Disease relevance of Lyn

• Remarkably, CD19 deficiency suppressed the hyper-responsive phenotype of Lyn(-/-) B cells and autoimmunity characterized by serum autoantibodies and immune complex-mediated glomerulonephritis in Lyn(-/-) mice [1].
• This study also suggests that reduced activity of Lyn, a negative regulator of mast cell activation, underlies the susceptibility of ASK mice to anaphylaxis and implies that dysregulation of Lyn and other Src family kinases contributes to epileptogenesis [2].
• BCR signals are down-regulated by Lyn, which phosphorylates inhibitory receptors. lyn(-/-) mice have reduced BCR signaling thresholds and develop autoantibodies, glomerulonephritis, splenomegaly due to myeloid hyperplasia, and increased B-1 cell numbers [3].
• In vivo infection of Lyn deficient animals also results in a massive splenomegaly characteristic of the virus [4].
• However, we observe differences in the pathogenesis of Friend erythroleukemia in Lyn-/- mice [4].

Psychiatry related information on Lyn

• We examined the biochemical consequences of BCR ligation in mouse B cells lacking either Lyn or CD19 for evidence of interaction or codependence [5].

High impact information on Lyn

• Data from knockout experiments in cell lines and mice have revealed distinct functions for the intracellular protein tyrosine kinases (Lyn, Syk, Btk) in BCR signaling and B cell development [6].
• Mice homozygous for a disruption at the Lyn locus display abnormalities associated with the B lymphocyte lineage and in mast cell function [7].
• Lyn-/- mice have circulating autoreactive antibodies, and many show severe glomerulonephritis caused by the deposition of IgG immune complexes in the kidney, a pathology reminiscent of systemic lupus erythematosus [7].
• Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease [7].
• In these cells, activation of the tyrosine kinase Lyn, an important anti-apoptotic event, was prevented as a consequence of death-receptor stimulation, most likely through association of the receptor with activated SHP-1 [8].

Chemical compound and disease context of Lyn

• In this report we analyze the role of the Lyn tyrosine kinase in the pathogenesis of Friend virus [4].

Biological context of Lyn

• From these data, we conclude that Lyn plays a role in signal transduction for not only clonal expansion and terminal differentiation of peripheral B cells but also elimination of autoreactive B cells [9].
• Increased dosage of Lyn in B cells augmented BCR-induced phosphorylation at both sites [10].
• Loss of Lyn, PTEN (phosphatase and tensin homolog), or SH2-containing inositol phosphatase suppressed the Btk(lo) phenotype in vitro but not in vivo, whereas CD19 and the p85alpha form of phosphoinositide 3-kinase behaved as Btk(lo) enhancers in vivo but not in vitro [11].
• These data imply that Lyn is involved in B cell triggering by CD38 ligation plus IL-5 for isotype switching [12].
• In agreement with this, Lyn enhanced the Stat5-dependent transcriptional activation when overexpressed in 32D/EpoR-Wt cells [13].

Anatomical context of Lyn

• We examined FcgammaR signaling and phagocytic function in bone marrow-derived macrophages from mutant mice lacking the major Src family kinases expressed in these cells, Hck, Fgr, and Lyn [14].
• Positive and negative regulation of mast cell activation by Lyn via the FcepsilonRI [15].
• The importance of Lyn kinase for eosinophil differentiation was studied using antisense oligodeoxynucleotides [16].
• Quantitative immunoelectron microscopy studies confirmed that Lyn accumulated under the plasma membrane beneath the bound particles [17].
• The IL-5-stimulated eosinophil differentiation from bone marrow cells is significantly inhibited in Lyn(-/-) mice as compared with that in control mice [16].

Associations of Lyn with chemical compounds

• In addition, the enhanced intracellular Ca(2+) responses following B cell Ag receptor ligation that typify Lyn deficiency were delayed by the loss of CD19 expression [1].
• Receptor engagement also resulted in the rapid association of Lyn with the phosphotyrosine phosphatase, CD45 [18].
• Conversely, there was very little basal or stimulated tyrosine phosphorylation or activity of the inositol phosphatase, SHIP, in Lyn(-/-) BMMCs [19].
• The loss of SHIP phosphorylation and activity very likely contributes to the increased levels of phosphatidylinositol 3,4,5-trisphosphate and the excess FcepsilonRI signaling in Lyn(-/-) BMMCs [19].
• This association of Lyn with receptor components was stable in the detergent Brij 96, but was readily disrupted by Nonidet P-40, suggesting the involvement of hydrophobic interactions in stabilizing formation of the Lyn-receptor complex [18].

