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Vol. 12, Issue 4, 1079-1091, April 2001
Induces Nuclear Import of Smad3 in
an Importin-1 and Ran-dependent Manner
*Ludwig Institute for Cancer Research, SE-751 24 Uppsala, Sweden;
and Smad proteins are cytoplasmic signaling effectors of transforming
growth factor-Department of Cell Biology and Neuroscience, Graduate
School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
(TGF-) family cytokines and regulate gene transcription in the nucleus. Receptor-activated Smads (R-Smads) become
phosphorylated by the TGF- type I receptor. Rapid and precise
transport of R-Smads to the nucleus is of crucial importance for signal
transduction. By focusing on the R-Smad Smad3 we demonstrate that 1)
only activated Smad3 efficiently enters the nucleus of permeabilized
cells in an energy- and cytosol-dependent manner. 2) Smad3, via its
N-terminal domain, interacts specifically with importin-1 and only
after activation by receptor. In contrast, the unique insert of exon3
in the N-terminal domain of Smad2 prevents its association with
importin-1. 3) Nuclear import of Smad3 in vivo requires the action
of the Ran GTPase, which mediates release of Smad3 from the complex
with importin-1. 4) Importin-1, Ran, and p10/NTF2 are sufficient
to mediate import of activated Smad3. The data describe a pathway
whereby Smad3 phosphorylation by the TGF- receptor leads to enhanced
interaction with importin-1 and Ran-dependent import and release
into the nucleus. The import mechanism of Smad3 shows distinct features
from that of the related Smad2 and the structural basis for this
difference maps to the divergent sequences of their N-terminal domains.
Corresponding author. E-mail
address: aris.moustakas{at}licr.uu.se.
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