Activin was initially discovered as an activator of follicle stimulating hormone in the pituitary gland. It has since been shown to be an important participant in the differentiation of embryonic cells into mesodermal and endodermal layers. Activin binds the Activin receptor and triggers downstream events: phosphorylation of SMAD2 and SMAD3 followed by activation of gene expression (reviewed in Attisano et al. 1996, Willis et al. 1996, Chen et al. 2006, Hinck 2012). Activins are dimers comprising activin A (INHBA:INHBA), activin AB (INHBA:INHBB), and activin B (INHBB:INHBB). Activin first binds the type II receptor (ACVR2A, ACVR2B) and this complex then interacts with the type I receptor (ACVR1B, ACVR1C) (Attisano et al. 1996). The type II receptor phosphorylates the type I receptor and then the phosphorylated type I receptor phosphorylates SMAD2 and SMAD3. Dimers of phosphorylated SMAD2/3 bind SMAD4 and the resulting ternary complex enters the nucleus and activates target genes.
View original pathway at:Reactome.
Sidis Y, Tortoriello DV, Holmes WE, Pan Y, Keutmann HT, Schneyer AL.; ''Follistatin-related protein and follistatin differentially neutralize endogenous vs. exogenous activin.''; PubMedEurope PMCScholia
Kawabata M, Inoue H, Hanyu A, Imamura T, Miyazono K.; ''Smad proteins exist as monomers in vivo and undergo homo- and hetero-oligomerization upon activation by serine/threonine kinase receptors.''; PubMedEurope PMCScholia
Hinck AP.; ''Structural studies of the TGF-βs and their receptors - insights into evolution of the TGF-β superfamily.''; PubMedEurope PMCScholia
Zhou Y, Sun H, Danila DC, Johnson SR, Sigai DP, Zhang X, Klibanski A.; ''Truncated activin type I receptor Alk4 isoforms are dominant negative receptors inhibiting activin signaling.''; PubMedEurope PMCScholia
Thompson TB, Lerch TF, Cook RW, Woodruff TK, Jardetzky TS.; ''The structure of the follistatin:activin complex reveals antagonism of both type I and type II receptor binding.''; PubMedEurope PMCScholia
Chen YG, Wang Z, Ma J, Zhang L, Lu Z.; ''Endofin, a FYVE domain protein, interacts with Smad4 and facilitates transforming growth factor-beta signaling.''; PubMedEurope PMCScholia
Harrison CA, Gray PC, Fischer WH, Donaldson C, Choe S, Vale W.; ''An activin mutant with disrupted ALK4 binding blocks signaling via type II receptors.''; PubMedEurope PMCScholia
Willis SA, Mathews LS.; ''Regulation of activin type I receptor function by phosphorylation of residues outside the GS domain.''; PubMedEurope PMCScholia
Zhou Y, Scolavino S, Funderburk SF, Ficociello LF, Zhang X, Klibanski A.; ''Receptor internalization-independent activation of Smad2 in activin signaling.''; PubMedEurope PMCScholia
Yanagisawa K, Uchida K, Nagatake M, Masuda A, Sugiyama M, Saito T, Yamaki K, Takahashi T, Osada H.; ''Heterogeneities in the biological and biochemical functions of Smad2 and Smad4 mutants naturally occurring in human lung cancers.''; PubMedEurope PMCScholia
Schneyer AL, O'Neil DA, Crowley WF.; ''Activin-binding proteins in human serum and follicular fluid.''; PubMedEurope PMCScholia
Schmierer B, Hill CS.; ''Kinetic analysis of Smad nucleocytoplasmic shuttling reveals a mechanism for transforming growth factor beta-dependent nuclear accumulation of Smads.''; PubMedEurope PMCScholia
Chen X, Weisberg E, Fridmacher V, Watanabe M, Naco G, Whitman M.; ''Smad4 and FAST-1 in the assembly of activin-responsive factor.''; PubMedEurope PMCScholia
Lebrun JJ, Vale WW.; ''Activin and inhibin have antagonistic effects on ligand-dependent heteromerization of the type I and type II activin receptors and human erythroid differentiation.''; PubMedEurope PMCScholia
Nakao A, Imamura T, Souchelnytskyi S, Kawabata M, Ishisaki A, Oeda E, Tamaki K, Hanai J, Heldin CH, Miyazono K, ten Dijke P.; ''TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4.''; PubMedEurope PMCScholia
Yeo CY, Chen X, Whitman M.; ''The role of FAST-1 and Smads in transcriptional regulation by activin during early Xenopus embryogenesis.''; PubMedEurope PMCScholia
Zhou S, Zawel L, Lengauer C, Kinzler KW, Vogelstein B.; ''Characterization of human FAST-1, a TGF beta and activin signal transducer.''; PubMedEurope PMCScholia