Physical interactions of Lyn

• We could previously show that, through the Tec-homology domain, Tec is bound to Lyn kinase both in vitro and in vivo [20].
• Our proposed docking models of the NS-187/Abl complex support the notion that NS-187 is more specific for Lyn than for Src [21].
• The Lyn SH2 binding profile resembled that of Blk, but differences in the binding specificities of these kinases were also observed [22].
• HS1 interacts with Lyn and is critical for erythropoietin-induced differentiation of erythroid cells [23].
• Constitutive CD19/Lyn/Vav complex signaling may therefore be responsible for the establishment of baseline signaling thresholds in B cells before Ag receptor ligation, in addition to accelerating signaling following BCR engagement or other transmembrane signals [24].

Enzymatic interactions of Lyn

• In addition, Lyn was demonstrated to phosphorylate the EpoR and Stat5 on tyrosines in vitro [13].
• Here we demonstrate that Lyn can phosphorylate tyrosine residues of the Tec protein, and thereby activate Tec in 3T3 fibroblasts [20].
• Immunoprecipitation experiments revealed that gamma-tubulin from activated cells formed complexes with Fyn and Syk protein tyrosine kinases and several tyrosine phosphorylated proteins from both wild-type and Lyn(-/-) BMMCs [25].
• The biochemical basis of this complex trait involves a pathway requiring Lyn to phosphorylate CD22 and recruit SHP-1 to the CD22/BCR complex [26].

Regulatory relationships of Lyn

• Lyn tyrosine kinase regulates thrombopoietin-induced proliferation of hematopoietic cell lines and primary megakaryocytic progenitors [27].
• Because Tec is coexpressed with Lyn in many hematopoietic cell types, it has been intriguing to investigate the biological role of the Tec-Lyn association [20].
• Lyn promoted phosphorylation of c-Kit and association of c-Kit and Dok-1 [28].
• When wild type Btk is activated by coexpression with Lyn, the tyrosine phosphorylated pool of Btk is highly enriched in the membrane fraction [29].
• Fast protein liquid chromatography Mono Q column-fractionated MAPK maintains the ability to bind bacterially expressed Lyn, suggesting that the two kinases may interact directly [30].

Other interactions of Lyn

• We infer from these results that both Fyn and Lyn are required and that their signals are synergistic for B cell triggering after CD38 ligation [12].
• A critical role of Lyn and Fyn for B cell responses to CD38 ligation and interleukin 5 [12].
• Effects of Lyn, PTEN, or p85alpha haploinsufficiency were observed [11].
• In the present study, we demonstrate that Lyn, a Src family tyrosine kinase, physically associates with the EpoR in Epo-dependent hematopoietic cell lines, 32D/EpoR-Wt and F36E [13].
• Similarly, proliferation is increased after introducing a dominant-negative form of Lyn into BaF3/Mpl cells [27].

Analytical, diagnostic and therapeutic context of Lyn

• Far-Western blotting and synthetic phosphopeptide competition assays further indicated that the Lyn SH2 domain directly binds to the tyrosine-phosphorylated EpoR, most likely through its interaction with phosphorylated Y-464 or Y-479 in the carboxy-terminal region of the EpoR [13].
• On the basis of immunoprecipitation and sequence analysis data, we propose that the human G-CSFR forms a three-component signaling complex with Lyn and Syk [31].
• Microarray analysis of Lyn-deficient B cells reveals germinal center-associated nuclear protein and other genes associated with the lymphoid germinal center [32].
• The presence of Lyn enhanced PU.1 expression in a Northern blot [32].
• Complementary DNA array analysis of Lyn-deficient DT40 cells shows that the absence of Lyn leads to down-regulation of numerous genes encoding proteins involved in B cell receptor signaling, proliferation, control of transcription, immunity/inflammation response, and cytoskeletal organization [32].

References