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Nucleocytoplasmic shuttling of signal transducers

Nature Reviews Molecular Cell Biology volume 5, pages 209–219 (2004)Cite this article

Key Points

  • Many signal transducers are transcription factors that undergo nuclear translocation in response to extracellular stimuli. This is a key step of many signal-transduction pathways and imparts inducibility to transcriptional regulation in response to extracellular signals.

  • Some signal transducers, such as the nuclear factor of activated T cells (NF-AT), contain the classic nuclear localization signal (NLS) motif, which allows its recognition and binding by the importin-α–importin-β transport receptor complex. The importins transport their cargoes across the nuclear envelope by interacting with nucleoporins, which are constituents of the nuclear pore complex (NPC).

  • Signal transducers such as β-catenin, SMAD2, SMAD3 and SMAD4 and extracellular signal-regulated kinase (ERK)1 and ERK2 use an importin-independent mechanism for nuclear import. This is due to their ability to interact directly with the NPC without the need for importins as bridging factors.

  • The direct interaction with the NPC might also facilitate nuclear export of β-catenin and SMAD2. Such intrinsic nuclear import and export activity of β-catenin and SMAD2 results in continuous nucleocytoplasmic shuttling of these signal transducers in the basal state.

  • Cytoplasmic and nuclear retention factors can restrict the shuttling of many signal transducers by immobilizing them to intracellular structures, or by blocking their interaction with the nucleoporins or transport receptors.

  • The affinity between signal transducers and their retention factors is subject to regulation by signals. In this way, the extracellular stimuli not only activate the signal transducers by post-translational modification, but also promote their accumulation in the appropriate cellular compartment to propagate the signal.

Abstract

The nuclear translocation of signal-transduction proteins is an essential step in the control of gene expression by numerous extracellular signals. Recent studies have shown that some signal transducers are imported into the nucleus by nuclear-localization-signal- and importin-independent processes. Such a mechanism could allow bidirectional movement across the nuclear envelope. Extracellular signals modify the affinity between signal transducers and anchoring factors, thereby regulating the nucleocytoplasmic shuttling of signalling molecules.

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Figure 1: Nuclear translocation of β-catenin, SMAD2, SMAD3, ERK1 and ERK2.
Figure 2: Classic NLS- and NES-mediated nuclear transport across the NPC.
Figure 3: The control of subcellular localization of β-catenin by WNT signalling.
Figure 4: TGFβ-controlled subcellular localization of SMAD2, SMAD3 and SMAD4.
Figure 5: Control of subcellular localization of p53 by DNA-damage signals.

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Authors and Affiliations

  1. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, 01605, Massachusetts, USA

    Lan Xu

  2. Cancer Biology and Genetics Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, 10021, New York, USA

    Joan Massagué

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  1. Lan Xu
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DATABASES

LocusLink

axin

importin-α

importin-β

NF-AT

Swiss-Prot

APC

ATF3

β-catenin

CRM1

ERK1

ERK2

FoxH1

GSK3β

Hdac1

Mdm2

MEK1

Nup1

NUP153

NUP214

p53

PARC

SARA

Sir2a

SMAD2

SMAD3

SMAD4

Glossary

SMADS

A family of homologous proteins that mediate transforming growth factor β (TGFβ) signal transduction. Some of the SMADs are transcription factors that are activated and translocate into the nucleus in response to TGFβ.

NUCLEAR LOCALIZATION SIGNAL

(NLS). A protein motif that consists of a cluster of basic residues that is recognized and bound by importin-α and targets heterologous proteins for import into the nucleus.

IMPORTINS

A family of proteins that transport macromolecules into the nucleus.

PHENYLALANINE-GLYCINE (FG) REPEAT

A region that is found in many nucleoporins that contains several copies of the dipeptide sequence phenylalanine-glycine.

NUCLEOPORIN

A protein subunit of the nuclear pore complex.

CATENIN

A structurally unrelated component of cell adhesion junctions that link cadherin cell-adhesion receptors to the cytoskeleton. There are two forms of catenin, α and β.

MH1 DOMAIN

(Mad homology domain 1). The conserved amino-terminal part of SMAD proteins, which is named after the prototypic SMAD protein from Drosophila, Mad.

CRM1

(chromosome region maintenance 1). A nuclear export receptor for proteins that have the nuclear export signal.

NUCLEAR EXPORT SIGNAL

(NES). A short leucine/isoleucine-rich sequence motif that can direct the nuclear export of heterologous proteins. It is recognized and bound by the nuclear export factor CRM1.

ADENOMATOUS POLYPOSIS COLI

(APC). A tumour suppressor protein that is frequently mutated in familial adenomatous polyposis (FAP) and sporadic colorectal cancers. It is part of the cytoplasmic protein complex that sequesters and phosphorylates β-catenin in the absence of WNT signalling.

ADHERENCE JUNCTION COMPLEX

A protein complex that mediates cell–cell adhesion. This complex contains cadherins that span the cell membrane and interact with cadherins on adjacent cells and catenins in the cytoplasm.

SCF-TYPE UBIQUITIN LIGASE

One of the principal classes of ubiquitin ligases. It is a complex that consists of Skp1, Cullin and F-box proteins.

CADHERIN

A cell-surface glycoprotein that mediates Ca2+-dependent cell adhesion. Classical cadherins and cadherin-related proteins form an ∼80-member superfamily in humans.

EARLY ENDOSOME

An intracellular vesicular structure that is a precursor of the mature endosome and that has an important role in endocytosis.

RING DOMAIN

A unique zinc-finger-type protein motif that is characteristic of a class of E3 ubiquitin ligase.

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Xu, L., Massagué, J. Nucleocytoplasmic shuttling of signal transducers. Nat Rev Mol Cell Biol 5, 209–219 (2004). https://doi.org/10.1038/nrm1331

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