Cárcamo J, Weis FM, Ventura F, Wieser R, Wrana JL, Attisano L, Massagué J.; ''Type I receptors specify growth-inhibitory and transcriptional responses to transforming growth factor beta and activin.''; PubMedEurope PMCScholia
Tortoriello DV, Sidis Y, Holtzman DA, Holmes WE, Schneyer AL.; ''Human follistatin-related protein: a structural homologue of follistatin with nuclear localization.''; PubMedEurope PMCScholia
Kurisaki A, Kose S, Yoneda Y, Heldin CH, Moustakas A.; ''Transforming growth factor-beta induces nuclear import of Smad3 in an importin-beta1 and Ran-dependent manner.''; PubMedEurope PMCScholia
Xiao Z, Latek R, Lodish HF.; ''An extended bipartite nuclear localization signal in Smad4 is required for its nuclear import and transcriptional activity.''; PubMedEurope PMCScholia
Xu L, Chen YG, Massagué J.; ''The nuclear import function of Smad2 is masked by SARA and unmasked by TGFbeta-dependent phosphorylation.''; PubMedEurope PMCScholia
Schneyer A, Schoen A, Quigg A, Sidis Y.; ''Differential binding and neutralization of activins A and B by follistatin and follistatin like-3 (FSTL-3/FSRP/FLRG).''; PubMedEurope PMCScholia
Watanabe R, Shen ZP, Tsuda K, Yamada Y.; ''Insulin gene is a target in activin receptor-like kinase 7 signaling pathway in pancreatic beta-cells.''; PubMedEurope PMCScholia
Chacko BM, Qin BY, Tiwari A, Shi G, Lam S, Hayward LJ, De Caestecker M, Lin K.; ''Structural basis of heteromeric smad protein assembly in TGF-beta signaling.''; PubMedEurope PMCScholia
Willis SA, Zimmerman CM, Li LI, Mathews LS.; ''Formation and activation by phosphorylation of activin receptor complexes.''; PubMedEurope PMCScholia
Stamler R, Keutmann HT, Sidis Y, Kattamuri C, Schneyer A, Thompson TB.; ''The structure of FSTL3.activin A complex. Differential binding of N-terminal domains influences follistatin-type antagonist specificity.''; PubMedEurope PMCScholia
Krummen LA, Woodruff TK, DeGuzman G, Cox ET, Baly DL, Mann E, Garg S, Wong WL, Cossum P, Mather JP.; ''Identification and characterization of binding proteins for inhibin and activin in human serum and follicular fluids.''; PubMedEurope PMCScholia
Chen YG, Wang Q, Lin SL, Chang CD, Chuang J, Ying SY.; ''Activin signaling and its role in regulation of cell proliferation, apoptosis, and carcinogenesis.''; PubMedEurope PMCScholia
Burdette JE, Jeruss JS, Kurley SJ, Lee EJ, Woodruff TK.; ''Activin A mediates growth inhibition and cell cycle arrest through Smads in human breast cancer cells.''; PubMedEurope PMCScholia
Wu JW, Hu M, Chai J, Seoane J, Huse M, Li C, Rigotti DJ, Kyin S, Muir TW, Fairman R, Massagué J, Shi Y.; ''Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-beta signaling.''; PubMedEurope PMCScholia
Schneyer AL, Rzucidlo DA, Sluss PM, Crowley WF.; ''Characterization of unique binding kinetics of follistatin and activin or inhibin in serum.''; PubMedEurope PMCScholia
Chen X, Rubock MJ, Whitman M.; ''A transcriptional partner for MAD proteins in TGF-beta signalling.''; PubMedEurope PMCScholia
Qin BY, Chacko BM, Lam SS, de Caestecker MP, Correia JJ, Lin K.; ''Structural basis of Smad1 activation by receptor kinase phosphorylation.''; PubMedEurope PMCScholia
Dai F, Duan X, Liang YY, Lin X, Feng XH.; ''Coupling of dephosphorylation and nuclear export of Smads in TGF-beta signaling.''; PubMedEurope PMCScholia
Coutts SM, Childs AJ, Fulton N, Collins C, Bayne RA, McNeilly AS, Anderson RA.; ''Activin signals via SMAD2/3 between germ and somatic cells in the human fetal ovary and regulates kit ligand expression.''; PubMedEurope PMCScholia
Attisano L, Wrana JL, Montalvo E, Massagué J.; ''Activation of signalling by the activin receptor complex.''; PubMedEurope PMCScholia
Saito S, Sidis Y, Mukherjee A, Xia Y, Schneyer A.; ''Differential biosynthesis and intracellular transport of follistatin isoforms and follistatin-like-3.''; PubMedEurope PMCScholia
Wang Q, Huang Z, Xue H, Jin C, Ju XL, Han JD, Chen YG.; ''MicroRNA miR-24 inhibits erythropoiesis by targeting activin type I receptor ALK4.''; PubMedEurope PMCScholia
Upon binding Activin A (INHBA:INHBA), Activin AB (INHBA:INHBB), or Activin B (INHBB:INHBB), the type II component of the activin receptor (ACVR2A or ACVR2B) phosphorylates the type I component ACVR1B (ALK4) at multiple serine and threonine residues within the GS domain (Attisano et al. 1996, Willis et al. 1996, Willis and Mathews 1997, Zhou et al. 2000).
