Attenuation of Interleukin 2 Signal in the Spleen Cells of Complex Ganglioside-lacking Mice

Zhao, Jinmin; Fukumoto, Satoshi; Okada, Masahiko; Furugen, Reiko; Miyazaki, Hiroshi; Takamiya, Kogo; Aizawa, Shinichi; Shiku, Hiroshi; Matsuyama, Tomohiro; Furukawa, Koichi

doi:10.1074/jbc.274.20.13744

Cited by 47 publications

(40 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Of course, Ho/Ho mutants should have various defects other than those in peripheral nerves as expected from abnormal phenotypes such as immunodysfunction and endocrinological defects in the single mutant mice (14,15). These factors might also be involved in the generation of the severe skin injury.…”

Section: Discussionmentioning

confidence: 99%

“…GM2/GD2 synthase gene knock-out mice lacking all complex gangliosides showed almost normal morphogenesis of the nervous system and no definite abnormal behaviors (11), although they showed nerve degeneration along with aging (12,13) as well as immunodeficiency (14) and male infertility (15). GD3 synthase gene knock-out mice lacking all b-series gangliosides 1 also showed no marked abnormal appearance in nerve tissues and exhibited almost intact behaviors (16,17), although regeneration of the lesioned hypoglossal nerve was largely reduced (17).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Refractory Skin Injury in Complex Knock-out Mice Expressing Only the GM3 Ganglioside

Inoue

Fujii

Furukawa

et al. 2002

Journal of Biological Chemistry

Self Cite

108

View full text Add to dashboard Cite

We generated double knock-out mice lacking the GM2/ GD2 and the GD3 synthase gene by mating single gene mutants, and we analyzed the abnormal phenotypes of the mutant mice expressing only the GM3 ganglioside. We observed a refractory skin lesion that appeared primarily on the face of the mutant mice at 25 weeks after birth or later. Frequent scratching of the wound sites was observed in mutant mice with the skin injury, suggesting that it is a triggering factor that exacerbates the injury. This was confirmed by isolating mice in special cages for metabolic study in which the skin injury developed more rapidly. Characteristic proliferation of nerve fibers was found in the epidermis and subepidermis at the injured sites of the mutants, probably a result of continuous skin injury. Peripheral nerve degeneration was observed in young mutant mice, suggesting that reduced sensory function induced over-scratching and the resulting skin lesion. The fact that sensory response to mechanical stimuli decreased while that to hot stimuli increased in the mutant mice supports this interpretation. Thus, only GM3-expressing mice displayed the important role of gangliosides in maintaining skin integrity via regulation of the peripheral nerves.Acidic glycosphingolipids, gangliosides, are ubiquitously expressed in the various tissues of vertebrates and play important roles in the regulation of highly organized multicellular systems (1). In particular, they are very much enriched in the nervous system and have been considered to control development, proliferation, differentiation, and maintenance of the neural tissues and cells (2, 3). Expression patterns of various ganglioside species in the nervous system vary during development and are strictly regulated in a spatio-temporal manner (4), suggesting that individual structures of gangliosides contain significant implications for individual situations.A number of studies have been performed to demonstrate the biological function of gangliosides primarily by modifying their structures with enzymes or using inhibitors to block some steps of synthesis (5). Otherwise, the effects of addition of gangliosides to the culture medium or injection into the conditioned animals have been the primary approaches in addressing the significance of gangliosides. However, recent success in the molecular cloning of glycosyltransferase genes brought about an evolutional change in the experimental approaches for carbohydrate function analysis. Availability of glycosyltransferase genes responsible for the synthesis of gangliosides enabled us to remodel ganglioside compositions of cells and tissues in vivo (6, 7) and in vitro (8).Because we isolated GM2/GD2 synthase (EC 2.4.1.92) cDNA (9) and GD3 synthase (EC 2.4.99.8) cDNA (10), we established gene knock-out mice lines of the individual glycosyltransferases. GM2/GD2 synthase gene knock-out mice lacking all complex gangliosides showed almost normal morphogenesis of the nervous system and no definite abnormal behaviors (11), although they showed nerve degene...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Refractory Skin Injury in Complex Knock-out Mice Expressing Only the GM3 Ganglioside

