Biology:LYN

Lyn is a member of the Src family of protein tyrosine kinases, which is mainly expressed in hematopoietic cells, in neural tissues liver, and adipose tissue. 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), CD40, or CD19. 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. 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,

See also

• Lyn-CD22-SHP-1 pathway

Further reading

• "Signal transduction through the conserved motifs of the high affinity IgE receptor Fc epsilon RI". Seminars in Immunology 7 (1): 29–35. Feb 1995. doi:10.1016/1044-5323(95)90005-5. PMID 7612892. 
• "Lyn, a src-like tyrosine kinase". The International Journal of Biochemistry & Cell Biology 29 (3): 397–400. Mar 1997. doi:10.1016/S1357-2725(96)00104-5. PMID 9202419. 
• "Lyn/CD22/SHP-1 and Their Importance in Autoimmunity". Current Directions in Autoimmunity. 5. 2002. pp. 151–160. doi:10.1159/000060551. ISBN 978-3-8055-7308-5. 
• "HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication". Journal of Biosciences 28 (3): 323–335. Apr 2003. doi:10.1007/BF02970151. PMID 12734410. 
• "HIV/SIV escape from immune surveillance: focus on Nef". Current HIV Research 2 (2): 141–151. Apr 2004. doi:10.2174/1570162043484924. PMID 15078178. 
• "Nef: "necessary and enforcing factor" in HIV infection". Current HIV Research 3 (1): 87–94. Jan 2005. doi:10.2174/1570162052773013. PMID 15638726. 
• "Modelling thymic HIV-1 Nef effects". Current HIV Research 4 (1): 57–64. Jan 2006. doi:10.2174/157016206775197583. PMID 16454711. 

External links

• Overview of all the structural information available in the PDB for UniProt: P07948 (Tyrosine-protein kinase Lyn) at the PDBe-KB.