Activin binds the Activin receptor composed of a type II receptor (ACVR2A/B) and a type I receptor, in this case ACVR1B (ALK4) (Attisano et al. 1996, Zhou et al. 2000). Activin appears to interact initially with the type II receptor component (Attisano et al. 1996). It is unclear if the type II and type I receptors are associated before binding Activin. Any of Activin A (INHBA:INHBA), Activin AB (INHBA:INHBB), and Activin B (INHBB:INHBB) can bind and signal via an activin receptor containing the ACVR1B (ALK4) type I receptor.
SMAD2 and SMAD3 do not bind DNA efficiently. They must interact with DNA-binding proteins to activate transcription. FOXH1 interacts with phospho-SMAD2 and phospho-SMAD3 complexed with CO-SMAD (SMAD4) at promoters containing the Activin Response Element (Zhou et al. 1998, Yanagisawa et al. 2000, inferred from Xenopus in Chen et al. 1996, Chen et al. 1997, Yeo et al. 1999). Follicle-stimulating hormone beta subunit (FSHB) and the Lim1 homeobox gene (LXH1) are examples of genes regulated by Activin.
Activin receptors containing the type II receptors ACVR2A/B (ActRIIA, ActRIIB) and the type I receptors ACVR1B/C (ALK4, ALK7) signal through SMAD2 and SMAD3. The phosphorylated type I receptor (ACVR1B/C) phosphorylates SMAD2 or SMAD3. Homodimers or heterodimers of SMAD2 and SMAD3 bind the co-Smad SMAD4 and the ternary complex (SMAD2/3:SMAD2/3:SMAD4) enters the nucleus and activates expression of target genes.
The phosphorylated C-terminal tail of R-SMAD induces a conformational change in the MH2 domain (Qin et al. 2001, Chacko et al. 2004), which now acquires high affinity towards Co-SMAD i.e. SMAD4 (common mediator of signal transduction in TGF-beta/BMP signaling). The R-SMAD:Co-SMAD complex (Nakao et al. 1997) most likely is a trimer of two R-SMADs with one Co-SMAD (Kawabata et al. 1998). It is important to note that the Co-SMAD itself cannot be phosphorylated as it lacks the C-terminal serine motif.
ZFYVE16 (endofin) promotes SMAD heterotrimer formation. ZFYVE16 can bind TGFBR1 and facilitate SMAD2 phosphorylation, and it can also bind SMAD4, but the exact mechanism of ZFYVE16 (endofin) action in the context of TGF-beta receptor signaling is not known (Chen et al. 2007).
The phosphorylated R-SMAD:CO-SMAD complex rapidly translocates to the nucleus (Xu et al. 2000, Kurisaki et al. 2001, Xiao et al. 2003) where it binds directly to DNA and interacts with a plethora of transcription co-factors. Regulation of target gene expression can be either positive or negative. A classic example of a target gene of the pathway are the genes encoding for I-SMADs. Thus, TGF-beta/SMAD signaling induces the expression of the negative regulators of the pathway (negative feedback loop).
As inferred from mouse, Activin binds the Activin receptor composed of a type II receptor (ACVR2A/B) and a type I receptor, in this case ACVR1C (ALK7). It is unclear if the type II receptor and the type I receptor are associated before binding Activin, Activin AB (INHBA:INHBB) and Activin B (INHBB:INHBB), but not Activin A (INHBA:INHBA) can bind and signal via an activin receptor containing the ACVR1C (ALK7) type I receptor.
As inferred from mouse, upon binding Activin AB (INHBA:INHBB) or Activin B (INHBB:INHBB), the type II component of the activin receptor (ACVR2A or ACVR2B) phosphorylates the type I component ACVR1C (ALK7) at multiple serine and threonine residues within the GS domain.
Two molecules of Follistatin (FST) bind an Activin dimer in serum or follicular fluid (Schneyer et al. 1992, Krummen et al. 1993, Schneyer et al. 1994, Thompson et al. 2005). FST has been experimentally shown to bind Activin A and Activin B (Schneyer et al. 2003). Binding of FST to Activin AB is inferred.
Two molecules of FSTL3 bind an Activin dimer (Sidis et al. 2002, Stamler et al. 2008). FSTL3 has been experimentally shown to bind Activin A and Activin B (Schneyer et al. 2003). Binding of FSTL3 to Activin AB is inferred. A portion of FSTL3 is also located in the nucleus (Tortoriello et al. 2001), however FSTL3:Activin complexes have not been demonstrated in the nucleus.
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ZFYVE16 (endofin) promotes SMAD heterotrimer formation. ZFYVE16 can bind TGFBR1 and facilitate SMAD2 phosphorylation, and it can also bind SMAD4, but the exact mechanism of ZFYVE16 (endofin) action in the context of TGF-beta receptor signaling is not known (Chen et al. 2007).