HECT-like E3 ubiquitin ligase Smurf2
Mol
Cell. 2000 Dec;6(6):1365-75.
Smad7 binds to
Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta
receptor for degradation.
Abstract
Ubiquitin-mediated
proteolysis regulates the activity of diverse receptor systems. Here,
we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show
that Smurf2 associates constitutively with Smad7. Smurf2 is nuclear,
but binding to Smad7 induces export and recruitment to the activated
TGF beta receptor, where it causes degradation of receptors and Smad7
via proteasomal and lysosomal pathways. IFN gamma, which stimulates
expression of Smad7, induces Smad7-Smurf2 complex formation and
increases TGF beta receptor turnover, which is stabilized by blocking
Smad7 or Smurf2 expression. Furthermore, Smad7 mutants that interfere
with recruitment of Smurf2 to the receptors are compromised in their
inhibitory activity. These studies thus define Smad7 as an adaptor in
an E3 ubiquitin-ligase complex that targets the TGF beta receptor for
degradation.
PMID: 11163210
[Indexed for MEDLINE]
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Cancer
Sci. 2008 Nov;99(11):2107-12. doi:
10.1111/j.1349-7006.2008.00925.x. Epub 2008 Sep 18.
Regulation of
TGF-beta family signaling by E3 ubiquitin ligases.
Abstract
Members of the
transforming growth factor-beta (TGF-beta) family, including
TGF-beta, activin and bone morphogenetic proteins (BMPs), are
multifunctional proteins that regulate a wide variety of cellular
responses, such as proliferation, differentiation, migration and
apoptosis. Alterations in their downstream signaling pathways are
associated with a range of human diseases like cancer. TGF-beta
family members transduce signals through membrane serine/threonine
kinase receptors and intracellular Smad proteins. The
ubiquitin-proteasome pathway, an evolutionarily conserved cascade,
tightly regulates TGF-beta family signaling. In this pathway, E3
ubiquitin ligases play a crucial role in the recognition and
degradation of target proteins by the 26S proteasomes. Smad
degradation regulates TGF-beta family signaling; HECT (homologous to
the E6-accessory protein C-terminus)-type E3 ubiquitin ligases, Smad
ubiquitin regulatory factor 1 (Smurf1), Smurf2, and a RING-type E3
ubiquitin ligase, ROC1-SCF(Fbw1a) have been implicated in Smad
degradation. Smurf1 and Smurf2 bind to TGF-beta family receptors via
the inhibitory Smads, Smad6 and Smad7, to induce their
ubiquitin-dependent degradation. Arkadia, a RING-type E3 ubiquitin
ligase, induces the ubiquitination and degradation of Smad7 and
corepressors, c-Ski and SnoN, to enhance TGF-beta family signaling.
Abnormalities in E3 ubiquitin ligases that control components of
TGF-beta family signaling may lead to the development and progression
of various cancers.
PMID:
18808420
DOI:
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