T cell development and function in CrkL‐deficient mice

Peterson, Amy; Marks, Reinhard; Fields, Patrick E.; Imamoto, Akira; Gajewski, Thomas F.

doi:10.1002/eji.200324294

Cited by 17 publications

(15 citation statements)

References 52 publications

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“…We conclude that reduction in B cell outgrowth from Crkl − / − and Crkl +/ − fetal liver in Whitlock-Witte cultures was not due to a deficiency in B cell progenitors. This finding is consistent with previous findings that there was no difference in the ability of hematopoietic progenitor cells derived from Crkl − / − fetal livers to reconstitute the bone marrow of irradiated Rag2 −/ − recipients compared to Wt with similar numbers of circulating B220+ cells (32). …”

Section: Resultssupporting

confidence: 93%

A Specific Need for CRKL in p210BCR-ABL–Induced Transformation of Mouse Hematopoietic Progenitors

et al. 2010

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CRKL (CRK-like) is an adapter protein predominantly phosphorylated in cells that express the tyrosine kinase p210 BCR-ABL , the fusion product of a (9;22) chromosomal translocation causative for chronic myeloid leukemia. It has been unclear, however, whether CRKL plays a functional role in p210 BCR-ABL transformation.Here, we show that CRKL is required for p210 BCR-ABL to support interleukin-3-independent growth of myeloid

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Section: Resultssupporting

confidence: 93%

A Specific Need for CRKL in p210BCR-ABL–Induced Transformation of Mouse Hematopoietic Progenitors

et al. 2010

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“…Inhibition of T-lymphoblast proliferation is associated with downregulation of LMNB1 protein (78). CRKL is targeted by 4 miRNAs and involved in signal transduction through WIP, JNK and Zap70(79). IQGAP1, targeted by 2 miRNAs, regulates lymphocyte cytoskeleton rearrangement in the immune synapse (80).…”

Section: Resultsmentioning

confidence: 99%

MicroRNA Regulation of Molecular Networks Mapped by Global MicroRNA, mRNA, and Protein Expression in Activated T Lymphocytes

Grigoryev

Kurian

Hart

et al. 2011

The Journal of Immunology

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MicroRNAs (miRNAs) regulate specific immune mechanisms but their genome-wide regulation of T-lymphocyte activation is largely unknown. We performed a multidimensional functional genomics analysis to integrate genome-wide differential mRNA, miRNA, and protein expression as a function of human T-lymphocyte activation and time. We surveyed expression of 420 human miRNAs in parallel with genome-wide mRNA expression. We identified a unique signature of 71 differentially expressed miRNAs, 57 of which were previously not known as regulators of immune activation. The majority of miRNAs are upregulated, mRNA expression of these target genes is downregulated and this is a function of binding multiple miRNAs (combinatorial targeting). Our data reveal that consideration of this complex signature, rather than single miRNAs, is necessary to construct a full picture of miRNA-mediated regulation. Molecular network mapping of miRNA targets revealed the regulation of activation-induced immune signaling. In contrast, pathways populated by genes that are not miRNA targets are enriched for metabolism and biosynthesis. Finally, we specifically validated miR-155 (known) and miR-221 (novel in T-lymphocytes) using locked nucleic acid inhibitors. Inhibition of these 2 highly upregulated miRNAs in CD4+ T cells were shown to increase proliferation by removing suppression of 4 target genes linked to proliferation and survival. Thus, multiple lines of evidence link top functional networks directly to T-lymphocyte immunity underlining the value of mapping global gene, protein and miRNA expression.

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“…Another CRKL knockout study had shown shortly before this, that the loss of CRKL can lead to multiple and severe developmental defects 'in utero', particularly in neural crest-derived cells [100]. Further defects were later seen when fibroblasts derived from these mice were analysed in more detail [101], but T-cell function does not appear to be affected [102]. Taken together, these findings suggest that Crk and CRKL proteins, although widely expressed and of considerable homology, are not merely redundant adaptors.…”

Section: Crk Family Adaptorsmentioning

confidence: 93%

Potential Disease Targets for Drugs that Disrupt Protein - Protein Interactions of Grb2 and Crk Family Adaptors

Feller¹,

Lewitzky²

2006

CPD

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This review summarises some of the knowledge we have about Crk and Grb2 family adaptor protein signalling in health and disease and outlines the current status and the challenges still remaining in the development of efficient and selective inhibitors of their protein -protein interactions. It also highlights briefly some recent successes and problems of inhibitors for proteins that functionally interact with Crk and Grb2 family adaptors, as well as opportunities, which may arise from combination therapies. Grb2 and Crk family adaptors regulate signalling pathways linked to human diseases. They are mainly composed of Src homology 2 (SH2) and Src homology 3 (SH3) domains, which serve as docking sites for signalling proteins, including various receptors, cytoplasmic kinases and GTPase regulators. Considerable insight into the biological functions and mechanisms of action of small SH2/SH3 domain adaptors has been gained in the last years from experimental approaches as diverse as targeted gene disruption and structural studies at the atomic level. This has already indicated several strategies to utilise SH2 and SH3 domain interaction inhibitors in human disease therapy. Additional molecular targets for Crk and Grb2 domain interaction blockers are expected to surface as further protein-protein interactions are discovered. Examples include newly found DOCK family proteins (DOCK3, DOCK4, and DOCK5) which are known or suspected effectors of Crk proteins and the interaction of Grb2 with the cell cycle regulator p27Kip1.

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T cell development and function in CrkL‐deficient mice

Cited by 17 publications

References 52 publications

A Specific Need for CRKL in p210BCR-ABL–Induced Transformation of Mouse Hematopoietic Progenitors

A Specific Need for CRKL in p210BCR-ABL–Induced Transformation of Mouse Hematopoietic Progenitors

MicroRNA Regulation of Molecular Networks Mapped by Global MicroRNA, mRNA, and Protein Expression in Activated T Lymphocytes

Potential Disease Targets for Drugs that Disrupt Protein - Protein Interactions of Grb2 and Crk Family Adaptors

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