The RhoA‐ and CDC42‐specific exchange factor Dbs promotes expansion of immature thymocytes and deletion of double‐positive and single‐positive thymocytes

Klinger, Mark; Guilbault, Benoit; Kay, R.

doi:10.1002/eji.200324400

Cited by 5 publications

(5 citation statements)

References 44 publications

(59 reference statements)

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“…DBS is a GEF for RHOA and CDC42, which is expressed throughout thymocyte development. Transgenic mice expressing an activated form of DBS had larger numbers of CD4 - CD8 - DN thymocytes, but increased apoptosis in later DP and SP thymocyte subsets55.…”

Section: Gtpases and Their Regulators In T Cellsmentioning

confidence: 94%

Rho family GTPases and their regulators in lymphocytes

Tybulewicz¹,

Henderson²

2009

Nat Rev Immunol

237

252

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Rho family GTPases, and the proteins that regulate them, have important roles in many cellular processes, including cell division, survival, migration and adhesion. Although most of our understanding of these proteins has come from studies using cell lines, more recent gene targeting studies in mice are providing insights into the in vivo function of these proteins. Here we review recent progress revealing crucial roles for these proteins in lymphocyte development, activation, differentiation and migration. The emerging picture shows that Rho family GTPases transduce signals from receptors for antigens, chemokines and cytokines, as well as adhesion molecules and pattern recognition receptors, and that they function as focal points for crosstalk between different signalling pathways.

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Section: Gtpases and Their Regulators In T Cellsmentioning

confidence: 94%

Rho family GTPases and their regulators in lymphocytes

Tybulewicz¹,

Henderson²

2009

Nat Rev Immunol

237

252

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“…The Dbl family members all possess two tandem conserved domains, the Dbl Homology (DH) and the Pleckstrin Homology (PH) domains (13-18). The DH domains of Dbl-GEFs are directly responsible for catalyzing GDP-GTP exchange activity while the PH domains are important for protein localization to the plasma membrane.…”

mentioning

confidence: 99%

“…Two families of GEFs have been discovered for Rho GTPases, which we here term the Dbl and Dock180 superfamilies − . The Dbl family members all possess two tandem conserved domains, the Dbl homology (DH) and pleckstrin homology (PH) domains − . The DH domains of Dbl-GEFs are directly responsible for catalyzing GDP−GTP exchange activity, while the PH domains are important for the localization of these proteins to the plasma membrane.…”

mentioning

confidence: 99%

A Minimal Rac Activation Domain in the Unconventional Guanine Nucleotide Exchange Factor Dock180

Ramachandran

Lin

et al. 2011

Biochemistry

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Guanine nucleotide exchange factors (GEFs) activate Rho GTPases by catalyzing the exchange of bound GDP for GTP, thereby resulting in downstream effector recognition. Two metazoan families of GEFs have been described: Dbl-GEF family members that share conserved Dbl homology (DH) and Pleckstrin homology (PH) domains and the more recently described Dock180 family members that share little sequence homology with the Dbl family and are characterized by conserved Dock homology regions 1 and 2 (DHR-1 and -2). While extensive characterization of the Dbl family has been performed, less is known about how Dock180 family members act as GEFs, with only a single x-ray structure having recently been reported for the Dock9-Cdc42 complex. In order to learn more about the mechanisms used by the founding member of the family, Dock180, to act as a Rac-specific GEF, we set out to identify and characterize its limit functional GEF domain. A C-terminal portion of the DHR-2 domain, composed of approximately 300 residues (designated as Dock180 ), is shown to be necessary and sufficient for robust Rac-specific GEF activity both in vitro and in vivo. We further show that Dock180 binds to Rac in a manner distinct from Rac-GEFs of the Dbl family. Specifically, Ala 27 and Trp 56 of Rac appear to provide a bipartite binding site for the specific recognition of Dock180 , whereas, for Dbl family Rac-GEFs, Trp 56 of Rac is the sole primary determinant of GEF specificity. Based on our findings, we are able to define the core of Dock180 responsible for its Rac-GEF activity as well as highlight key recognition sites that distinguish different Dock180 family members and determine their corresponding GTPase specificities.Members of the Rho family of GTPases regulate a wide range of cellular activities including cell-cycle progression, gene transcription, cell migration, cell polarity, and vesicular trafficking through their abilities to bind to multiple downstream effectors (1-4). Rho GTPases switch between two states, the GDP-bound inactive state and the GTP-bound active state. Tight regulation of Rho GTPases and their nucleotide-bound state is important for mediating their different cellular functions (5). Three main classes of regulatory proteins for Rho GTPases have been identified and characterized. Guanine nucleotide exchange factors (GEFs) include ~70 mammalian/human proteins that promote the exchange of GDP for GTP on Rho GTPases. GTPase-activating proteins (GAPs) catalyze the hydrolysis of the bound GTP to GDP, and Rho GDP-dissociation inhibitors (GDIs) slow nucleotide exchange while serving to sequester Rho GTPases in the cytoplasm (6-8).Two families of GEFs have been discovered for Rho GTPases, which we refer to here as the Dbl (9) and Dock180 superfamilies (10-12). The Dbl family members all possess two † This work was supported by National Institutes of Health R01 Grants GM40654 and GM47458.* To whom correspondence should be addressed: Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Itha...

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“…A previous study has demonstrated that the DBS-130 inhibitors can reduce the motility of MDA-MB-231 cells in Transwell and scratch assays ( 48 , 49 ). DBS becomes activated and highly tumorigenic via truncation of the N-terminus, and the activation of DBS can promote cell proliferation during the development of hemocytes ( 50 ). However, the role of MCF2L/DBS in the drug resistance of tumor cells has not yet been studied.…”

Section: Discussionmentioning

confidence: 99%

Establishment of a human primary pancreatic cancer mouse model to examine and investigate gemcitabine resistance

et al. 2017

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Pancreatic cancer is one of the most fatal types of cancer and is associated with a dismal prognosis. Gemcitabine-based chemotherapy is clinically used for the treatment of advanced pancreatic cancer. However, many forms of pancreatic cancer have acquired resistance to gemcitabine. In order to prevent patients from suffering from the side effects of chemotherapy and to have the chance to receive more effective intervention, assessment of whether the patient pancreatic cancer cells are resistant to gemcitabine before clinical practice is crucial. Recently, patient-derived xenograft (PDX) models have been regarded as a practical approach for preclinical drug resistance test. In the present study, we harvested tumor specimens from 28 pancreatic cancer patients to establish PDX models. The tumor formation rate of the xenografts was 100%, several of which could be re-implanted in nude mice for more than 10 passages. Primary cells were further obtained from the PDX xenografts to determine their morphological features and evaluate their proliferation rate, migration capacity and angiopoietic ability. In addition, the sensitivities of the primary cells and PDX xenografts to gemcitabine were correlated with each other. When compared to the gemcitabine-sensitive cells, the gemcitabine-resistant cells had a higher level of MCF2L expression, suggesting that MCF2L plays an important role in gemcitabine resistance.

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The RhoA‐ and CDC42‐specific exchange factor Dbs promotes expansion of immature thymocytes and deletion of double‐positive and single‐positive thymocytes

Cited by 5 publications

References 44 publications

Rho family GTPases and their regulators in lymphocytes

Rho family GTPases and their regulators in lymphocytes

A Minimal Rac Activation Domain in the Unconventional Guanine Nucleotide Exchange Factor Dock180

Establishment of a human primary pancreatic cancer mouse model to examine and investigate gemcitabine resistance

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