SC35 Plays a Role in T Cell Development and Alternative Splicing of CD45

Wang, Huan-You; Xu, Xiangdong; Ding, Jingzhong; Bermingham, John R.; Fu, Xiang‐Dong

doi:10.1016/s1097-2765(01)00181-2

Cited by 138 publications

(125 citation statements)

References 55 publications

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“…Finally, it has been shown that ablation of SC35, which also regulates alternative splicing of CD45, correlates with a reduced number of peripheral CD4 and CD8 T cells in the spleen. However, in contrast to our findings, the CD45RO isoform was predominant and CD45RB was undetectable in SC35-deficient mice (51). Although our hnRNP L 2/2 -deficient SP cells show a similar migration defect as SC35-deficient animals, higher m.w.…”

Section: Discussioncontrasting

confidence: 99%

Alternative Splicing Controlled by Heterogeneous Nuclear Ribonucleoprotein L Regulates Development, Proliferation, and Migration of Thymic Pre-T Cells

Gaudreau

Heyd

Bastien

et al. 2012

The Journal of Immunology

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The regulation of posttranscriptional modifications of pre-mRNA by alternative splicing is important for cellular function, development, and immunity. The receptor tyrosine phosphatase CD45, which is expressed on all hematopoietic cells, is known for its role in the development and activation of T cells. CD45 is known to be alternatively spliced, a process that is partially regulated by heterogeneous nuclear ribonucleoprotein (hnRNP) L. To investigate the role of hnRNP L further, we have generated conditional hnRNP L knockout mice and found that LckCre-mediated deletion of hnRNP L results in a decreased thymic cellularity caused by a partial block at the transition stage between double-negative 4 and double-positive cells. In addition, hnRNP L−/− thymocytes express aberrant levels of the CD45RA splice isoforms and show high levels of phosphorylated Lck at the activator tyrosine Y394, but lack phosphorylation of the inhibitory tyrosine Y505. This indicated an increased basal Lck activity and correlated with higher proliferation rates of double-negative 4 cells in hnRNP L−/− mice. Deletion of hnRNP L also blocked the migration and egress of single-positive thymocytes to peripheral lymphoid organs in response to sphingosine-1-phosphate and the chemokines CCL21 and CXCL12 very likely as a result of aberrant splicing of genes encoding GTPase regulators and proteins affecting cytoskeletal organization. Our results indicate that hnRNP L regulates T cell differentiation and migration by regulating pre-TCR and chemokine receptor signaling.

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Section: Discussioncontrasting

confidence: 99%

Alternative Splicing Controlled by Heterogeneous Nuclear Ribonucleoprotein L Regulates Development, Proliferation, and Migration of Thymic Pre-T Cells

Gaudreau

Heyd

Bastien

et al. 2012

The Journal of Immunology

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“…1 and Supplementary Table 1). These observations markedly expand the number of known endogenous alternatively spliced gene targets of SR proteins 20,[35][36][37][38] .…”

Section: Mechanism Of Sf2/asf-driven Transformationmentioning

confidence: 84%

The gene encoding the splicing factor SF2/ASF is a proto-oncogene

Karni

Stanchina

Lowe

et al. 2007

Nat Struct Mol Biol

821

968

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Alternative splicing modulates the expression of many oncogene and tumor-suppressor isoforms. We have tested whether some alternative splicing factors are involved in cancer. We found that the splicing factor SF2/ASF is upregulated in various human tumors, in part due to amplification of its gene, SFRS1. Moreover, slight overexpression of SF2/ASF is sufficient to transform immortal rodent fibroblasts, which form sarcomas in nude mice. We further show that SF2/ASF controls alternative splicing of the tumor suppressor BIN1 and the kinases MNK2 and S6K1. The resulting BIN1 isoforms lack tumor-suppressor activity; an isoform of MNK2 promotes MAP kinase-independent eIF4E phosphorylation; and an unusual oncogenic isoform of S6K1 recapitulates the transforming activity of SF2/ASF. Knockdown of either SF2/ASF or isoform-2 of S6K1 is sufficient to reverse transformation caused by the overexpression of SF2/ASF in vitro and in vivo. Thus, SF2/ASF can act as an oncoprotein and is a potential target for cancer therapy.For about three-quarters of human genes, individual or partial exons can be included in or excluded from different versions of the mature messenger RNA by alternative splicing 1 . Many alternative splicing factors combinatorially affect this process to determine which mRNA isoforms will serve as the templates for protein synthesis in a given cell type, developmental stage or physiological state 2 .SR proteins are a family of RNA-binding proteins that are essential for splicing. They act at multiple steps of spliceosome assembly and function in both constitutive and regulated splicing. Some heterogeneous nuclear ribonucleoprotein (hnRNP) proteins, which rapidly associate with nascent transcripts, have been implicated in the repression of certain alternative splicing events 2 . hnRNP and SR proteins can have antagonistic effects on the alternative splicing of particular exons in several genes 2 . Both types of factor can bind directly to precursor (pre)-mRNA transcripts, eliciting changes in the alternative splicing of various pre-mRNA substrates in a concentration-dependent manner, both in vitro and in transfection experiments 3,4 . Thus, changes in the expression of these proteins can affect the Reprints and permissions information is available online at

