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Function and regulation of Rnd proteins

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From Nature Reviews Molecular Cell Biology

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Key Points

  • The three Rnd proteins appeared late in evolution (in vertebrates) and are Rho-family proteins with unusual biochemical properties. They do not cycle between GDP (inactive) and GTP (active) states, but are constitutively active (GTP bound).

  • Because Rnd proteins are constitutively active and do not cycle, they are regulated by other mechanisms, including expression levels, localization, phosphorylation and degradation.

  • Rnd proteins have effects antagonistic to Rho, and they inhibit the formation of contractile acto-myosin cables (stress fibres). Rnd proteins are expressed in neurons where they participate in the extension of growth cones.

  • Rnd proteins are involved in axon guidance and interact with plexins (the semaphorin receptors) to modulate downstream pathways. Rnd proteins are also involved in fibroblast-growth-factor-receptor-1 signalling.

  • Rnd3 overexpression blocks cell-cycle progression, and Rnd3 protein expression is frequently decreased in prostate and breast cancer. However, increased expression of Rnd3 has also been observed in cancers with a constitutively active Ras–Raf pathway. Additional studies are required to understand the basis for these apparent discrepancies.

  • Further studies in animal models are needed to investigate the roles of Rnd proteins in brain development, and a more precise understanding of the functions of Rnd partners is required. A role in axonal regeneration of injured nerve cells is another exciting possibility.

Abstract

The Rnd proteins, which form a distinct sub-group of the Rho family of small GTP-binding proteins, have been shown to regulate the organization of the actin cytoskeleton in several tissues. In the brain, they participate in neurite extension, whereas in smooth muscle, they modulate contractility. Recent evidence has shown that Rnd3 (RhoE) is also involved in the regulation of cell-cycle progression and transformation, indicating that these proteins might have other, as yet unexplored roles.

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Figure 1: The Rho family in humans and emergence of Rnds during evolution.
Figure 2: Rnd1 effects on the actin cytoskeleton.
Figure 3: Model of Rnd protein regulation and action in axon guidance.
Figure 4: Mechanisms of Rnd1 activation in response to FGF.

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Acknowledgements

I would like to thank A. Ridley, A. Püschel, M. Negishi and P. Pacaud for sharing results before publication and for stimulating discussions, and I. Mus-Veteau for helpful comments. P.C. is supported by INSERM, Association pour la Recherche sur le Cancer, La Ligue Contre le Cancer, and Fondation pour la Recherche Médicale.

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  1. Institut de Pharmacologie Moleculaire et Cellulaire, Centre National de la Recherche Scientifique, 660 Route des Lucioles, Sophia Antipolis, 06560, Valbonne, France

    Pierre Chardin

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DATABASES

UniProtKB

FGFR1

p190 RhoGAP

PDZ-RhoGEF

plexin-B1

R-Ras

RhoA

Rock I

Rock II

Rnd1

Rnd2

Rnd3

FURTHER INFORMATION

Pierre Chardin's laboratory

Cancer Genome Anatomy Project

Rnd1 expression

Rnd2 expression

Rnd3 expression

Glossary

Guanine nucleotide-exchange factor

(GEF). A protein that facilitates the exchange of GDP (guanosine diphosphate) for GTP (guanosine triphosphate) in the nucleotide-binding pocket of a GTP-binding protein.

GTPase-activating protein

(GAP). A protein that stimulates the intrinsic ability of a GTPase to hydrolyse GTP to GDP. GAPs negatively regulate GTPases by converting them from active (GTP-bound) to inactive (GDP-bound). There are approximately 70 different RhoGAPs in the human genome; p190 RhoGAP is one of the most highly and ubiquitously expressed.

Guanine nucleotide-dissociation inhibitor

(GDI). A protein that interacts with a small GTP-binding protein and covers its lipid modification to form a cytosolic complex. It also inhibits the dissociation of GDP and therefore its replacement by GTP in a small GTP-binding protein, thereby maintaining it in an inactive cytosolic state.

Geranylgeranyl

A 20 carbon (C20) prenyl modification that is added to the C terminus of Rho-family proteins by geranylgeranyl transferase.

Ascidians

Chordates that are more closely related to vertebrates than flies or nematodes.

Farnesylated

The addition of a 15 carbon (C15) lipid modification to the C terminus of Rho-family proteins by farnesyl transferase.

Rock I and Rock II

Serine/threonine kinases that are Rho·GTP and control the phosphorylation of myosin light chain by phosphorylating and inhibiting myosin-light-chain phosphatase. Rocks are among the best-characterized Rho effectors.

Lamellipodia

Thin, flat extensions at the cell periphery that are filled with a branching meshwork of actin filaments.

Filopodia

Thin, transient actin protrusions that extend out from the cell surface and are formed by the elongation of bundled actin filaments in its core.

PDZ–RhoGEF

A small protein domain that specifically binds the C-terminal motifs of some proteins (frequently membrane-associated), allowing the formation of a multi-protein complex.

Growth-factor-receptor-bound-protein-2

(GRB2). An adaptor protein with one SH2 and two SH3 domains. The SH2 domain binds specific motifs with a phosphorylated tyrosine on several receptors or adaptors such as Shc, and the two SH3 domains bind proline-rich motifs of Sos (a Ras activator) and other signalling proteins.

SH2-containing protein tyrosine phosphatase-2

(SHP2). Its two SH2 domains interact with many receptors, adhesion molecules, adaptors and other tyrosine-phosphorylated proteins that it might subsequently dephosphorylate owing to its phosphatase activity.

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Chardin, P. Function and regulation of Rnd proteins. Nat Rev Mol Cell Biol 7, 54–62 (2006). https://doi.org/10.1038/nrm1788

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