase Lyn with B-cell antigen receptor". Immunological Reviews.
56. (Sep 1989). "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.
57. (Feb 1992). "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.
58. (Nov 2000). "Stem cell factor induces phosphatidylinositol 3'-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells". Blood.