Inoue

Fujii

Furukawa

et al. 2002

Journal of Biological Chemistry

Self Cite

108

View full text Add to dashboard Cite

show abstract

“…41 In contrast, T cells from mice lacking all complex gangliosides, including GM1, because of targeted deletion of the gene encoding the GM2/GD2 synthase display decreased IL-2-induced signaling and proliferation. 42 Whether the defects in IL-2R signaling in these cells relate to lipid rafts awaits further investigation.…”

Section: Discussionmentioning

confidence: 99%

Role for lipid rafts in regulating interleukin-2 receptor signaling

Marmor

Julius

2001

Blood

114

View full text Add to dashboard Cite

IntroductionLipid rafts are plasma membrane microdomains postulated to function in signaling and membrane trafficking. [1][2][3] Lipid rafts are enriched in gangliosides (glycosphingolipids) and cholesterol, which form liquid-ordered domains of decreased membrane fluidity. The long, saturated acyl chains of gangliosides impart a high degree of order further stabilized by intercalating cholesterol molecules, leading to the insolubility of lipid rafts in nonionic detergents. Lipid rafts can be isolated based on their detergent insolubility and low-buoyancy density using discontinuous sucrose gradient ultracentrifugation of nonionic detergent lysates. Lipid rafts are not artifacts of detergent extraction. They have been detected in living cells using chemical cross-linking and fluorescence resonance energy transfer. 4,5 The modification of proteins with saturated acyl groups can result in their localization within lipid rafts. Thus, these microdomains are enriched in glycosyl-phosphatidyl-inositol anchored proteins (GPI-AP) and in many signaling molecules such as Src family protein tyrosine kinases (PTKs), the adaptor protein LAT, heterotrimeric and small G-proteins, and phosphoinositides. 3 In addition, several transmembrane receptors are inducibly recruited to or stabilized within lipid rafts, including T-cell receptor (TCR), B-cell receptor (BCR), and Fc⑀RI. 2 Subsequent activation of signaling molecules in lipid rafts may facilitate signaling through these immunoreceptors. Lipid rafts may act to segregate molecules in the plasma membrane and to regulate signaling through the spatial coordination of intermolecular associations.Stimulation of T cells through TCR results in the activation of multiple signaling pathways, leading to interleukin-2 (IL-2) responsiveness and the secretion of IL-2 and resulting in autocrine cell growth. 6 The high-affinity receptor for IL-2 is composed of the IL-2R␣ chain, which functions solely in IL-2 binding, and IL-2R␤ and IL-2R␥ c , which contribute to IL-2 binding and mediate signal transduction. 7 IL-2-induced proliferation requires activation of the Janus family kinases JAK1 and JAK3, which are constitutively associated with IL-2R␤ and IL-2R␥, respectively. 8,9 Ligandinduced IL-2R aggregation leads to the juxtaposition of JAK1 and JAK3, resulting in their phosphorylation and activation. Subsequent phosphorylation of tyrosine residues in receptor chains leads to the SH2-domain-mediated recruitment of signal transducer and activator of transcription (STAT) proteins STAT5a and STAT5b. 7 JAK-mediated phosphorylation of STAT proteins leads to their dimerization by SH2 domain-phosphotyrosine interactions and their translocation to the nucleus, where STAT proteins regulate gene transcription. Signaling through the IL-2R also induces the recruitment and activation of phosphatidylinositol 3 kinase (PI3K), which is implicated in IL-2-mediated proliferation and survival through its downstream effector protein kinase B/Akt. 10,11 In addition, the tyrosine phosphorylation of IL-2R␤ results i...

show abstract

“…The mutant male mice were sterile and showed morphological and functional defects in the testis (70). Within their immune system, the response of spleen T cells to interleukin 2 was impaired (71). The molecular bases for these observations are currently unknown.…”

Section: Genetically Engineered Micementioning

confidence: 99%