scholarly journals RHO Family GTPases in the Biology of Lymphoma

Cells ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 646 ◽  
Author(s):  
Voena ◽  
Chiarle
Keyword(s):  
Rho Gtpases ◽  
Intracellular Signaling ◽  
Human Cancer ◽  
Loss Of Function ◽  
Cellular Processes ◽  
Ras Gtpase ◽  
Rho Family Gtpases ◽  
Ras Family ◽  
Human Lymphoma ◽  
Rho Family

RHO GTPases are a class of small molecules involved in the regulation of several cellular processes that belong to the RAS GTPase superfamily. The RHO family of GTPases includes several members that are further divided into two different groups: typical and atypical. Both typical and atypical RHO GTPases are critical transducers of intracellular signaling and have been linked to human cancer. Significantly, both gain-of-function and loss-of-function mutations have been described in human tumors with contradicting roles depending on the cell context. The RAS family of GTPases that also belong to the RAS GTPase superfamily like the RHO GTPases, includes arguably the most frequently mutated genes in human cancers (K-RAS, N-RAS, and H-RAS) but has been extensively described elsewhere. This review focuses on the role of RHO family GTPases in human lymphoma initiation and progression.

scholarly journals Rac GTPases in Hematological Malignancies

2018 ◽  
Vol 19 (12) ◽  
pp. 4041 ◽  
Author(s):  
Valerie Durand-Onaylı ◽  
Theresa Haslauer ◽  
Andrea Härzschel ◽  
Tanja Hartmann
Keyword(s):  
Tyrosine Kinases ◽  
Chemokine Receptors ◽  
Hematological Malignancies ◽  
Hematologic Malignancies ◽  
Cell Microenvironment ◽  
Cellular Processes ◽  
Rac Gtpases ◽  
Rho Family Gtpases ◽  
Rho Family ◽  
Specific Contribution

Emerging evidence suggests that crosstalk between hematologic tumor cells and the tumor microenvironment contributes to leukemia and lymphoma cell migration, survival, and proliferation. The supportive tumor cell-microenvironment interactions and the resulting cellular processes require adaptations and modulations of the cytoskeleton. The Rac subfamily of the Rho family GTPases includes key regulators of the cytoskeleton, with essential functions in both normal and transformed leukocytes. Rac proteins function downstream of receptor tyrosine kinases, chemokine receptors, and integrins, orchestrating a multitude of signals arising from the microenvironment. As such, it is not surprising that deregulation of Rac expression and activation plays a role in the development and progression of hematological malignancies. In this review, we will give an overview of the specific contribution of the deregulation of Rac GTPases in hematologic malignancies.

Rho family GTPases

2012 ◽  
Vol 40 (6) ◽  
pp. 1378-1382 ◽  
Author(s):  
Alan Hall
Keyword(s):  
Actin Cytoskeleton ◽  
Rho Gtpases ◽  
Cellular Response ◽  
Molecular Switches ◽  
Effector Proteins ◽  
Eukaryotic Cells ◽  
Cell Behaviour ◽  
Wide Range ◽  
Rho Family Gtpases ◽  
Rho Family

Rho GTPases comprise a family of molecular switches that control signal transduction pathways in eukaryotic cells. A conformational change induced upon binding GTP promotes an interaction with target (effector) proteins to generate a cellular response. A highly conserved function of Rho GTPases from yeast to humans is to control the actin cytoskeleton, although, in addition, they promote a wide range of other cellular activities. Changes in the actin cytoskeleton drive many dynamic aspects of cell behaviour, including morphogenesis, migration, phagocytosis and cytokinesis, and the dysregulation of Rho GTPases is associated with numerous human diseases and disorders.

Integrin regulation of membrane domain trafficking and Rac targeting

2005 ◽  
Vol 33 (4) ◽  
pp. 609-613 ◽  
Author(s):  
A. Grande-García ◽  
A. Echarri ◽  
M.A. Del Pozo
Keyword(s):  
Cell Growth ◽  
Binding Sites ◽  
Cell Cycle Progression ◽  
Membrane Microdomains ◽  
Cycle Progression ◽  
Cellular Processes ◽  
Rho Family Gtpases ◽  
Rho Family ◽  
And Migration ◽  
Integrin Regulation

