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RHO–GTPases and cancer

Key Points

  • The RHO genes encode a related family of proteins that can bind to and hydrolyse GTP. When bound to GTP, they can bind to effector proteins and modulate cell behaviour and cell morphology.

  • Activated RHO-protein mutants are capable of transforming fibroblasts, and dominant inhibitory mutants of RHO proteins block transformation by RAS. There is increasing evidence that RHO proteins are deregulated during tumour progression and that this correlates with poor prognosis.

  • Modulation of RHO-protein activity can promote the metastasis of tumour cells by disrupting epithelial-sheet organization, increasing cell motility and promoting the degradation of the extracellular matrix.

  • RHO proteins can promote cell-cycle progression, which is controlled by cyclin-dependent kinases (CDKs). RHO proteins affect CDK activity by regulating the levels of cyclin D1, as well as p21WAF1 and p27KIP1, which bind to and modulate CDK activity. There is also evidence that RHO proteins might protect cells against apoptosis.

  • Given the involvement of RHO proteins in cancer, they might make good therapeutic targets. Methods of interfering with RHO function include: inhibition of membrane localization; blocking the function of RHO–GEFs (guanine nucleotide exchange factors); preventing RHO's interaction with its effectors; and inhibiting RHO's effector functions.

Abstract

The RAS oncogenes were identified almost 20 years ago. Since then, we have learnt that they are members of a large family of small GTPases that bind GTP and hydrolyse it to GDP. This is then exchanged for GTP and the cycle is repeated. The switching between these two states regulates a wide range of cellular processes. A branch of the RAS family — the RHO proteins — is also involved in cancer, but what is the role of these proteins and would they make good therapeutic targets?

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Figure 1: The RHO-protein family.
Figure 2: Model of RHO-protein regulation.
Figure 3: Involvement of RHO proteins at different stages of tumour progression.
Figure 4: Possible links between RHO-family GTPases and the cell-cycle machinery.
Figure 5: Role of physical cues and RHO-family GTPases in proliferation.
Figure 6: Methods of interfering with RHO-protein function.

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Acknowledgements

We thank M. Coleman, D. Croft, G. D'Abaco, M. Olson and S. Wilkinson for their advice. E.S. and C.J M. are funded by the Cancer Research Campaign.

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DATABASES

CancerNet:

breast cancer

colon carcinomas

multiple myeloma

non-Hodgkin's lymphoma

pancreatic ductal adenocarcinoma

testicular germ-cell tumours

 LocusLink:

ABL

actin

AKT

APC

ARF1

ATF

A-type cyclins

BAD

BCR

β-catenin

CD44

CDC42

CDK2

CDK4

CDK6

CDKIs

γCOP coatomer protein

D-type cyclins

EGF

EGFR

ERK1

ERK2

ETS

E-type cyclins

ezrin

FAK

FAS

fibronectin

FOS

HGF

IκB

IKK

JNK

JUN

kinectin

laminin

LARG

MAPK

MEF2C

MEKKs

MLKs

MLL

MMPs

moesin

MYC

NF-κB

NF1

NF2

p21WAF1

p27KIP1

p38

p38γ MAPK

PAR6

PDGF

PKC

POSH

PRK1

RAC1

RAC2

RAC3

radixin

RAF

RAS

RHOA

RHOB

RHOC

RHOD

RHOE

RHOG

RHOH

RND1

RND2

ROCKs

SRC

SRF

synaptojanin 2

TC10

TGF-β

Tiam1

TIMPs

WNT1

WRCH1

Glossary

EFFECTOR

A protein that mediates the cellular effects of a signal-transduction pathway.

FIBROBLAST

A cell that makes up connective tissue, and is responsible for the production of most of the extracellular matrix components. Fibroblasts are relatively easy to culture, and have been used extensively in in vitro models of transformation. However, very few tumours arise from fibroblasts.

CHROMOSOMAL TRANSLOCATION

The breaking and rejoining of different chromosomes to produce inappropriate hybrid chromosomes. Specific translocations are particularly associated with certain tumours of myeloid origin.

EPITHELIUM

A layer of cells that lines body cavities or exposed surfaces. Cells in epithelial sheets are tightly packed and have specialized cell–cell junctions, and usually rest on a basement membrane. Most tumours arise from epithelial cells.

EXTRACELLULAR MATRIX (ECM)

The molecular network outside the cell that provides structure to tissues.

EPITHELIAL–MESENCHYMAL TRANSITION

The switching of epithelial tumour cells to a fibroblastic phenotype, which is characterized by loss of cell–cell junctions, increased motility and altered gene expression.

ADHERENS JUNCTIONS

Cell–cell adhesive junctions that are linked to cytoskeletal filaments of the microfilament type.

TIGHT JUNCTIONS

Connections between individual cells in an epithelium that form a diffusion barrier between the two surfaces of the epithelium.

BASEMENT MEMBRANE

A layer of extracellular matrix that underlies the epithelium.

MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) CASCADE

MAPKs are a family of kinases that are activated by phosphorylation in response to extracellular stimuli. The kinases that phoshorylate MAPKs — MEKs — are, themselves, regulated by phosphorylation. Such sequential chains of kinase phosphorylation and activation are called kinase cascades.

ATYPICAL PKC

A member of the protein kinase C family that lacks a C2 domain and is insensitive to Ca2+, diacylglycerol and phorbol esters.

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Sahai, E., Marshall, C. RHO–GTPases and cancer. Nat Rev Cancer 2, 133–142 (2002). https://doi.org/10.1038/nrc725

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