Histone H2, Histone H4, SMAD3, ActRIIA, SMAD4, IGSF1, N-CoR, FKBP12, Histone H3, ALK-4, CBP, p300, SMURF1, PC2 (TIG1), FKHL1, MAN1, Follistatin, Inhibin alpha subunit, BAMBI, Ski, Activin A, SMAD7, Evi-1, Sin3A, Ubiquitin, SMAD2, Inhibin, TGF-beta receptor type III (betaglycan), FSRP, HDAC1, DLX1, FAST-1/2, ActRIIB
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 proliferation, apoptosis and immune response , , .
There are different types of Activins , 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 Activin A receptors type II ( ActRIIA or ActRIIB ) and then recruitsActivin A receptor, type IB ( ALK-4 ) , .
ALK-4 interacts with and phosphorylates adaptors of SMAD family member 2 and 3 ( SMAD2 and SMAD3 ). Subsequently, SMAD family member 4 ( SMAD4 ) bounds to phosphorylated SMAD2 and SMAD3 and this complex is translocated to the nucleus . After translocation into the nucleus, SMAD2 and SMAD3 may activate transcription of different genes.
Activin A signaling may be inhibited by extracellular proteins Follistatin and Follistatin-like 3 ( FSRP ). Follistatin and FSRP bind to Activin A with high affinity, and their binding is nearly irreversible. Activin A in the complex with Follistatin s is impeded the binding to ActRIIA or ActRIIB , .
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 , , .
Moreover, some membrane proteins inhibit Activin A signal via repression of ALK-4. Immunoglobulin superfamily, member 1 ( IGSF1 )  and BMP and activin membrane-bound inhibitor homolog ( BAMBI )  form a complex with the ALK4, which then attenuates Activin A -stimulated reporter gene activity .
In addition, FK506 binding protein 1A 12kDa ( FKBP12 ) may recruit the SMAD7/ SMAD specific E3 ubiquitin protein ligase 1 ( SMURF1 ) complex to ALK-4 and enhance ubiquitination of the receptor . It has been shown that SMAD7 stably interacts with ALK-4 directly and inhibits it . SMAD7 expression is upregulated by activin, representing auto-inhibitory feedback mechanism of ligand-induced signaling .
Several transcriptional co-repressors, such as Distal-less homeobox 1 ( DLX1 ) , Ecotropic viral integration site 1 ( Evi-1 )  and LEM domain containing 3 ( MAN1 ) ,  interact with SMAD s and inhibit them directly.
Activin A signal may be stimulated by different activators, such as, Forkhead box H1 ( FAST-1/2 )  and Positive cofactor 2 ( PC2 (TIG1) ) . FAST-1/2 -dependent transcription may be inhibited by Forkhead box G1 ( FKHL1 ) .
Another pathway regulated by Activin A signaling is acetylation/deacetylation of SMAD s and different Histone s at Activin A -dependent promoters. For example, V-ski sarcoma viral oncogene homolog ( Ski ) may inhibit SMAD3/ SMAD4 - dependent transcription by recruiting Histone deacetylase 1 ( HDAC1 ) , . E1A binding protein p300 ( p300 )/ CREB binding protein ( CBP ) may activate Activin A signaling by acetylation of SMAD s and Histone s ,