scholarly journals Progress in the therapeutic inhibition of Cdc42 signalling

2021 ◽  
Author(s):  
Natasha P. Murphy ◽  
Helen R. Mott ◽  
Darerca Owen
Keyword(s):  
Cell Cycle Progression ◽  
Cell Transformation ◽  
Cancer Therapeutics ◽  
Small Gtpases ◽  
Direct Inhibition ◽  
Cycle Progression ◽  
Tumour Metastasis ◽  
Downstream Effectors ◽  
Cell Architecture ◽  
Rho Family

Cdc42 is a member of the Rho family of small GTPases and a key regulator of the actin cytoskeleton, controlling cell motility, polarity and cell cycle progression. It signals downstream of the master regulator Ras and is essential for cell transformation by this potent oncogene. Overexpression of Cdc42 is observed in several cancers, where it is linked to poor prognosis. As a regulator of both cell architecture and motility, deregulation of Cdc42 is also linked to tumour metastasis. Like Ras, Cdc42 and other components of the signalling pathways it controls represent important potential targets for cancer therapeutics. In this review, we consider the progress that has been made targeting Cdc42, its regulators and effectors, including new modalities and new approaches to inhibition. Strategies under consideration include inhibition of lipid modification, modulation of Cdc42–GEF, Cdc42–GDI and Cdc42-effector interactions, and direct inhibition of downstream effectors.

Function and regulation of RhoE

2005 ◽  
Vol 33 (4) ◽  
pp. 649-651 ◽  
Author(s):  
K. Riento ◽  
P. Villalonga ◽  
R. Garg ◽  
A. Ridley
Keyword(s):  
Cell Cycle Progression ◽  
Small Gtpases ◽  
Serine Threonine Kinase ◽  
Cycle Progression ◽  
Cultured Fibroblasts ◽  
Multifunctional Protein ◽  
Threonine Kinase ◽  
Inhibit Cell Cycle Progression ◽  
Rho Family ◽  
Stress Fibre Formation

The three Rnd proteins, Rnd1, Rnd2 and RhoE/Rnd3, are a subset of Rho family proteins that are unusual in that they bind but do not hydrolyse GTP, and are therefore not regulated by the classical GTP/GDP conformational switch of small GTPases. Increased expression of each Rnd protein induces loss of stress fibres in cultured fibroblasts and epithelial cells, acting antagonistically to RhoA, which stimulates stress fibre formation. RhoE is farnesylated and localizes partly on membranes, including the Golgi and plasma membrane, and in the cytosol. RhoE inhibits RhoA signalling in part by binding to the RhoA-activated serine/threonine kinase ROCK I (Rho-associated kinase I), thereby preventing it from phosphorylating its targets. RhoE activity is itself regulated by phosphorylation by ROCK I on multiple sites. RhoE phosphorylation enhances its stability, leading to an increase in RhoE levels. In addition, phosphorylation reduces its association with membranes and correlates with its ability to induce loss of stress fibres. RhoE also acts independently of ROCK to inhibit cell cycle progression, in part by preventing translation of cyclin D1, and to inhibit transformation of fibroblasts by oncogenic H-Ras. RhoE is therefore a multifunctional protein whose localization and actions are regulated by phosphorylation.

scholarly journals Molecular subversion of Cdc42 signalling in cancer

2021 ◽  
Author(s):  
Natasha P. Murphy ◽  
Ana Masara binti Ahmad Mokhtar ◽  
Helen R. Mott ◽  
Darerca Owen
Keyword(s):  
G Protein ◽  
Cell Cycle Progression ◽  
Small Gtpases ◽  
Signalling Pathways ◽  
Cycle Progression ◽  
Small G Protein ◽  
Genomics And Proteomics ◽  
The Subject ◽  
Rho Family

Cdc42 is a member of the Rho family of small GTPases and a master regulator of the actin cytoskeleton, controlling cell motility, polarity and cell cycle progression. This small G protein and its regulators have been the subject of many years of fruitful investigation and the advent of functional genomics and proteomics has opened up new avenues of exploration including how it functions at specific locations in the cell. This has coincided with the introduction of new structural techniques with the ability to study small GTPases in the context of the membrane. The role of Cdc42 in cancer is well established but the molecular details of its action are still being uncovered. Here we review alterations found to Cdc42 itself and to key components of the signal transduction pathways it controls in cancer. Given the challenges encountered with targeting small G proteins directly therapeutically, it is arguably the regulators of Cdc42 and the effector signalling pathways downstream of the small G protein which will be the most tractable targets for therapeutic intervention. These will require interrogation in order to fully understand the global signalling contribution of Cdc42, unlock the potential for mapping new signalling axes and ultimately produce inhibitors of Cdc42 driven signalling.