Integrins are crucial regulators of essential cellular processes such as gene expression, cell proliferation and migration. Alteration of these processes is central to tumourigenesis. Integrin signals mediate anchorage dependence of cell growth, while growth of cancer cells is anchorage-independent. Integrins critically regulate Rho family GTPases, that are also involved in cell-cycle progression and oncogenesis. In addition to their effect on GTP loading, integrins independently control the translocation of GTP-bound Rac to the plasma membrane. This step is essential for Rac binding to effectors. Integrins increase membrane affinity for Rac, leading to RhoGDI dissociation and effector coupling locally, in the vicinity of activated/bound integrins. Integrin-regulated Rac binding sites are within CEMMs (cholesterol-enriched membrane microdomains). Integrins control Rac signalling by preventing the internalization of its binding sites in CEMMs. Integrin regulation of signalling pathways initiated in CEMMs may be important for the spatial control of cell migration and anchorage dependence of cell growth.

scholarly journals Differential activation and function of Rho GTPases during Salmonella–host cell interactions

2006 ◽  
Vol 175 (3) ◽  
pp. 453-463 ◽  
Author(s):  
Jayesh C. Patel ◽  
Jorge E. Galán
Keyword(s):  
Rho Gtpases ◽  
Food Poisoning ◽  
Bacterial Pathogen ◽  
Cellular Responses ◽  
Host Cells ◽  
Nucleotide Exchange ◽  
Exchange Factor ◽  
Rho Family Gtpases ◽  
Rho Family ◽  
And Function

Salmonella enterica, the cause of food poisoning and typhoid fever, has evolved sophisticated mechanisms to modulate Rho family guanosine triphosphatases (GTPases) to mediate specific cellular responses such as actin remodeling, macropinocytosis, and nuclear responses. These responses are largely the result of the activity of a set of bacterial proteins (SopE, SopE2, and SopB) that, upon delivery into host cells via a type III secretion system, activate specific Rho family GTPases either directly (SopE and SopE2) or indirectly (SopB) through the stimulation of an endogenous exchange factor. We show that different Rho family GTPases play a distinct role in Salmonella-induced cellular responses. In addition, we report that SopB stimulates cellular responses by activating SH3-containing guanine nucleotide exchange factor (SGEF), an exchange factor for RhoG, which we found plays a central role in the actin cytoskeleton remodeling stimulated by Salmonella. These results reveal a remarkable level of complexity in the manipulation of Rho family GTPases by a bacterial pathogen.

scholarly journals Rho-family GTPases modulate Ca2+-dependent ATP release from astrocytes

2008 ◽  
Vol 295 (1) ◽  
pp. C231-C241 ◽  
Author(s):  
Andrew E. Blum ◽  
Sheldon M. Joseph ◽  
Ronald J. Przybylski ◽  
George R. Dubyak
Keyword(s):  
Rho Gtpases ◽  
Atp Release ◽  
Rho Kinase ◽  
Astrocytoma Cells ◽  
Gap Junction Channel ◽  
Rho Family Gtpases ◽  
Clostridium Difficile Toxin ◽  
Protease Activated Receptor 1 ◽  
Rho Family ◽  
Clostridium Difficile Toxin B

Previously, we reported that activation of G protein-coupled receptors (GPCR) in 1321N1 human astrocytoma cells elicits a rapid release of ATP that is partially dependent on a Gq/phophospholipase C (PLC)/Ca2+ mobilization signaling cascade. In this study we assessed the role of Rho-family GTPase signaling as an additional pathway for the regulation of ATP release in response to activation of protease-activated receptor-1 (PAR1), lysophosphatidic acid receptor (LPAR), and M3-muscarinic (M3R) GPCRs. Thrombin (or other PAR1 peptide agonists), LPA, and carbachol triggered quantitatively similar Ca2+ mobilization responses, but only thrombin and LPA caused rapid accumulation of active GTP-bound Rho. The ability to elicit Rho activation correlated with the markedly higher efficacy of thrombin and LPA, relative to carbachol, as ATP secretagogues. Clostridium difficile toxin B and Clostridium botulinum C3 exoenzyme, which inhibit Rho-GTPases, attenuated the thrombin- and LPA-stimulated ATP release but did not decrease carbachol-stimulated release. Thus the ability of certain Gq-coupled receptors to additionally stimulate Rho-GTPases acts to strongly potentiate a Ca2+-activated ATP release pathway. However, pharmacological inhibition of Rho kinase I/II or myosin light chain kinase did not attenuate ATP release. PAR1-induced ATP release was also reduced twofold by brefeldin treatment suggesting the possible mobilization of Golgi-derived, ATP-containing secretory vesicles. ATP release was also markedly repressed by the gap junction channel inhibitor carbenoxolone in the absence of any obvious thrombin-induced change in membrane permeability indicative of hemichannel gating.

