ActRIIA, FSHR, SP1, PKA-reg (cAMP-dependent), Oct-3/4, NANOG, p27KIP1, OTX1, SMAD2, MAD, 22.214.171.124, VDR, SMAD4, LHX3, G-protein alpha-s, CREB1, ATP, CYP11A1, GnRH receptor, SMAD3, PKA-cat (cAMP-dependent), p21, SF1, Activin A, p15, cAMP, ALK-4, c-Myc, PBX1/PREP1, LH-beta, NODAL, Lefty-2, Adenylate cyclase, ActRIIB, FSH-beta, Lutropin, Pitx1, Lefty-1, STAR, LH receptor
Role of Activin A in cell differentiation and proliferation
Activins are the members of the Transforming growth factor beta (TGF-beta) superfamily which participate in regulation of several biological processes, including cell differentiation and proliferation. Among many activins, role of Activin A in this regulation is studied the best.
Like most members of the TGF beta superfamily, Activin A mediates its biological effects through a complex of transmembrane receptor serine/threonine kinases. Activin A initially binds to Activin A receptors type II ( ActRIIA or ActRIIB ) and then recruits Activin A receptor, type IB ( ALK4 ) , .
ALK4 interacts with and phosphorylates adaptors SMAD family member 2 and 3 ( SMAD2 and SMAD3 ). SMAD family member 4 ( SMAD4 ) is then binds to phosphorylated SMAD2 and SMAD3, followed by translocation of the complex into the nucleus . Once in the nucleus, SMAD2 and SMAD3 may activate transcription of different genes.
It has been shown, that Activin A participates in regulation of stem cell maintenance, via SMAD -dependent activation transcription of marker of pluripotency like POU class 5 homeobox 1 ( Oct-3/4 ), NANOG, NODAL and NODAL -signaling regulators, Left-right determination factor 1 and 2 ( Lefty-B and Lefty-A ) , , .
Activin A inhibits cell growth and proliferation and activates cell differentiation via multiple pathways. In nonmalignant keratinocytes, Activin A stimulates transcription of MAX dimerization protein 1 ( MAD ) ,  and inhibits transcription of c-Myc . In addition, Activin A can stimulate transcription of cell cycle inhibitors Cyclin-dependent kinase inhibitor 2B ( p15 ), Cyclin-dependent kinase inhibitor 1A ( p21 ) and Cyclin-dependent kinase inhibitor 1B ( p27KIP1 ) , , . p15 and p21 can be activated by SMAD2 and/or SMAD3 directly (as shown for other members of TGF-beta superfamily)  . Transcription of p27KIP1 can be activated via Vitamin D receptor ( VDR )/ Sp1 complex , .
Moreover, Activin A may stimulate differentiation of granulosa cells from prehierarchal follicles via activation of Follicle stimulating hormone receptor ( FSHR ) and Luteinizing hormone/choriogonadotropin receptor ( LH receptor ). It is believed that initially Activin A activates FSHR -signaling , probably via transcription activation of FSHR . Transcription activation of FSHR may be realized via Nuclear receptor subfamily 5 group A member 1 ( SF1 ) , . In addition, Activin A may activate FSHR -signaling via transcription activation of Follicle stimulating hormone beta polypeptide ( FSH-beta ) (e.g., via LIM homeobox 3 ( LHX3 )  or SMAD/ Pre-B-cell leukemia homeobox 1 ( PBX1 )/ PBX/knotted 1 homeobox 1 ( PREP1 ) complex ,  ). Then, Activin A and/or FSHR signaling pathways stimulate LH receptor -signaling, possibly, via activation of expression of LH receptor and/or LH-beta , , .
Then, LH receptor stimulates the G-protein alpha-s/ Adenylate cyclase/ cAMP/ Protein kinase cAMP-dependent ( PKA )/ cAMP responsive element binding protein 1 ( CREB1 ) cascade , which in turn leads to transcription of proteins critical to initiating progesterone production, e.g. Steroidogenic acute regulatory protein ( STAR ) and Cytochrome P450 family 11 subfamily A polypeptide 1 ( CYP11A1 ) , .