Signal transduction - Activin A signaling regulation

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:

References:

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