scholarly journals Rho GTPases and their effector proteins

2000 ◽  
Vol 348 (2) ◽  
pp. 241-255 ◽  
Author(s):  
Anne L. BISHOP ◽  
Alan HALL
Keyword(s):  
Rho Gtpases ◽  
Cell Cycle Progression ◽  
Biological Effects ◽  
Effector Proteins ◽  
Actin Dynamics ◽  
Filamentous Actin ◽  
Cycle Progression ◽  
Cellular Processes ◽  
Specific Effector ◽  
Rho Family

Rho GTPases are molecular switches that regulate many essential cellular processes, including actin dynamics, gene transcription, cell-cycle progression and cell adhesion. About 30 potential effector proteins have been identified that interact with members of the Rho family, but it is still unclear which of these are responsible for the diverse biological effects of Rho GTPases. This review will discuss how Rho GTPases physically interact with, and regulate the activity of, multiple effector proteins and how specific effector proteins contribute to cellular responses. To date most progress has been made in the cytoskeleton field, and several biochemical links have now been established between GTPases and the assembly of filamentous actin. The main focus of this review will be Rho, Rac and Cdc42, the three best characterized mammalian Rho GTPases, though the genetic analysis of Rho GTPases in lower eukaryotes is making increasingly important contributions to this field.

scholarly journals EXC-4/CLIC, Gα, and Rho/Rac signaling regulate tubulogenesis in C. elegans

2021 ◽  
Author(s):  
Anthony F Arena ◽  
Daniel D Shaye
Keyword(s):  
G Protein ◽  
Small Gtpases ◽  
Loss Of Function ◽  
C Elegans ◽  
C Terminus ◽  
Evolutionarily Conserved ◽  
Rho Family Gtpases ◽  
Rho Family ◽  
Vessel Development ◽  
G Protein Coupled

The Rho-family of small GTPases, which play crucial roles in development and disease, are regulated by many signal-transduction cascades, including G-protein-coupled receptor (GPCR)-heterotrimeric G-protein (Gα/β/γ) pathways. Using genetic approaches in C. elegans we identified a new role for Gα and Rho/Rac signaling in cell outgrowth during tubulogenesis and show that the Chloride Intracellular Channel (CLIC) protein EXC-4 is an evolutionarily-conserved player in this pathway. The gene exc-4 was identified by its role in tubulogenesis of the excretory canal (ExCa) cell: a unicellular tube required for osmoregulation and fluid clearance. We identified a new exc-4 loss-of-function allele that affects an evolutionarily conserved residue in the C-terminus. Using this mutant we identified genetic interactions between exc-4, Gα's and Rho-family GTPases, defining novel roles for Gα-encoding genes (gpa-12/Gα12/13, gpa-7/Gαi, egl-30/Gαq, and gsa-1/Gαs) and the Rho-family members ced-10/Rac and mig-2/RhoG in ExCa outgrowth. EXC-4 and human CLICs have conserved functions in tubulogenesis, and CLICs and Gα-Rho/Rac signaling regulate tubulogenesis during blood vessel development. Therefore, our work defines a primordial role for EXC-4/CLICs in Gα-Rho/Rac-signaling during tubulogenesis.

scholarly journals The Large GTPase, GBP-2, Regulates Rho Family GTPases to Inhibit Migration and Invadosome Formation in Breast Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5632
Author(s):  
Geoffrey O. Nyabuto ◽  
John P. Wilson ◽  
Samantha A. Heilman ◽  
Ryan C. Kalb ◽  
Jonathan P. Kopacz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Rho Gtpases ◽  
Breast Cancer Cells ◽  
Primary Site ◽  
Common Cancer ◽  
Rho Family Gtpases ◽  
Rho Family ◽  
4T1 Cells ◽  
Guanylate Binding Protein

