Disease relevance of Lyn

• However, the role of Lyn in infectious diseases is not clear [1].
• Here, we demonstrate that Lyn activation by phosphorylation significantly impacted invasion of an alveolar epithelial cell line, primary lung cells, and rat lungs by Pseudomonas aeruginosa (PA), a common opportunistic lung pathogen affecting individuals with deficient lung immunity [1].

Psychiatry related information on Lyn

• The present data suggest that the NMDA receptor signal that is enhanced in the absence of Lyn suppresses the motor activity, probably through inhibition of dopaminergic pathway at striatum.We conclude that Lyn contributes to coordination of motor activity through regulation of the NMDA pathway [2].

High impact information on Lyn

• Upon cross-linking by antigen, the high affinity receptor for immunoglobulin E (IgE), FcepsilonRI, is phosphorylated by the Src family tyrosine kinase Lyn to initiate mast cell signaling, leading to degranulation [3].
• In mast cells, cross-linking the high-affinity IgE receptor (Fc(epsilon)RI) initiates the Lyn-mediated phosphorylation of receptor ITAMs, forming phospho-ITAM binding sites for Syk [4].
• We have determined the membrane topography of the high-affinity IgE receptor, FcstraightepsilonRI, and its associated tyrosine kinases, Lyn and Syk, by immunogold labeling and transmission electron microscopic (TEM) analysis of membrane sheets prepared from RBL-2H3 mast cells [5].
• Subsequent to concentration of Fcepsilon receptor I, the mast cell receptor for IgE, and colocalized tyrosine phosphorylation activity, Lyn kinase and other proteins anchored to the inner leaflet of the plasma membrane redistribute selectively with the receptor clusters in a process that depends on actin polymerization [6].
• Moreover, we found that exosome-associated Lyn (1) had a lower molecular weight compared with Lyn detected in cell-isolated detergent-resistant domains, (2) was absent from the Triton X-100-insoluble fraction isolated from exosomes, and (3) had lost its partitioning capacity in Triton X-114 [7].

Biological context of Lyn

• In rat basophilic leukemia-2H3 cells, Lyn thus plays a dual role by positively regulating Fc epsilonRI phosphorylation and degranulation while negatively regulating LTC4 production [8].
• A fraction of the total cellular Lyn is associated via its N-terminal unique domain with the cytoplasmic domain of the Fc epsilonRI beta subunit before receptor aggregation [8].
• A lipid raft environment enhances Lyn kinase activity by protecting the active site tyrosine from dephosphorylation [9].
• In the current study, we stably transfected the unique domain of Lyn into rat basophilic leukemia-2H3 mast cells and examined the consequences on Fc epsilonRI-induced signal transduction and mediator secretion to further define the role of the unique domain of Lyn in mast cell secretion [8].
• Here, we report that fusion proteins containing the Src homology 2 (SH2) domains of Syk and Lyn precipitated tyrosine-phosphorylated proteins from RBL-2H3 cell lysates [10].

Anatomical context of Lyn

• Regulation of rat basophilic leukemia-2H3 mast cell secretion by a constitutive Lyn kinase interaction with the high affinity IgE receptor (Fc epsilon RI) [8].
• We used differential detergent solubility and sucrose gradient fractionation to isolate Lyn from raft and nonraft regions of the plasma membrane in the presence or absence of tyrosine phosphatase inhibitors [9].
• Chimeric Syk with the myristylation sequence was membrane associated, and a small fraction was constitutively colocalized with FcepsilonRI, Lyn, and LAT (linker for T-cell activation) in the glycolipid-enriched microdomains or rafts [11].
• Recently, it is suggested that the localization of Lyn in lipid rafts is critical for its activation in several cell lines, although the precise mechanism is still unknown [12].
• Lyn is an important B cell signaling kinase of the Src tyrosine kinase family with a broad range of functions from cytoskeletal changes to induction of apoptosis [1].

