Development Role of Activin A in cell differentiation and proliferation
Role of Activin A in cell differentiation and proliferation
Activins are the members of the Transforming growth factor beta (TGF-beta) superfamilywhich participate in regulation of several biological processes, including celldifferentiation and proliferation. Among many activins, role of Activin A in thisregulation is studied the best.
Like most members of the TGF beta superfamily, Activin A mediates itsbiological effects through a complex of transmembrane receptor serine/threonine kinases.Activin A initially binds to Activin A receptors type II ( ActRIIA orActRIIB ) and then recruits Activin A receptor, type IB ( ALK4 ) [1], [2].
ALK4 interacts with and phosphorylates adaptors SMAD family member 2 and 3 (SMAD2 and SMAD3 ). SMAD family member 4 ( SMAD4 ) is then binds tophosphorylated SMAD2 and SMAD3, followed by translocation of the complexinto the nucleus [1]. Once in the nucleus, SMAD2 and SMAD3 mayactivate transcription of different genes.
It has been shown, that Activin A participates in regulation of stem cellmaintenance, via SMAD -dependent activation transcription of marker ofpluripotency like POU class 5 homeobox 1 ( Oct-3/4 ), NANOG, NODALand NODAL -signaling regulators, Left-right determination factor 1 and 2 (Lefty-B and Lefty-A ) [3], [4], [5].
Activin A inhibits cell growth and proliferation and activates celldifferentiation via multiple pathways. In nonmalignant keratinocytes, Activin Astimulates transcription of MAX dimerization protein 1 ( MAD ) [6],[7] and inhibits transcription of c-Myc [8]. Inaddition, Activin A can stimulate transcription of cell cycle inhibitorsCyclin-dependent kinase inhibitor 2B ( p15 ), Cyclin-dependent kinase inhibitor 1A( p21 ) and Cyclin-dependent kinase inhibitor 1B ( p27KIP1 ) [9], [10], [11]. p15 and p21 can be activatedby SMAD2 and/or SMAD3 directly (as shown for other members of TGF-betasuperfamily) [12] [13]. Transcription of p27KIP1 can beactivated via Vitamin D receptor ( VDR )/ Sp1 complex [14],[15].
Activin A also stimulates transcription of several hormones. For example,Gonadotropin-releasing hormone receptor ( GnRH receptor ) [16], [17].
Moreover, Activin A may stimulate differentiation of granulosa cells fromprehierarchal 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 [18], probably via transcription activation of FSHR [18].Transcription activation of FSHR may be realized via Nuclear receptor subfamily 5group A member 1 ( SF1 ) [19], [20]. In addition,Activin A may activate FSHR -signaling via transcription activation ofFollicle stimulating hormone beta polypeptide ( FSH-beta ) (e.g., via LIM homeobox3 ( LHX3 ) [21] or SMAD/ Pre-B-cell leukemia homeobox 1 (PBX1 )/ PBX/knotted 1 homeobox 1 ( PREP1 ) complex [22],[23]). Then, Activin A and/or FSHR signaling pathwaysstimulate LH receptor -signaling, possibly, via activation of expression of LHreceptor and/or LH-beta [24], [18], [25].
Then, LH receptor stimulates the G-protein alpha-s/ Adenylatecyclase/ cAMP/ Protein kinase cAMP-dependent ( PKA )/ cAMP responsiveelement binding protein 1 ( CREB1 ) cascade [24], which in turnleads to transcription of proteins critical to initiating progesterone production, e.g.Steroidogenic acute regulatory protein ( STAR ) and Cytochrome P450 family 11subfamily A polypeptide 1 ( CYP11A1 ) [24], [18].
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