PubMed Journals: J Biol Chem
Source: PMID: 10085140
⇦ ⇨ J Biol Chem. 1999 Mar 26;274(13):8949-57.
ATF-2 is a common nuclear target of Smad
and TAK1 pathways in transforming growth
Sano Y(1), Harada J, Tashiro S, Gotoh-Mandeville
R, Maekawa T, Ishii S.
(1) Laboratory of Molecular Genetics, Tsukuba
Life Science Center, RIKEN, 3-1-1 Koyadai,
Tsukuba, Ibaraki 305-0074, Japan.
Upon transforming growth factor-beta (TGF-beta)
binding to its cognate receptor, Smad3 and
Smad4 form heterodimers and transduce the
TGF-beta signal to the nucleus. In addition
to the Smad pathway, another pathway involving
a member of the mitogen-activated protein
kinase kinase kinase family of kinases,
TGF-beta-activated kinase-1 (TAK1), is required
for TGF-beta signaling. However, it is unknown
how these pathways function together to
synergistically amplify TGF-beta signaling.
Here we report that the transcription factor
ATF-2 (also called CRE-BP1) is bound by
a hetero-oligomer of Smad3 and Smad4 upon
TGF-beta stimulation. ATF-2 is one member
of the ATF/CREB family that binds to the
cAMP response element, and its activity
is enhanced after phosphorylation by
stress-activated protein kinases such as
c-Jun N-terminal kinase and p38. The binding
between ATF-2 and Smad3/4 is mediated via
the MH1 region of the Smad proteins and
the basic leucine zipper region of ATF-2.
TGF-beta signaling also induces the phosphorylation
of ATF-2 via TAK1 and p38. Both of these
actions are shown to be responsible for
the synergistic stimulation of ATF-2
trans-activating capacity. These results
indicate that ATF-2 plays a central role
in TGF-beta signaling by acting as a common
nuclear target of both Smad and TAK1 pathways.
PMID: 10085140 [Indexed for MEDLINE]