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 Activation of STAT transcription factors by the Rho-family GTPases

2020 ◽  
Vol 48 (5) ◽  
pp. 2213-2227
Author(s):  
Jessica Corry ◽  
Helen R. Mott ◽  
Darerca Owen
Keyword(s):  
Transcription Factors ◽  
Rho Gtpase ◽  
Therapeutic Potential ◽  
Small Gtpases ◽  
Cellular Morphology ◽  
Invasion And Metastasis ◽  
Family Control ◽  
Signal Transducers ◽  
Downstream Effectors ◽  
Rho Family

The Rho-family of small GTPases are biological molecular switches that are best known for their regulation of the actin cytoskeleton. Through their activation and stimulation of downstream effectors, the Rho-family control pathways involved in cellular morphology, which are commonly activated in cancer cell invasion and metastasis. While this makes them excellent potential therapeutic targets, a deeper understanding of the downstream signalling pathways they influence will be required for successful drug targeting. Signal transducers and activators of transcription (STATs) are a family of transcription factors that are hyper-activated in most cancer types and while STATs are widely understood to be activated by the JAK family of kinases, many additional activators have been discovered. A growing number of examples of Rho-family driven STAT activation, largely of the oncogenic family members, STAT3 and STAT5, are being identified. Cdc42, Rac1, RhoA, RhoC and RhoH have all been implicated in STAT activation, contributing to Rho GTPase-driven changes in cellular morphology that lead to cell proliferation, invasion and metastasis. This highlights the importance and therapeutic potential of the Rho-family as regulators of non-canonical activation of STAT signalling.

scholarly journals Chemotactic Signaling Pathways in Neutrophils: from Receptor to Actin Assembly

2002 ◽  
Vol 13 (3) ◽  
pp. 220-228 ◽  
Author(s):  
Gregor Cicchetti ◽  
Philip G. Allen ◽  
Michael Glogauer
Keyword(s):  
G Proteins ◽  
Neutrophil Function ◽  
Small Gtpases ◽  
Regulatory Proteins ◽  
Heterotrimeric G Proteins ◽  
Actin Assembly ◽  
Receptor Ligand ◽  
Downstream Effectors ◽  
Ligand Interactions ◽  
Rho Family

In this review, we present an overview of the signaling elements between neutrophil chemotactic receptors and the actin cytoskeleton that drives cell motility. From receptor-ligand interactions, activation of heterotrimeric G-proteins, their downstream effectors PLC and PI-3 kinase, the activation of small GTPases of the Rho family, and their regulation of particular cytoskeletal regulatory proteins, we describe pathways specific to the chemotaxing neutrophil and elements documented to be important for neutrophil function.

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 Significance of Ras Signaling in Cancer and Strategies for its Control

2015 ◽  
Vol 11 (02) ◽  
pp. 147
Author(s):  
Arun Bahadur Gurung ◽  
Atanu Bhattacharjee ◽  
◽  
Keyword(s):  
Drug Targets ◽  
Cell Cycle Progression ◽  
Cancer Therapeutics ◽  
Ras Signaling ◽  
Post Translational Modification ◽  
Downstream Effector ◽  
Downstream Effectors ◽  
Ras Effectors ◽  
A Cell ◽  
Effector Pathways

Ras is a GTP-binding protein and is the most widely studied oncoprotein. To achieve its biological activity, it must undergo post-translation modification. Ras acts as a typical molecular switch. The GTP-bound Ras can activate several downstream effector pathways. Ras signaling regulates many important physiologic processes within a cell, such as cell cycle progression, survival, apoptosis, etc. Several studies have found mutation in Ras or its effectors in various types of tumors. Therefore, Ras or its downstream effectors can be attractive drug targets against various types of tumors in cancer therapeutics. Some therapeutic agents against Ras effectors, such as Raf, MEK1/2, PI3K, AKT etc., have successfully managed to enter into phase I and II trials. This targeted drug design could be envisaged in mainly four ways, such as prevention of Ras-GTP formation, covalent locking of the GDP-bound Ras, inhibition of Ras-effector interactions, or impairment of post-translational modification of Ras. In this review we summarize the normal Ras signaling as well its aberrant signaling in tumors and various strategies to inhibit Ras signaling.

scholarly journals The Rho Family Member RhoE Interacts with Skp2 and Is Degraded at the Proteasome during Cell Cycle Progression

2013 ◽  
Vol 288 (43) ◽  
pp. 30872-30882 ◽  
Author(s):  
Marta Lonjedo ◽  
Enric Poch ◽  
Enric Mocholí ◽  
Marta Hernández-Sánchez ◽  
Carmen Ivorra ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Family Member ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Rho Family
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