Olsen, Oddrun Elise, Hella, Hanna, Elsaadi, Samah, Jacobi, Carsten and Holien, Toril (2020) Activins as dual specificity TGF-β family molecules: SMAD-activation via activin- and BMP-type I receptors. Biomolecules, 10 (4). p. 519. ISSN 2218-273X

Abstract

Activins belong to the transforming growth factor (TGF)-β family of multifunctional cytokines and signal via the activin receptors ALK4 or ALK7 to activate the SMAD2/3 pathway. In some cases, activins also signal via the bone morphogenetic protein (BMP) receptor ALK2 causing activation of the SMAD1/5/8 pathway. We here aimed to describe more carefully activation of the two main SMAD branches by activin A and activin B homodimers, and activin AB and activin AC heterodimers. We compared the activin-induced signaling kinetics of ALK4/7-SMAD2/3 and ALK2-SMAD1/5 in a multiple myeloma cell line. Signaling via ALK2 to SMAD1/5 varied more between ligands than signaling via ALK4/ALK7 to SMAD2/3. Interestingly, activin B and activin AB very potently activated SMAD1/5, resembling the activation commonly seen with BMPs. SMAD1/5 was also activated by activins in other cell types, indicating a general mechanism. The antagonist follistatin inhibited signaling by all the tested activins, whereas cerberus specifically antagonized activin B. Interestingly, ALK2-mediated activation of SMAD1/5 was blunted by mutations in the follistatin-binding region of activin A, whereas ALK4-mediated SMAD2/3 activation remained unchanged. Taken together, we propose that activins may be considered dual-specificity TGF-β family members and that this may affect the way activins are targeted clinically.

Item Type:	Article
Keywords:	Activin; SMAD; BMP; ALK2; ACVR1; Signal Transduction
Date Deposited:	11 Apr 2020 00:45
Last Modified:	11 Apr 2020 00:45
URI:	https://oak.novartis.com/id/eprint/42099