Associations of Lyn with chemical compounds

• Cross-linking of IgE-receptor complexes by antigen causes their coalescence with lipid rafts, where they are phosphorylated by the Src family tyrosine kinase, Lyn [9].
• Conversely, tyrosine phosphorylation of the adaptor protein Gab2, which is essential for mast cell degranulation, was inhibited after Ag stimulation of Lyn unique domain transfectants, and Ag-induced release of histamine was inhibited up to 48% [8].
• Instead, Src tyrosine kinases are mainly located in the intermembrane space - in particular, as revealed by immunogold experiments for Lyn kinase, in the cristal lumen [13].
• We reported previously that FcepsilonRI dimers formed by a particular anti-FcepsilonRI alpha mAb (H10) initiate signaling through Lyn activation and FcepsilonRI subunit phosphorylation, but cause only modest activation of Syk and little Ca(2+) mobilization and secretion [14].
• In RBL-2H3 rat tumor mast cells, cross-linking the high affinity IgE receptor, Fc epsilon R1, activates the protein-tyrosine kinases Lyn and Syk and initiates a series of responses including protein-tyrosine phosphorylation, inositol 1,4,5-trisphosphate synthesis, Ca2+ mobilization, secretion, membrane ruffling, and actin plaque assembly [15].

Physical interactions of Lyn

• A fusion protein containing Src homology 2 (SH2) and SH3 domains of Lyn bound Syk from lysates of nonactivated RBL cells; an increased binding was observed when lysates from Ag- or pervanadate-activated cells were used [16].

Enzymatic interactions of Lyn

• Further experiments have indicated that Syk-Lyn interactions occur in Ag-activated RBL cells under in vivo conditions and that these interactions could involve direct binding of the Lyn SH2 domain with phosphorylated tyrosine of Syk [16].

Regulatory relationships of Lyn

• These findings provide further evidence that the initiations of the FcepsilonRI-mediated signals are upstreamly regulated by Src family protein tyrosine kinases and revealed that their terminations are regulated by Lyn-dependent (Syk and MAP kinase) and -independent ([Ca2+]i elevation and histamine release) mechanisms [17].
• These findings indicate (i) Csk negatively regulates rapid FcepsilonRI/Lyn coupling, and (ii) Csk activity is potentially required for its termination [17].
• Therefore, the NMDA receptor-mediated signaling is enhanced in lyn-/- mice, indicating that Lyn regulates the NMDA receptor pathway negatively [2].

Other interactions of Lyn

• We find that Lck, Lyn, and Yes are localized to the postsynaptic density (PSD), the primary structural component of excitatory synapses [18].
• Lipid rafts isolated using Brij-96 and Triton X-100 differed in density, protein content and the distribution between high- and low-density fractions of the known raft constituents, Thy-1, and the non-receptor protein tyrosine kinases, Yes and Lyn [19].
• We suggest that the PDE4A splice variant RPDE-6 has a propensity for interaction with selective SH3 domains, in particular those from Src and the Src-related tyrosyl kinases Lyn and Fyn [20].
• CCK stimulated an association of Lyn with PKC-delta, Shc, p125(FAK) and PYK2 as well as with their autophosphorylated forms, but not with Cbl, p85, p130(CAS) or ERK 1/2 [21].
• The onset of FcepsilonRI-mediated Lyn activation was delayed in Csk-expressing cells, and further delayed in mCsk-expressing cells [17].

Analytical, diagnostic and therapeutic context of Lyn

• Sepharose 4B gel chromatography of postnuclear supernatants from Nonidet-P40-solubilized antigen (Ag)- or pervanadate-activated RBL cells revealed extensive changes in the size of complexes formed by Lyn and Syk kinases and other cellular components [16].
• Once phosphorylated by TPK-IIB, however, p50 is converted into a good substrate for c-Fgr and, to a lesser extent, for Lyn. p50 phosphorylated by TPK-IIB associates with c-Fgr and Lyn, as judged by co-immunoprecipitation with anti-Fgr IgG and anti-Lyn IgG, respectively [22].
• Immunoblotting analysis showed Fyn and Lyn were present in most tissue cytosols [23].
• In sucrose gradient centrifugation analyses of detergent-extracted cells, H10-treated cells show a more complete redistribution of FcepsilonRI beta from heavy (detergent-soluble) to light (Lyn-enriched, detergent-resistant) fractions than cells activated with FcepsilonRI multimers [14].
• Immunogold electron microscopy showed that H10-FcepsilonRI dimers colocalize preferentially with Lyn and are rarely within the osmiophilic "signaling domains" that accumulate FcepsilonRI and Syk in Ag-treated cells [14].

References