Rho GTPase Signaling in Health and Disease: A Complex Signaling Network

Rho guanosine triphosphatases (GTPases) are key regulators in a number of cellular functions, including actin cytoskeleton remodeling and vesicle traffic. Traditionally, Rho GTPases are studied because of their function in cell migration and cancer, while their roles in metabolism are less documented. However, emerging evidence implicates Rho GTPases as regulators of processes of crucial importance for maintaining metabolic homeostasis. Thus, the time is now ripe for reviewing Rho GTPases in the context of metabolic health. Rho GTPase-mediated key processes include the release of insulin from pancreatic β cells, glucose uptake into skeletal muscle and adipose tissue, and muscle mass regulation. Through the current review, we cast light on the important roles of Rho GTPases in skeletal muscle, adipose tissue, and the pancreas and discuss the proposed mechanisms by which Rho GTPases act to regulate glucose metabolism in health and disease. We also describe challenges and goals for future research.

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Ras Superfamily Small G Proteins: Biology and Mechanisms 1

10.1007/978-3-7091-1806-1 ◽

2014 ◽

Cited By ~ 2

Keyword(s):

G Proteins ◽

Ras Superfamily ◽

Small G Proteins

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Small GTP-binding protein-coupled receptors

Biochemical Society Transactions ◽

10.1042/bst0321040 ◽

2004 ◽

Vol 32 (6) ◽

pp. 1040-1044 ◽

Cited By ~ 71

Author(s):

M. Bhattacharya ◽

A.V. Babwah ◽

S.S.G. Ferguson

Keyword(s):

G Protein ◽

G Proteins ◽

Rho Gtpases ◽

Eukaryotic Cell ◽

Small Gtpases ◽

Heterotrimeric G Proteins ◽

Nucleotide Exchange ◽

Cell Functions ◽

Effector Pathways ◽

Small G Proteins

Heterotrimeric GPCRs (G-protein-coupled receptors) form the largest group of integral membrane receptor proteins and mediate diverse physiological processes. In addition to signalling via heterotrimeric G-proteins, GPCRs can also signal by interacting with various small G-proteins to regulate downstream effector pathways. The small G-protein superfamily is structurally classified into at least five families: the Ras, Rho/Rac/cdc42, Rab, Sar1/Arf and Ran families. They are monomeric G-proteins with molecular masses over the range 20–30 kDa, which function as molecular switches to control many eukaryotic cell functions. Several studies have provided evidence of crosstalk between GPCRs and small G-proteins. It is well documented that GPCR signalling through heterotrimeric G-proteins can lead to the activation of Ras and Rho GTPases. In addition, RhoA, Rabs, ARFs and ARF GEFs (guanine nucleotide-exchange factors) can associate directly with GPCRs, and GPCRs may also function as GEFs for small GTPases. In this review, we summarize the recent progress made in understanding the interaction between GPCRs and small GTPases, focusing on understanding how the association of small G-proteins with GPCRs and GPCR-regulatory proteins may influence GPCR signalling and intracellular trafficking.

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Rho GTPases – Emerging Regulators of Glucose Homeostasis and Metabolic Health

10.20944/preprints201904.0155.v1 ◽

2019 ◽

Author(s):

Lisbeth L.V. Møller ◽

Amira Klip ◽

Lykke Sylow

Keyword(s):

Skeletal Muscle ◽

Adipose Tissue ◽

Rho Gtpases ◽

Rho Gtpase ◽

Metabolic Health ◽

Future Research ◽

Cellular Functions ◽

Vesicle Traffic ◽

Cytoskeleton Remodeling ◽

Health And Disease

Rho guanosine triphosphatases (GTPases) are key regulators in a number of cellular functions, including actin cytoskeleton remodeling and vesicle traffic. Traditionally, Rho GTPases are studied because of their function in cell migration and cancer, while their roles in metabolism are less documented. However, emerging evidence implicates Rho GTPases as regulators of processes of crucial importance for maintaining metabolic homeostasis. Thus, the time is now ripe for reviewing Rho GTPases in the context of metabolic health. Rho GTPase-mediated key processes include the release of insulin from pancreatic β-cells, glucose uptake into skeletal muscle and adipose tissue, and muscle mass regulation. Through the current review, we cast light on the important role of Rho GTPases in skeletal muscle, adipose tissue, and the pancreas and mechanisms by which Rho GTPases act to regulate glucose metabolism in health and disease. We also describe challenges and goals for future research.

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Regulation of Rho GTPases by RhoGDIs in Human Cancers

Cells ◽

10.3390/cells8091037 ◽

2019 ◽

Vol 8 (9) ◽

pp. 1037 ◽

Cited By ~ 6

Author(s):

Cho ◽

Kim ◽

Baek ◽

Kim ◽

Lee

Keyword(s):

Cell Migration ◽

Cancer Progression ◽

Anticancer Agents ◽

Rho Gtpases ◽

Rho Gtpase ◽

Regulatory Mechanisms ◽

Malignant Phenotype ◽

Cellular Processes ◽

Human Cancers

Rho GDP dissociation inhibitors (RhoGDIs) play important roles in various cellular processes, including cell migration, adhesion, and proliferation, by regulating the functions of the Rho GTPase family. Dissociation of Rho GTPases from RhoGDIs is necessary for their spatiotemporal activation and is dynamically regulated by several mechanisms, such as phosphorylation, sumoylation, and protein interaction. The expression of RhoGDIs has changed in many human cancers and become associated with the malignant phenotype, including migration, invasion, metastasis, and resistance to anticancer agents. Here, we review how RhoGDIs control the function of Rho GTPases by regulating their spatiotemporal activity and describe the regulatory mechanisms of the dissociation of Rho GTPases from RhoGDIs. We also discuss the role of RhoGDIs in cancer progression and their potential uses for therapeutic intervention.

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PAK and other Rho-associated kinases – effectors with surprisingly diverse mechanisms of regulation

Biochemical Journal ◽

10.1042/bj20041638 ◽

2005 ◽

Vol 386 (2) ◽

pp. 201-214 ◽

Cited By ~ 190

Author(s):

Zhou-shen ZHAO ◽

Ed MANSER

Keyword(s):

Rho Gtpases ◽

Cell Biology ◽

Rho Gtpase ◽

Rho Kinase ◽

Molecular Switches ◽

Eukaryotic Cell ◽

Effector Proteins ◽

Downstream Effector ◽

P21 Activated Kinase ◽

Do So

The Rho GTPases are a family of molecular switches that are critical regulators of signal transduction pathways in eukaryotic cells. They are known principally for their role in regulating the cytoskeleton, and do so by recruiting a variety of downstream effector proteins. Kinases form an important class of Rho effector, and part of the biological complexity brought about by switching on a single GTPase results from downstream phosphorylation cascades. Here we focus on our current understanding of the way in which different Rho-associated serine/threonine kinases, denoted PAK (p21-activated kinase), MLK (mixed-lineage kinase), ROK (Rho-kinase), MRCK (myotonin-related Cdc42-binding kinase), CRIK (citron kinase) and PKN (protein kinase novel), interact with and are regulated by their partner GTPases. All of these kinases have in common an ability to dimerize, and in most cases interact with a variety of other proteins that are important for their function. A diversity of known structures underpin the Rho GTPase–kinase interaction, but only in the case of PAK do we have a good molecular understanding of kinase regulation. The ability of Rho GTPases to co-ordinate spatial and temporal phosphorylation events explains in part their prominent role in eukaryotic cell biology.

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