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Hypoxia induces calpain activity and degrades SMAD2 to attenuate TGFβ signaling in macrophages.

Cui W, Zhou J, Dehne N, Brüne B - Cell Biosci (2015)

Bottom Line: Exposing human primary macrophages to TGFβ elicited a rapid SMAD2/SMAD3 phosphorylation.The dual specific proteasome/calpain inhibitor MG132 and the specific calpain inhibitor 1 rescued SMAD2 degradation, substantiating the ability of calpain to degrade SMAD2.Decreased SMAD2 expression reduced TGFβ transcriptional activity of its target genes thrombospondin 1, dystonin, and matrix metalloproteinase 2.

View Article: PubMed Central - PubMed

Affiliation: College of Life Sciences, Beijing Normal University, 100875 Beijing, China ; Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.

ABSTRACT

Background: Under inflammatory conditions or during tumor progression macrophages acquire distinct phenotypes, with factors of the microenvironment such as hypoxia and transforming growth factor β (TGFβ) shaping their functional plasticity. TGFβ is among the factors causing alternative macrophage activation, which contributes to tissue regeneration and thus, resolution of inflammation but may also provoke tumor progression. However, the signal crosstalk between TGFβ and hypoxia is ill defined.

Results: Exposing human primary macrophages to TGFβ elicited a rapid SMAD2/SMAD3 phosphorylation. This early TGFβ-signaling remained unaffected by hypoxia. However, with prolonged exposure periods to TGFβ/hypoxia the expression of SMAD2 declined because of decreased protein stability. In parallel, hypoxia increased mRNA and protein amount of the calpain regulatory subunit, with the further notion that TGFβ/hypoxia elicited calpain activation. The dual specific proteasome/calpain inhibitor MG132 and the specific calpain inhibitor 1 rescued SMAD2 degradation, substantiating the ability of calpain to degrade SMAD2. Decreased SMAD2 expression reduced TGFβ transcriptional activity of its target genes thrombospondin 1, dystonin, and matrix metalloproteinase 2.

Conclusions: Hypoxia interferes with TGFβ signaling in macrophages by calpain-mediated proteolysis of the central signaling component SMAD2.

No MeSH data available.


Related in: MedlinePlus

Graphical abstract. TGFβ binds to its receptor (TGFβR1 and TGFβR2), induces phosphorylation of TGFβR1 and downstream signaling molecules like SMAD2. Active SMAD2 translocates to the nucleus to provoke expression of target genes, i.e., TSP1, DST, and MMP2. Hypoxia in combination with TGFβ activates calpain to degrade SMAD2, which in turn attenuates SMAD2-dependent transcriptional activation and thus, diminishes the induction of TSP1, DST, and MMP2
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Fig6: Graphical abstract. TGFβ binds to its receptor (TGFβR1 and TGFβR2), induces phosphorylation of TGFβR1 and downstream signaling molecules like SMAD2. Active SMAD2 translocates to the nucleus to provoke expression of target genes, i.e., TSP1, DST, and MMP2. Hypoxia in combination with TGFβ activates calpain to degrade SMAD2, which in turn attenuates SMAD2-dependent transcriptional activation and thus, diminishes the induction of TSP1, DST, and MMP2

Mentions: Our results indicate that hypoxia attenuates SMAD2 activation in TGFβ-stimulated macrophages (Fig. 6). Mechanistically, this results from degradation of SMAD2 by calpain.Fig. 6


Hypoxia induces calpain activity and degrades SMAD2 to attenuate TGFβ signaling in macrophages.

Cui W, Zhou J, Dehne N, Brüne B - Cell Biosci (2015)

Graphical abstract. TGFβ binds to its receptor (TGFβR1 and TGFβR2), induces phosphorylation of TGFβR1 and downstream signaling molecules like SMAD2. Active SMAD2 translocates to the nucleus to provoke expression of target genes, i.e., TSP1, DST, and MMP2. Hypoxia in combination with TGFβ activates calpain to degrade SMAD2, which in turn attenuates SMAD2-dependent transcriptional activation and thus, diminishes the induction of TSP1, DST, and MMP2
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4491253&req=5

Fig6: Graphical abstract. TGFβ binds to its receptor (TGFβR1 and TGFβR2), induces phosphorylation of TGFβR1 and downstream signaling molecules like SMAD2. Active SMAD2 translocates to the nucleus to provoke expression of target genes, i.e., TSP1, DST, and MMP2. Hypoxia in combination with TGFβ activates calpain to degrade SMAD2, which in turn attenuates SMAD2-dependent transcriptional activation and thus, diminishes the induction of TSP1, DST, and MMP2
Mentions: Our results indicate that hypoxia attenuates SMAD2 activation in TGFβ-stimulated macrophages (Fig. 6). Mechanistically, this results from degradation of SMAD2 by calpain.Fig. 6

Bottom Line: Exposing human primary macrophages to TGFβ elicited a rapid SMAD2/SMAD3 phosphorylation.The dual specific proteasome/calpain inhibitor MG132 and the specific calpain inhibitor 1 rescued SMAD2 degradation, substantiating the ability of calpain to degrade SMAD2.Decreased SMAD2 expression reduced TGFβ transcriptional activity of its target genes thrombospondin 1, dystonin, and matrix metalloproteinase 2.

View Article: PubMed Central - PubMed

Affiliation: College of Life Sciences, Beijing Normal University, 100875 Beijing, China ; Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.

ABSTRACT

Background: Under inflammatory conditions or during tumor progression macrophages acquire distinct phenotypes, with factors of the microenvironment such as hypoxia and transforming growth factor β (TGFβ) shaping their functional plasticity. TGFβ is among the factors causing alternative macrophage activation, which contributes to tissue regeneration and thus, resolution of inflammation but may also provoke tumor progression. However, the signal crosstalk between TGFβ and hypoxia is ill defined.

Results: Exposing human primary macrophages to TGFβ elicited a rapid SMAD2/SMAD3 phosphorylation. This early TGFβ-signaling remained unaffected by hypoxia. However, with prolonged exposure periods to TGFβ/hypoxia the expression of SMAD2 declined because of decreased protein stability. In parallel, hypoxia increased mRNA and protein amount of the calpain regulatory subunit, with the further notion that TGFβ/hypoxia elicited calpain activation. The dual specific proteasome/calpain inhibitor MG132 and the specific calpain inhibitor 1 rescued SMAD2 degradation, substantiating the ability of calpain to degrade SMAD2. Decreased SMAD2 expression reduced TGFβ transcriptional activity of its target genes thrombospondin 1, dystonin, and matrix metalloproteinase 2.

Conclusions: Hypoxia interferes with TGFβ signaling in macrophages by calpain-mediated proteolysis of the central signaling component SMAD2.

No MeSH data available.


Related in: MedlinePlus