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Src Family (src + family)
Terms modified by Src Family Selected AbstractsUp-regulation of leukocyte CXCR4 expression by sulfatide: An L-selectin-dependent pathway on CD4+ T cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2007Pascal Duchesneau Abstract CXCR4 plays significant roles in immune and inflammatory responses and is important for selective recruitment of leukocytes. We previously showed that CXCR4 surface expression of human lymphocytes was affected by sulfatide, an in vivo ligand for L-selectin. Increased CXCR4 expression was shown to promote biologically relevant functions such as integrin-dependent adhesion and transmigration. Here, we show that sulfatide-induced CXCR4 up-regulation also occurs on other leukocyte subsets in humans and mice. B cells and CD4+CD25+ T cells had the highest CXCR4 up-regulation after sulfatide stimulation. Transfection of L-selectin was sufficient for K562 cells to acquire sulfatide-induced CXCR4 up-regulation, while analysis of L-selectin knockout mice revealed that this response was critically L-selectin dependent only for CD4+ T cells, suggesting an alternative pathway in CD8+ T cells and B cells. Sulfatide triggered several intracellular signaling events in CD4+ T cells, but only tyrosine kinase activation, including members of the Src family, were essential for L-selectin to CXCR4 signaling. CXCR4 up-regulation was rapid, enhanced CXCL12-induced signaling and increased chemotaxis toward CXCL12, and therefore has potentially important roles in vivo. Thus, the response to CXCL12 depends in part on tissue expression of sulfatide and, specifically in CD4+ T cells, also depends on the surface level of L-selectin. [source] c-Src kinase activation regulates preprotachykinin gene expression and substance P secretion in rat sensory gangliaEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2003Orisa J. Igwe Abstract Increased synthesis of substance P (SP) in the dorsal root ganglia (DRG) and enhanced axonal transport to and secretion from the primary afferent sensory neurons might enhance pain signalling in the spinal dorsal horn by modifying pronociceptive pathways. IL-1, increases SP synthesis by enhancing the expression of preprotachykinin (PPT) mRNA encoding for SP and other tachykinins in the DRG. Stimulation of IL-1 receptor by IL-1, may induce the phosphorylation of tyrosine residues in many effector proteins through the activation of p60c-src kinase. The hypothesis that the synthesis of SP in and secretion from the primary sensory ganglia are regulated by the activation of p60c-src kinase induced by IL-1, was tested. Pretreatment of DRG neurons in culture with herbimycin A, genistein or PP2, three structurally different nonreceptor tyrosine kinase inhibitors that act by different mechanisms, decreased the kinase activity of p60c-src induced by the activation of IL-1 receptor. PP3, a negative control for the Src family of tyrosine kinase inhibitor PP2 had no effect. Herbimycin A and genistein also decreased IL-1,-induced expression of PPT mRNA-encoding transcripts and the levels of SP-li synthesized in the cells and secreted into the culture medium in a concentration-dependent manner. SB 203580 [a p38 mitogen-activated protein kinase (p38 MAPK) inhibitor] and PD 98059 (a p44/42 MAPK kinase inhibitor) were ineffective in modulating IL-1,-induced SP synthesis and secretion, and p60c-src kinase activity in DRG neurons. Whereas, IL-1 receptor antagonist and cycloheximide inhibited IL-1,-evoked secretion of SP-like immunoreactivity (SP-li), actinomycin D decreased it significantly but did not entirely abolish it. These findings show that phosphorylation of specific protein tyrosine residue(s) following IL-1 receptor activation might play a key role in IL-1, signalling to modulate PPT gene expression and SP secretion in sensory neurons. In view of the role of SP as an immunomodulator, these studies provide a new insight into neural-immune intercommunication in pain regulation in the sensory ganglia through the IL-1,-induced p60c-src activation. [source] Contribution of the Src family of kinases to the appearance of malignant phenotypes in renal cancer cellsMOLECULAR CARCINOGENESIS, Issue 4 2005Yuko Yonezawa Abstract Although the constitute activation of the Src family of kinases (Src) has been established as a poor prognostic factor in several types of cancer, the role of Src in renal cell carcinoma (RCC) has not been defined. This study aimed to determine whether Src could contribute to the appearance of malignant phenotypes in RCC. The role of Src in the appearance of malignant phenotypes in RCC was examined in two human renal cancer cell lines, Caki-1 from human metastatic RCC and ACHN from human primary RCC. Src activity in Caki-1 cells was higher than that in ACHN cells, and this difference corresponded to the difference of PP1 (a Src family inhibitor)-induced cytotoxicity on the two cells. The difference in cytotoxicity between the cells did not depend on cell cycle regulation but on the induction of apoptosis, and the difference in apoptosis particularly related to the reduction of the Bcl-xL level. Furthermore, in Caki-1 cells with higher Src activity, Src stimulated the production of vascular endothelial growth factor (VEGF), partially via the activation of Stat3, and the inhibition of Src activity caused a reduction of the VEGF level in serum, angiogenesis, and tumor development in a xenograft model. These results suggested that Src contributed to the appearance of malignant phenotypes in renal cancer cells, particularly due to the resistance against apoptosis by Bcl-xL and angiogenesis stimulated by Src-Stat3-VEGF signaling. © 2005 Wiley-Liss, Inc. [source] Tyrosine protein kinases and spermatogenesis: truncation mattersMOLECULAR REPRODUCTION & DEVELOPMENT, Issue 4 2006Abraham L. Kierszenbaum Abstract Protein phosphorylation on serine/threonine or tyrosine residues represents a significant regulatory mechanism in signal transduction during spermatogenesis, oogenesis, and fertilization. There are several families of tyrosine protein kinases operating during spermatogenesis: the Src family of