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“…S1]. Sfrs protein molecular masses are 25-28 kDa, but Sfrs proteins reportedly migrate at 35 kDa on SDS/PAGE gels (17). Proteomics analysis identified the 15-kDa protein as a fragment of annexin 1.…”

Section: Identification Of Iprsmentioning

confidence: 99%

Identification of mRNA splicing factors as the endothelial receptor for carbohydrate-dependent lung colonization of cancer cells

Hatakeyama

Sato

Nakayama

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Cell surfaces of epithelial cancer are covered by complex carbohydrates, whose structures function in malignancy and metastasis. However, the mechanism underlying carbohydrate-dependent cancer metastasis has not been defined. Previously, we identified a carbohydrate-mimicry peptide designated I-peptide, which inhibits carbohydrate-dependent lung colonization of sialyl Lewis X-expressing B16-FTIII-M cells in E/P-selectin doubly-deficient mice. We hypothesized that lung endothelial cells express an unknown carbohydrate receptor, designated as I-peptide receptor (IPR), responsible for lung colonization of B16-FTIII-M cells. Here, we visualized IPR by in vivo biotinylation, which revealed that the major IPR is a group of 35-kDa proteins. IPR proteins isolated by I-peptide affinity chromatography were identified by proteomics as Ser/Arg-rich alternative pre-mRNA splicing factors or Sfrs1, Sfrs2, Sfrs5, and Sfrs7 gene products. annexin ͉ galectin ͉ metastasis ͉ selectin ͉ vasculature T he apical cell surface of epithelia is covered by numerous carbohydrates attached to membrane proteins and lipids. When epithelial cells are transformed, the structure of these carbohydrates changes (1). Many investigators have suggested a correlation between cancer-associated carbohydrate antigens and poor patient prognosis, including metastasis (2-8). Despite extensive structural analysis and clinical observations using monoclonal antibodies against cancer-associated carbohydrate antigens, mechanisms underlying carbohydrate-dependent cancer metastasis through the circulation remain elusive. Because E-selectin is expressed on the inflammatory endothelial cell surface and binds to cancer-associated carbohydrate antigens such as sialyl Lewis A (sLeA) and sialyl Lewis X (sLeX), E-selectin provides a mechanism for sLeA and/or sLeX antigenexpressing cancer cells to be metastasized through the hematogenous route (4-6). Involvement of P-selectin and L-selectin in cancer metastasis has been also described (7,8). However, substantial clinical data indicate the existence of selectin-independent but carbohydrate-dependent cancer metastasis (6, 10, 11).In our previous studies, we screened a peptide-displaying phage library using a monoclonal anti-Lewis A antibody (clone 7LE) and identified a short peptide IELLQAR, designated I-peptide (12-14). When I-peptide was injected intravenously into a mouse, it bound to a specific subset of lung capillary endothelial cells but not to blood vessels of other organs including the liver (12). I-peptide administration inhibited carbohydrate-dependent lung colonization of fucosyltransferase-3-transfected sialyl Lewis X antigenpositive B16 (B16-FTIII-M) cells (15) in wild-type mice (12) and in E-and P-selectin doubly-deficient mutant mice (13), suggesting that the lung endothelial surface expresses unknown carbohydratebinding receptor(s) enabling colonization of B16-FTIII-M cells. We designated this presumptive receptor I-peptide receptor (IPR) (13).In this study, we isolated IPR candidate proteins by I-peptideaff...

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SC35 Plays a Role in T Cell Development and Alternative Splicing of CD45

Cited by 138 publications

References 55 publications

Alternative Splicing Controlled by Heterogeneous Nuclear Ribonucleoprotein L Regulates Development, Proliferation, and Migration of Thymic Pre-T Cells

Alternative Splicing Controlled by Heterogeneous Nuclear Ribonucleoprotein L Regulates Development, Proliferation, and Migration of Thymic Pre-T Cells

The gene encoding the splicing factor SF2/ASF is a proto-oncogene

Identification of mRNA splicing factors as the endothelial receptor for carbohydrate-dependent lung colonization of cancer cells

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