Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
Protein phosphatase
Lipid phosphatase
Generic phospholipase
Generic protease
Metalloprotease
G-alpha
RAS - superfamily
G beta/gamma
Regulators (GDI, GAP, GEF)
Generic channel
Ligand-gated channel
Voltage-gated channel
Transporter
Normal process
Pathological process
Positive effect
Negative effect
Unspecified effect
Technical link
Disrupts in disease
Emerges in disease
Enhances in disease
Weakens in disease
Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
DNA
RNA
Compound
Inorganic ion
Predicted metabolite or user's structure
Reaction
Generic receptor
GPCR
Receptors with enzyme activity
Mitochondria
EPR
Golgi
Nucleus
Lysosome
Peroxisome
Cytoplasm
Extracellular

Normal process
Pathological process
Binding
Cleavage
Covalent modifications
Phosphorylation
Dephosphorylation
Transformation
Transport
Catalysis
Transcription regulation
MicroRNA binding
Competition
Influence on expression
Unspecified interactions
Pharmacological effect
Toxic effect
Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

Development Role of Activin A in cell differentiation and proliferation


Log In to Post A Comment

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].