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Vol. 9, Issue 12, 3309-3319, December 1998
-induced Phosphorylation of Smad3 Regulates Its
Interaction with Coactivator p300/CREB-binding Protein
Department of Pharmacology and Cancer Biology, Duke University
Medical Center, Durham, North Carolina 27710
Smads are intermediate effector proteins that transduce
the TGF-
signal from the plasma membrane to the nucleus, where they participate in transactivation of downstream target genes. We have
shown previously that coactivators p300/CREB-binding protein are
involved in TGF--mediated transactivation of two Cdk inhibitor genes, p21 and p15. Here we examined the possibility that Smads function to regulate transcription by directly interacting with p300/CREB-binding protein. We show that Smad3 can interact with a
C-terminal fragment of p300 in a temporal and phosphorylation-dependent manner. TGF--mediated phosphorylation of Smad3 potentiates the association between Smad3 and p300, likely because of an induced conformational change that removes the autoinhibitory interaction between the N- and C-terminal domains of Smad3. Consistent with a role
for p300 in the transcription regulation of multiple genes, overexpression of a Smad3 C-terminal fragment causes a general squelching effect on multiple TGF--responsive reporter constructs. The adenoviral oncoprotein E1A can partially block Smad-dependent transcriptional activation by directly competing for binding to p300.
Taken together, these findings define a new role for phosphorylation of
Smad3: in addition to facilitating complex formation with Smad4 and
promoting nuclear translocation, the phosphorylation-induced conformational change of Smad3 modulates its interaction with coactivators, leading to transcriptional regulation.
Corresponding author. E-mail address:
wang{at}galactose.mc.duke.edu.
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