In or out? The dynamics of Smad nucleocytoplasmic shuttling

Reguly, Teresa; Wrana, Jeffrey L.

doi:10.1016/s0962-8924(03)00075-8

Cited by 71 publications

(54 citation statements)

References 28 publications

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“…This model was originally demonstrated to mediate Smad2 import (40) but recently has also been extended to Smad3 and Smad4 (42). This raises the possibility that Smads utilize multiple mechanisms of nuclear import that rely on structural signals in both of their MH1 and MH2 domains, possibly as a means to control more accurately the need for continuous shuttling of these proteins between the cytoplasm and the nucleus (21,27). It is currently unknown whether the two current models of Smad nuclear import apply to distinct sets of Smad complexes, such as monomeric Smads, homooligomeric Smads, or heterooligomeric Smads, for example.…”

Section: Discussionmentioning

confidence: 99%

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The Mechanism of Nuclear Export of Smad3 Involves Exportin 4 and Ran

Kurisaki

Kowanetz

et al. 2006

Molecular and Cellular Biology

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Transforming growth factor beta (TGF-␤) receptors phosphorylate Smad3 and induce its nuclear import so it can regulate gene transcription. Smad3 can return to the cytoplasm to propagate further cycles of signal transduction or to be degraded. We demonstrate that Smad3 is exported by a constitutive mechanism that is insensitive to leptomycin B. The Mad homology 2 (MH2) domain is responsible for Smad3 export, which requires the GTPase Ran. Inactive, GDP-locked RanT24N or nuclear microinjection of Ran GTPase activating protein 1 blocked Smad3 export. Inactivation of the Ran guanine nucleotide exchange factor RCC1 inhibited Smad3 export and led to nuclear accumulation of phosphorylated Smad3. A screen for importin/exportin family members that associate with Smad3 identified exportin 4, which binds a conserved peptide sequence in the MH2 domain of Smad3 in a Ran-dependent manner. Exportin 4 is sufficient for carrying the in vitro nuclear export of Smad3 in cooperation with Ran. Knockdown of endogenous exportin 4 completely abrogates the export of endogenous Smad3. A short peptide representing the minimal interaction domain in Smad3 effectively competes with Smad3 association to exportin 4 and blocks nuclear export of Smad3 in vivo. We thus delineate a novel nuclear export pathway for Smad3.

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Section: Discussionmentioning

confidence: 99%

“…However, the nuclear export of the TGF-␤ R-Smads has remained poorly characterized (27,43). For these reasons, we have carefully examined the nuclear export of one TGF-␤ R-Smad, Smad3, whose nuclear import mechanism we previously elucidated (14).…”

Section: Discussionmentioning

confidence: 99%

The Mechanism of Nuclear Export of Smad3 Involves Exportin 4 and Ran

Kurisaki

Kowanetz

et al. 2006

Molecular and Cellular Biology

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“…In the same assays, TGF-b-dependent phosphorylation of Smad3 seemed to enhance both its interaction with importin b1 and its nuclear import [36]. The conserved NLS-like motif is non-functional in Smad2, perhaps because of an insertion encoded by exon 3 of Smad2, which is close to the NLS-like motif and might impair its accessibility for importin b1 binding [37] ( Figure 1). The proposed mechanism deviates from the classical import mechanism by avoiding the need for one of the several importin a proteins as a bridging factor between importin b1 and the cargo.…”

Section: Smad Import Into the Nucleusmentioning

confidence: 91%

“…As Smad4 is dispensable for nuclear accumulation of R-Smads and its own nuclear accumulation is strictly dependent on R-Smad accumulation [8,27,37], the mechanism of R-Smad nuclear accumulation is of most interest. An anchor-release model was originally suggested for Smad2 based on the finding that overexpression of SARA sequesters Smad2 into clusters in the cytoplasm [45,46], and that overexpression of the Smad2-interacting nuclear protein FAST-1/FoxH1 traps Smad2 in the nucleus even in uninduced cells [19].…”

Section: Mechanisms Underlying Tgf-β-induced Nuclear Accumulation Of mentioning

confidence: 99%

Nucleocytoplasmic shuttling of Smad proteins

2008

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Nuclear accumulation of active Smad complexes is crucial for transduction of transforming growth factor β (TGF-β)-superfamily signals from transmembrane receptors into the nucleus. It is now clear that the nucleocytoplasmic distributions of Smads, in both the absence and the presence of a TGF-β-superfamily signal, are not static, but instead the Smads are continuously shuttling between the nucleus and the cytoplasm in both conditions. This article presents the evidence for continuous nucleocytoplasmic shuttling of Smads. It then reviews different mechanisms that have been proposed to mediate Smad nuclear import and export, and discusses how the Smad steady-state distributions in the absence and the presence of a TGF-β-superfamily signal are established. Finally, the biological relevance of continuous nucleocytoplasmic shuttling for signaling by TGF-β superfamily members is discussed.

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“…Upon stimulation of cells with TGF-␤, Smad4 is known to rapidly translocate to the nucleus in complex with R-Smads. On the other hand, I-Smads are also shuttling, but at steady state, they reside primarily in the nucleus, and upon ligand stimulation they translocate to the cytoplasm together with Smurfs to bind to signaling receptors (3,51). It is therefore possible that the observed Smad4⅐I-Smad⅐Smurf complexes could form in the nucleus, the cytoplasm, or both.…”

Section: Smad4 Proteasomal Degradationmentioning

confidence: 99%