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The GTPase RAN regulates multiple steps of the centrosome life cycle

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Abstract

Growing lines of evidence implicate the small GTPase RAN, its regulators and effectors—predominantly, nuclear transport receptors—in practically all aspects of centrosome biology in mammalian cells. These include duplication licensing, cohesion, positioning, and microtubule-nucleation capacity. RAN cooperates with the protein nuclear export vector exportin 1/CRM1 to recruit scaffolding proteins containing nuclear export sequences that play roles in the structural organization of centrosomes. Together, they also limit centrosome reduplication by regulating the localization of key “licensing” proteins during the centrosome duplication cycle. In parallel, RAN also regulates the capacity of centrosomes to nucleate and organize functional microtubules, and this predominanlty involves importin vectors: many factors regulating microtubule nucleation or function harbor nuclear localization sequences that interact with importin molecules and such interaction inhibits their activity. Active RANGTP binding to importin molecules removes the inhibition and releases microtubule regulatory factors in the free productive form. A dynamic scenario emerges, in which RAN is pivotal in linking spatiotemporal control of centrosome regulators to the cell cycle machinery.

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Abbreviations

AKAP450:

A-kinase anchoring protein 450

BIC2:

bicaudal 2

CRM1:

chromosome region maintenance 1

gamma TuRC:

gamma tubulin ring complex

GDP:

guanosine diphosphate

GTP:

guanosine triphosphate

IF:

immunofluorescence

KT:

kinetochore

MT:

microtubule

MTOC:

microtubule-organizing center

NE:

nuclear envelope

NES:

nuclear export signal

NLS:

nuclear localization signal

NoLS:

nucleolar localization signal

NPC:

nuclear pore complex

NPM:

nucleophosmin

NUP:

nucleoporin

PAK4:

p21 protein (Cdc42/Rho)-activated kinase 4

PCM:

pericentriolar material

RANBP1:

RAN-binding protein 1

RANBP2:

RAN-binding protein 2

RANGAP1:

RAN GTPase activating protein 1

RCC1:

regulator of chromosome condensation 1

SAF:

spindle assembly factor

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Acknowledgments

I am grateful to members of my group for many stimulating discussions on issues addressed in this review and for critical reading of this work. Work in my laboratory is supported by grants from the Italian Association for Cancer Research (AIRC IG14534), Consiglio Nazionale delle Ricerche (CNR Interomics Flagship Project, grant IBISA), and MIUR-PRIN 2010–11 (2010W7YRLZ_001006).

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  1. Institute of Molecular Biology and Pathology, CNR National Research Council of Italy, c/o Sapienza University of Rome, via degli Apuli 4, Rome, 00185, Italy

    Patrizia Lavia

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Lavia, P. The GTPase RAN regulates multiple steps of the centrosome life cycle. Chromosome Res 24, 53–65 (2016). https://doi.org/10.1007/s10577-015-9514-4

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