Activin A signaling regulation
Activins are members of the Transforming growth factor beta (TGF-beta) superfamily that participate in regulation of several biological processes, including cell differentiation and cell proliferation, apoptosis and immune response [1], [2], [3].
There are different types of Activins [4], but the role of Activin A has been the most extensively studied by far.
Like most members of the Transforming growth factor beta superfamily, Activin A mediates its biological effects through complex of transmembrane receptor serine/threonine kinases. Activin A initially binds to ActRIIA or ActRIIB and then ALK-4 [2], [5].
ALK-4 interacts with and phosphorylates adaptors of SMAD2 and SMAD3. Subsequently, SMAD4 bounds to phosphorylated SMAD2 and SMAD3 and this complex is translocated to the nucleus [2]. After translocation into the nucleus, SMAD2 and SMAD3 may activate transcription of different genes.
Regulation of Activin A signal occurs at the extracellular, membrane, cytoplasmic and nuclear levels [2], [6].
Activin A signaling may be inhibited by extracellular proteins Follistatin and FSRP. Follistatin and FSRP bind to Activin A with high affinity, and their binding is nearly irreversible. Activin A in the complex with Follistatin is impeded the binding to ActRIIA or ActRIIB [7], [8].
Inhibin is another extracellular Activin A inhibitor. The association of ActRIIA or ActRIIB with Inhibin and TGF-beta receptor type III (betaglycan) prevents access of Activin A to the receptor and therefore leads to a competitive inhibition of Activin A signaling [4], [8], [9].
Moreover, some membrane proteins inhibit Activin A signal via repression of ALK-4. IGSF1 [10] and BAMBI [11] form a complex with the ALK-4, which then attenuates Activin A-stimulated reporter gene activity [10].
In addition, FKBP12 may recruit the SMAD7/ SMURF1 complex to ALK-4 and enhance ubiquitination of the receptor [12]. It has been shown that SMAD7 stably interacts with ALK-4 directly and inhibits it [13]. SMAD7 expression is upregulated by activin, representing auto-inhibitory feedback mechanism of ligand-induced signaling [6].
Several transcriptional co-repressors, such as DLX1 [14], Evi-1 [15] and MAN1 [16], [17] interact with SMADs and inhibit them directly. Activin A signal may be stimulated by different activators, such as, FAST-1/2 [18] and PC2 (TIG1) [19]. FAST-1/2 -dependent transcription may be inhibited by FKHL1 [20].
Another pathway regulated by Activin A signaling is acetylation/ deacetylation of SMADs and different Histones at Activin A-dependent promoters. For example, Ski may inhibit SMAD3/ SMAD4 - dependent transcription by recruiting HDAC1 [2], [21]. p300/ CBP may activate Activin A signaling by acetylation of SMADs and Histones [6], [22].
Objects list:
ALK-4 | Activin receptor type-1B |
ActRIIA | Activin receptor type-2A |
ActRIIB | Activin receptor type-2B |
Activin A | Activin A Complex |
BAMBI | BMP and activin membrane-bound inhibitor homolog |
CBP | CREB-binding protein |
DLX1 | Homeobox protein DLX-1 |
Evi-1 | MDS1 and EVI1 complex locus protein EVI1 |
FAST-1/2 | Forkhead box protein H1 |
FKBP12 | Peptidyl-prolyl cis-trans isomerase FKBP1A |
FKHL1 | Forkhead box protein G1 |
FSRP | Follistatin-related protein 3 |
Follistatin | Follistatin |
HDAC1 | Histone deacetylase 1 |
IGSF1 | Immunoglobulin superfamily member 1 |
Inhibin | Inhibins Group of complexes |
MAN1 | Inner nuclear membrane protein Man1 |
PC2 (TIG1) | Mediator of RNA polymerase II transcription subunit 15 |
SMAD2 | Mothers against decapentaplegic homolog 2 |
SMAD3 | Mothers against decapentaplegic homolog 3 |
SMAD4 | Mothers against decapentaplegic homolog 4 |
SMAD7 | Mothers against decapentaplegic homolog 7 |
SMURF1 | E3 ubiquitin-protein ligase SMURF1 |
Ski | Ski oncogene |
TGF-beta receptor type III (betaglycan) | Transforming growth factor beta receptor type 3 |
p300 | Histone acetyltransferase p300 |
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