Role of RTK/MAPK/ERK signaling in TGF-β and Activin mediated actions


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Srishti Gautam1
1Indian Institute of Science

Abstract

Background

Transforming growth factor-beta (TGF-β) and Activin belong to TGF-β super-family of secreted proteins that also includes Nodal, Bone Morphogenetic Proteins, Growth and Differentiation Factor and Mullerian Inhibiting Substance. These ligands play an important role in embryonic development, immune regulation, wound repair and are often dysregulated in cancer. Both TGF-β and Activin signal through transmembrane Serine/Threonine kinase receptors and signal transducers, SMAD2 and SMAD3, but what brings specificity to their actions remain unknown. Recent studies have reported, the differential regulation of SMAD2 and SMAD3 by TGF-β but, no information is available for Activin. This study aims to understand the potential differences in the signaling initiated by Activin and TGF-β.

Method

In addition to the SMAD-dependent signaling, both ligands activate and crosstalk with MAPK/ERK pathway. We used small-molecule inhibitors to study this interaction in Breast cancer and Lung cancer cellines.

Results

Active MAPK/ERK pathway was found indispensable for Activin-receptor mediated C-terminal phosphorylation of SMAD2, nuclear-translocation and SMAD2-dependent transcription of Activin-target genes. Furthermore, a MAPK/ERK regulated Serine/Threonine phosphatase was involved in regulation of Activin-mediated SMAD2 phosphorylation.  We established that Activin and TGF-β activate MAPK/ERK pathway through different mechanisms. Activin results in the ectodomain shedding of EGF-like ligands from the cell surface and EGFR transactivation, whereas TGF-β activates MAPK/ERK pathway through ligand-independent EGFR-activation. Besides MAPK/ERK pathway, both ligands also activate PI3K pathway. During Activin signaling but not TGF- β, molecules like PI3K, MEK and the Serine/Threonine phosphatase, function in an incoherent feed-forward loop and their respective activities govern SMAD2 action.

Conclusion

The crosstalk between Activin and RTK/MAPK/ERK signaling could serve as a fine-tuning mechanism to achieve context-dependency and hence regulate specific Activin-mediated responses. Determining how the SMAD2 and SMAD3 proteins are differentially regulated by Activin and TGF-β may help us to understand the differences between the two ligands and may also translate into developing better cancer therapies.