XB-ART-7844
EMBO J
January 15, 2002;
21
(1-2):
145-56.
Different Smad2 partners bind a common hydrophobic pocket in Smad2 via a defined proline-rich motif.
Randall RA
,
Germain S
,
Inman GJ
,
Bates PA
,
Hill CS
.
Abstract
Transforming growth factor-beta (TGF-beta)/activin-induced
Smad2/Smad4 complexes are recruited to different promoter elements by transcription factors, such as Fast-1 or the Mix family proteins
Mixer and
Milk, through a direct interaction between
Smad2 and a common Smad interaction motif (SIM) in the transcription factors. Here we identify residues in the SIM critical for
Mixer-
Smad2 interaction and confirm their functional importance by demonstrating that only Xenopus and zebrafish Mix family members containing a SIM with all the correct critical residues can bind
Smad2 and mediate TGF-beta-induced transcriptional activation in vivo. We identify significant sequence similarity between the SIM and the Smad-binding domain (SBD) of the membrane-associated protein
SARA (Smad anchor for receptor activation). Molecular modelling, supported by mutational analyses of
Smad2 and the SIM and the demonstration that the
SARA SBD competes directly with the SIM for binding to
Smad2, indicates that the SIM binds
Smad2 in the same hydrophobic pocket as does the proline-rich rigid coil region of the
SARA SBD. Thus, different
Smad2 partners, whether cytoplasmic or nuclear, interact with the same binding pocket in
Smad2 through a common proline-rich motif.
PubMed ID:
11782434
PMC ID:
PMC125817
Article link:
EMBO J
Species referenced:
Xenopus laevis
Genes referenced:
bix2
mixer
smad2
smad4
smad4.2
zfyve9
References [+] :
Alexander,
casanova plays an early and essential role in endoderm formation in zebrafish.
1999,
Pubmed,
Xenbase
Alexander,
casanova plays an early and essential role in endoderm formation in zebrafish.
1999,
Pubmed
,
Xenbase
Bardwell,
The POZ domain: a conserved protein-protein interaction motif.
1994,
Pubmed
Bates,
Model building by comparison at CASP3: using expert knowledge and computer automation.
1999,
Pubmed
Chacko,
The L3 loop and C-terminal phosphorylation jointly define Smad protein trimerization.
2001,
Pubmed
Chen,
A transcriptional partner for MAD proteins in TGF-beta signalling.
1996,
Pubmed
,
Xenbase
Chen,
Smad4 and FAST-1 in the assembly of activin-responsive factor.
1997,
Pubmed
,
Xenbase
Chen,
Determinants of specificity in TGF-beta signal transduction.
1998,
Pubmed
,
Xenbase
Ecochard,
A novel Xenopus mix-like gene milk involved in the control of the endomesodermal fates.
1998,
Pubmed
,
Xenbase
Germain,
Homeodomain and winged-helix transcription factors recruit activated Smads to distinct promoter elements via a common Smad interaction motif.
2000,
Pubmed
,
Xenbase
Henry,
Mixer, a homeobox gene required for endoderm development.
1998,
Pubmed
,
Xenbase
Hill,
TGF-beta signalling pathways in early Xenopus development.
2001,
Pubmed
,
Xenbase
Hill,
The Rho family GTPases RhoA, Rac1, and CDC42Hs regulate transcriptional activation by SRF.
1995,
Pubmed
Howell,
XSmad2 directly activates the activin-inducible, dorsal mesoderm gene XFKH1 in Xenopus embryos.
1998,
Pubmed
,
Xenbase
Howell,
Xenopus Smad4beta is the co-Smad component of developmentally regulated transcription factor complexes responsible for induction of early mesodermal genes.
1999,
Pubmed
,
Xenbase
Kikuchi,
The zebrafish bonnie and clyde gene encodes a Mix family homeodomain protein that regulates the generation of endodermal precursors.
2000,
Pubmed
,
Xenbase
Massagué,
Transcriptional control by the TGF-beta/Smad signaling system.
2000,
Pubmed
Masuyama,
Identification of two Smad4 proteins in Xenopus. Their common and distinct properties.
1999,
Pubmed
,
Xenbase
Nicholls,
Protein folding and association: insights from the interfacial and thermodynamic properties of hydrocarbons.
1992,
Pubmed
Pierreux,
Transforming growth factor beta-independent shuttling of Smad4 between the cytoplasm and nucleus.
2000,
Pubmed
,
Xenbase
Rosa,
Mix.1, a homeobox mRNA inducible by mesoderm inducers, is expressed mostly in the presumptive endodermal cells of Xenopus embryos.
1989,
Pubmed
,
Xenbase
Sadowski,
A vector for expressing GAL4(1-147) fusions in mammalian cells.
1989,
Pubmed
Schier,
Nodal signalling in vertebrate development.
2000,
Pubmed
Shi,
Structural insights on Smad function in TGFbeta signaling.
2001,
Pubmed
Shi,
A structural basis for mutational inactivation of the tumour suppressor Smad4.
1997,
Pubmed
Tada,
Bix1, a direct target of Xenopus T-box genes, causes formation of ventral mesoderm and endoderm.
1998,
Pubmed
,
Xenbase
Tsukazaki,
SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor.
1999,
Pubmed
,
Xenbase
Västrik,
Sema3A-induced growth-cone collapse is mediated by Rac1 amino acids 17-32.
2000,
Pubmed
Wilson,
Cooperative dimerization of paired class homeo domains on DNA.
1993,
Pubmed
Wu,
Structural basis of Smad2 recognition by the Smad anchor for receptor activation.
2000,
Pubmed
Xanthos,
Maternal VegT is the initiator of a molecular network specifying endoderm in Xenopus laevis.
2001,
Pubmed
,
Xenbase
Xu,
The nuclear import function of Smad2 is masked by SARA and unmasked by TGFbeta-dependent phosphorylation.
2000,
Pubmed
ten Dijke,
Signaling inputs converge on nuclear effectors in TGF-beta signaling.
2000,
Pubmed