Breast cancer is the most common cancer in women. Despite advances in early detection and treatment, it is predicted that over 43,000 women will die of breast cancer in 2021. To lower this number, more information about the molecular players in breast cancer are needed. Guanylate-Binding Protein-2 has been correlated with better prognosis in breast cancer. In this study, we asked if the expression of GBP-2 in breast cancer merely provided a biomarker for improved prognosis or whether it actually contributed to improving outcome. To answer this, the 4T1 model of murine breast cancer was used. 4T1 cells themselves are highly aggressive and highly metastatic, while 67NR cells, isolated from the same tumor, do not leave the primary site. The expression of GBP-2 was examined in the two cell lines and found to be inversely correlated with aggressiveness/metastasis. Proliferation, migration, and invadosome formation were analyzed after altering the expression levels of GBP-2. Our experiments show that GBP-2 does not alter the proliferation of these cells but inhibits migration and invadosome formation downstream of regulation of Rho GTPases. Together these data demonstrate that GBP-2 is responsible for cell autonomous activities that make breast cancer cells less aggressive.

scholarly journals Proximity-dependent proteomics reveals extensive interactions of Protocadherin-19 with regulators of Rho GTPases and the microtubule cytoskeleton

2020 ◽  
Author(s):  
Michelle R. Emond ◽  
Sayantanee Biswas ◽  
Matthew L. Morrow ◽  
James D. Jontes
Keyword(s):  
Nervous System ◽  
Behavioral Problems ◽  
Rho Gtpases ◽  
Protein Complexes ◽  
Epileptic Seizures ◽  
Centrosomal Protein ◽  
Surface Receptors ◽  
Rho Family Gtpases ◽  
Rho Family

AbstractProtocadherin-19 belongs to the cadherin family of cell surface receptors and has been shown to play essential roles in the development of the vertebrate nervous system. Mutations in human Protocadherin-19 (PCDH19) lead to PCDH19 Female-limited epilepsy (PCDH19 FLE) in humans, characterized by the early onset of epileptic seizures in children and a range of cognitive and behavioral problems in adults. Despite being considered the second most prevalent gene in epilepsy, very little is known about the intercellular pathways in which it participates. In order to characterize the protein complexes within which Pcdh19 functions, we generated Pcdh19-BioID fusion proteins and utilized proximity-dependent biotinylation to identify neighboring proteins. Proteomic identification and analysis revealed that the Pcdh19 interactome is enriched in proteins that regulate Rho family GTPases, microtubule binding proteins and proteins that regulate cell divisions. We cloned the centrosomal protein Nedd1 and the RacGEF Dock7 and verified their interactions with Pcdh19 in vitro. Our findings provide the first comprehensive insights into the interactome of Pcdh19, and provide a platform for future investigations into the cellular and molecular biology of this protein critical to the proper development of the nervous system.

scholarly journals Multi-omics integration of methyltransferase-like protein family reveals clinical outcomes and functional signatures in human cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ion John Campeanu ◽  
Yuanyuan Jiang ◽  
Lanxin Liu ◽  
Maksymilian Pilecki ◽  
Alvina Najor ◽  
...  
Keyword(s):  
Human Cancer ◽  
Function Analysis ◽  
Functional Study ◽  
Loss Of Function ◽  
Cancer Cell Growth ◽  
Genomic Amplification ◽  
Growth And Survival ◽  
Protein Levels ◽  
Cellular Processes ◽  
Associated Proteins

AbstractHuman methyltransferase-like (METTL) proteins transfer methyl groups to nucleic acids, proteins, lipids, and other small molecules, subsequently playing important roles in various cellular processes. In this study, we performed integrated genomic, transcriptomic, proteomic, and clinicopathological analyses of 34 METTLs in a large cohort of primary tumor and cell line data. We identified a subset of METTL genes, notably METTL1, METTL7B, and NTMT1, with high frequencies of genomic amplification and/or up-regulation at both the mRNA and protein levels in a spectrum of human cancers. Higher METTL1 expression was associated with high-grade tumors and poor disease prognosis. Loss-of-function analysis in tumor cell lines indicated the biological importance of METTL1, an m7G methyltransferase, in cancer cell growth and survival. Furthermore, functional annotation and pathway analysis of METTL1-associated proteins revealed that, in addition to the METTL1 cofactor WDR4, RNA regulators and DNA packaging complexes may be functionally interconnected with METTL1 in human cancer. Finally, we generated a crystal structure model of the METTL1–WDR4 heterodimeric complex that might aid in understanding the key functional residues. Our results provide new information for further functional study of some METTL alterations in human cancer and might lead to the development of small inhibitors that target cancer-promoting METTLs.

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