tyrosine protein kinases; the Fujinami poultry sarcoma/feline sarcoma (Fps/Fes) and Fes-related protein (Fer) subfamily of non-receptor proteins; and c-kit, the transmembrane tyrosine kinase receptor that belongs to the family of the PDGF receptor. A remarkable characteristic is the coexistence of full-length and truncated tyrosine kinases in testis. Most of the truncated forms are present during spermiogenesis. Examples include the truncated forms of Src tyrosine kinase hematopoietic cell kinase (Hck), FerT, and tr-kit. A feature of FerT and tr-kit is the kinase domain that ensures the functional properties of the truncated protein. FerT, a regulator of actin assembly/disassembly mediated by cortactin phosphorylation, is present in the acroplaxome, a cytoskeletal plate containing an F-actin network and linking the acrosome to the spermatid nuclear envelope. This finding suggests that Fer kinase represents one of the tyrosine protein kinases that may contribute to spermatid head shaping. The c-kit ligand, stem cell factor (SCF), which induces c-kit dimerization and autophosphorylation, exists as both membrane-associated and soluble. Although tyrosine protein kinases are prominent in spermatogenesis, a remarkable observation is the paucity of phenotypic alterations in spermatogenic cells in male mice targeted with Fer kinase-inactivating mutation. It is possible that the redundant functions of the tyrosine protein kinase pool present during spermatogenesis may explain the limited phenotypes of single mutant mice. The production of compound and viable mutant mice, lacking the expression of two or more tyrosine kinases, may shed light on this intriguing issue. Mol. Reprod. Dev. © 2006 Wiley-Liss, Inc. [source] Structural characterization of Lyn-SH3 domain in complex with a herpesviral protein reveals an extended recognition motif that enhances binding affinityPROTEIN SCIENCE, Issue 10 2005Finn Bauer Abstract The Src homology 3 (SH3) domain of the Src family kinase Lyn binds to the herpesviral tyrosine kinase interacting protein (Tip) more than one order of magnitude stronger than other closely related members of the Src family. In order to identify the molecular basis for high-affinity binding, the structure of free and Tip-bound Lyn-SH3 was determined by NMR spectroscopy. Tip forms additional contacts outside its classical proline-rich recognition motif and, in particular, a strictly conserved leucine (L186) of the C-terminally adjacent sequence stretch packs into a hydrophobic pocket on the Lyn surface. Although the existence of this pocket is no unique property of Lyn-SH3, Lyn is the only Src family kinase that contains an additional aromatic residue (H41) in the n-Src loop as part of this pocket. H41 covers L186 of Tip by forming tight hydrophobic contacts, and model calculations suggest that the increase in binding affinity compared with other SH3 domains can mainly be attributed to these additional interactions. These findings indicate that this pocket can mediate specificity even between otherwise closely related SH3 domains. [source] Activation of Epstein-Barr virus/C3d receptor (gp140, CR2, CD21) on human cell surface triggers pp60src and Akt-GSK3 activities upstream and downstream to PI 3-kinase, respectivelyEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2003Monique Barel Abstract We previously demonstrated that CR2 activation on human B lymphocyte surface specifically triggered tyrosine phosphorylation of the 95-kDa nucleolin, this leading to its binding on SH2 domainsof p85 sub-unit of PI 3-kinase and to activation of this enzyme. The specificity of CR2 pathway was clearly demonstrated as neither CD19 nor BCR could induce tyrosine phosphorylation of nucleolin in normal B lymphocytes. These data led us to investigate herein additional molecular events, which were triggered by CR2 activation, upstream and downstream to PI 3-kinase activation. Upstream, we demonstrated that pp60src, a tyrosine kinase of the src family, was involved in tyrosine phosphorylation of nucleolin, while syk tyrosine kinase was not. We also demonstrated a direct protein-proteininteraction of pp60src with nucleolin in a CR2-dependent and CD19-independent pathway. Downstream, we demonstrated that CR2 activation also triggered Akt and GSK3 enzyme activation, this pathway being under the control of pp60src tyrosine kinase activation. These regulatory functions of activated CR2 were specific as independent of syk tyrosine kinase and of CD19 and BCR activation. Thus, CR2 activation recruits a specific mechanism to activate PI 3-kinase and its subsequent pathways, this mechanism being different to those recruited by CD19 and BCR. [source] Gene expression profiling of aging in multiple mouse strains: identification of aging biomarkers and impact of dietary antioxidantsAGING CELL, Issue 4 2009Sang-Kyu Park Summary We used DNA microarrays to identify panels of transcriptional markers of aging that are differentially expressed in young (5 month) and old (25 month) mice of multiple inbred strains (129sv, BALB/c, CBA, DBA, B6, C3H and B6C3F1). In the heart, age-related changes of five genes were studied throughout the mouse lifespan: complement component 4, chemokine ligand 14, component of Sp100-rs, phenylalanine hydroxylase and src family associated phosphoprotein 2. A similar analysis in the brain (cerebellum) involved complement component 1q (alpha polypeptide), complement component 4, P lysozyme structural, glial fibrillary acidic protein and cathepsin S. Caloric restriction (CR) inhibited age-related expression of these genes in both tissues. Parametric analysis of gene set enrichment identified several biological processes that are induced with aging in multiple mouse strains. We also tested the ability of dietary antioxidants to oppose these transcriptional markers of aging. Lycopene, resveratrol, acetyl- l -carnitine and tempol were as effective as CR in the heart, and ,-lipoic acid and coenzyme Q10 were as effective as CR in the cerebellum. These findings suggest that transcriptional biomarkers of aging in mice can be used to estimate the efficacy of aging interventions on a tissue-specific basis. [source] | |||||||||||||