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Hypoxia-activated Smad3-specific dephosphorylation by PP2A.

Pekka T Heikkinen¹, Marika Nummela², Suvi-Katri Leivonen³

¹From the Turku Centre for Biotechnology, Turku University and Åbo Akademi University, FI-20520 Turku, Finland; Turku University School of Biological Sciences, Turku University, FI-20520 Turku, Finland.

The Journal of Biological Chemistry

|December 3, 2009

Summary

Hypoxia inhibits transforming growth factor-beta (TGF-beta)-induced Smad3 phosphorylation via protein phosphatase 2A (PP2A), a novel mechanism impacting tumor progression. This selective regulation of Smad3, not Smad2, highlights hypoxia

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Area of Science:

Cellular Biology
Molecular Biology
Cancer Research

Background:

Transforming growth factor-beta (TGF-beta) plays a dual role in cancer, initially suppressing tumors but promoting malignancy later.
TGF-beta signaling involves Smad2 and Smad3 phosphorylation, crucial for cellular responses, but their differential regulation remains unclear.

Purpose of the Study:

To investigate the differential regulation of Smad2 and Smad3 phosphorylation under hypoxic conditions.
To identify the molecular mechanisms underlying hypoxia's effect on TGF-beta signaling.

Main Methods:

Investigated TGF-beta-induced Smad2/3 phosphorylation in hypoxic cells.
Utilized protein phosphatase 2A (PP2A) inhibition and knockdown experiments.
Assessed Smad3 nuclear translocation and gene expression changes.

Main Results:

Hypoxia selectively inhibited TGF-beta-induced Smad3 phosphorylation, while Smad2 phosphorylation remained unaffected.
Protein phosphatase 2A (PP2A) was identified as the specific phosphatase responsible for Smad3 dephosphorylation under hypoxia.
Hypoxia-induced Smad3 dephosphorylation by PP2A reduced Smad3 nuclear accumulation and attenuated TGF-beta target gene expression.

Conclusions:

A novel mechanism exists where hypoxia regulates TGF-beta responses through Smad3-specific dephosphorylation by PP2A.
This finding identifies a new role for PP2A in modulating growth factor signaling in the context of hypoxia and cancer progression.