Search results for "CDC42"
showing 10 items of 26 documents
An immune escape screen reveals Cdc42 as regulator of cancer susceptibility to lymphocyte-mediated tumor suppression.
2007
Abstract Adoptive cellular immunotherapy inducing a graft-versus-tumor (GVT) effect is the therapeutic mainstay of allogeneic hematopoietic stem cell transplantation (ASCT) for high-risk leukemias. Autologous immunotherapies using vaccines or adoptive transfer of ex vivo–manipulated lymphocytes are clinically explored in patients with various cancer entities. Main reason for failure of ASCT and cancer immunotherapy is progression of the underlying malignancy, which is more prevalent in patients with advanced disease. Elucidating the molecular mechanisms contributing to immune escape will help to develop strategies for the improvement of immunologic cancer treatment. To this end, we have und…
New neurons use Slit-Robo signaling to migrate through the glial meshwork and approach a lesion for functional regeneration
2018
Appropriate positioning of new neurons in the brain promotes post-stroke functional recovery.
Variant toxin B and a functional toxin A produced by Clostridium difficile C34.
2001
A particular property of Clostridium difficile strain C34 is an insertion of approximately 2 kb in the tcdA-C34 gene that does not hinder expression of a fully active TcdA-C34 molecule. Intoxication with TcdA-C34 induced an arborized appearance in eukaryotic cells (D-type cytopathic effect); intoxication with TcdB-C34 induced a spindle-like appearance of cells (S-type cytopathic effect). Inactivation of GTPases with purified toxins revealed that Rho, Rac, Cdc42, and Rap are substrates of TcdA-C34. The variant cytotoxin TcdB-C34 inactivated Rho, Rac, Cdc42, Rap, Ral, and R-Ras. Hence, this is the first ‘S-type’ cytotoxin which inactivates both Rho and R-Ras, and is coexpressed with a ‘D-type…
Profilin 1 is required for peripheral nervous system myelination
2014
Myelination allows rapid saltatory propagation of action potentials along the axon and is an essential prerequisite for the normal functioning of the nervous system. During peripheral nervous system (PNS) development, myelin-forming Schwann cells (SCs) generate radial lamellipodia to sort and ensheath axons. This process requires controlled cytoskeletal remodeling, and we show that SC lamellipodia formation depends on the function of profilin 1 (Pfn1), an actin-binding protein involved in microfilament polymerization. Pfn1 is inhibited upon phosphorylation by ROCK, a downstream effector of the integrin linked kinase pathway. Thus, a dramatic reduction of radial lamellipodia formation is obs…
Rho protein inactivation induced apoptosis of cultured human endothelial cells.
2002
Small GTP-binding Rho GTPases regulate important signaling pathways in endothelial cells, but little is known about their role in endothelial cell apoptosis. Clostridial cytotoxins specifically inactivate GTPases by glucosylation [ Clostridium difficile toxin B-10463 (TcdB-10463), C. difficile toxin B-1470 (TcdB-1470)] or ADP ribosylation ( C. botulinum C3 toxin). Exposure of human umbilical cord vein endothelial cells (HUVEC) to TcdB-10463, which inhibits RhoA/Rac1/Cdc42, or to C3 toxin, which inhibits RhoA, -B, -C, resulted in apoptosis, whereas inactivation of Rac1/Cdc42 with TcdB-1470 was without effect, suggesting that Rho inhibition was responsible for endothelial apoptosis. Disruptio…
PAR1 signaling regulates the retention and recruitment of EPCR-expressing bone marrow hematopoietic stem cells
2015
Retention of long-term repopulating hematopoietic stem cells (LT-HSCs) in the bone marrow is essential for hematopoiesis and for protection from myelotoxic injury. We report that signaling cascades that are traditionally viewed as coagulation related also control retention of endothelial protein C receptor-positive (EPCR(+)) LT-HSCs in the bone marrow and their recruitment to the blood via two pathways mediated by protease activated receptor 1 (PAR1). Thrombin-PAR1 signaling induces nitric oxide (NO) production, leading to EPCR shedding mediated by tumor necrosis factor-α-converting enzyme (TACE), enhanced CXCL12-CXCR4-induced motility and rapid stem and progenitor cell mobilization. Conver…
Ras, Rap, and Rac Small GTP-binding Proteins Are Targets for Clostridium sordellii Lethal Toxin Glucosylation
1996
Lethal toxin (LT) from Clostridium sordellii is one of the high molecular mass clostridial cytotoxins. On cultured cells, it causes a rounding of cell bodies and a disruption of actin stress fibers. We demonstrate that LT is a glucosyltransferase that uses UDP-Glc as a cofactor to covalently modify 21-kDa proteins both in vitro and in vivo. LT glucosylates Ras, Rap, and Rac. In Ras, threonine at position 35 was identified as the target amino acid glucosylated by LT. Other related members of the Ras GTPase superfamily, including RhoA, Cdc42, and Rab6, were not modified by LT. Incubation of serum-starved Swiss 3T3 cells with LT prevents the epidermal growth factor-induced phosphorylation of m…
cIAP1 oncogenic properties analysis : contribution of its partners cdc42 and E2F1
2014
The inhibitor of apoptosis protein cIAP1 (cellular inhibitor of apoptosis protein-1) from the IAP family (Inhibitor of Apoptosis Protein) is an oncogene with an E3 ubiquitin ligase activity. cIAP1 is relocalized from the nucleus to the cytoplasm during the differentiation of many kind of cellular models (macrophages, dendritic cells, colon epithelial cells, hematopoietic stem cells, cardiomyocytes) and this relocalization is associated with a proliferation arrest. The well-known functions of cIAP1 are associated with its cytoplasmic localization, where it regulates the TNFa receptors and NF-?B signaling pathways. However, cIAP1 is mainly expressed in the nucleus on many cell types which is …
GTPases of the Rho Subfamily Are Required for Brucella abortus Internalization in Nonprofessional Phagocytes
2001
Members of the genus Brucella are intracellular -Proteobacteria responsible for brucellosis, a chronic disease of humans and animals. Little is known about Brucella virulence mechanisms, but the abilities of these bacteria to invade and to survive within cells are decisive factors for causing disease. Transmission electron and fluorescence microscopy of infected nonprofessional phagocytic HeLa cells revealed minor membrane changes accompanied by discrete recruitment of F-actin at the site of Brucella abortus entry. Cell uptake of B. abortus was negatively affected to various degrees by actin, actin-myosin, and microtubule chemical inhibitors. Modulators of MAPKs and protein-tyrosine kinases…
Impact of amino acids 22-27 of Rho-subfamily GTPases on glucosylation by the large clostridial cytotoxins TcsL-1522, TcdB-1470 and TcdB-8864
1999
Here we report data describing some principles of the interaction between small GTP-binding proteins and large Clostridial cytotoxins (LCTs). Our investigation was based on the differential glucosylation of Rac1 versus RhoA by LCTs TcsL-1522, TcdB-1470 and TcdB-8864. Chimeric RhoA/Rac1 proteins and GTPases mutated at defined regions or single amino acids were used as substrates. Starting with chimeric Rac/Rho proteins we demonstrated that proteins containing the N-terminal 73 amino acids of Rac1 (but not those of RhoA) were efficiently glucosylated. Within this stretch, three regions differ significantly in Rac1 and RhoA. Regions containing amino acids 41-45 and 50-54 had no effect on toxin…