Pathway Map Details

Signal transduction_Activin A signaling regulation



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Object list (links open in MetaCore):

Histone H2, Histone H4, SMAD3, ActRIIA, SMAD4, IGSF1, N-CoR, FKBP12, Histone H3, ALK-4, CBP, p300, SMURF1, PC2 (TIG1), FKHL1, MAN1, Follistatin, Inhibin alpha subunit, BAMBI, Ski, Activin A, SMAD7, Evi-1, Sin3A, Ubiquitin, SMAD2, Inhibin, TGF-beta receptor type III (betaglycan), FSRP, HDAC1, DLX1, FAST-1/2, ActRIIB

Description:

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 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 Activin A receptors type II ( ActRIIA or ActRIIB ) and then recruitsActivin A receptor, type IB ( ALK-4 ) [2], [5].

ALK-4 interacts with and phosphorylates adaptors of SMAD family member 2 and 3 ( SMAD2 and SMAD3 ). Subsequently, SMAD family member 4 ( 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 [6], [2].

Activin A signaling may be inhibited by extracellular proteins Follistatin and Follistatin-like 3 ( FSRP ). Follistatin and FSRP bind to Activin A with high affinity, and their binding is nearly irreversible. Activin A in the complex with Follistatin s 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 [9], [4], [8].

Moreover, some membrane proteins inhibit Activin A signal via repression of ALK-4. Immunoglobulin superfamily, member 1 ( IGSF1 ) [10] and BMP and activin membrane-bound inhibitor homolog ( BAMBI ) [11] form a complex with the ALK4, which then attenuates Activin A -stimulated reporter gene activity [10].

In addition, FK506 binding protein 1A 12kDa ( FKBP12 ) may recruit the SMAD7/ SMAD specific E3 ubiquitin protein ligase 1 ( 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 Distal-less homeobox 1 ( DLX1 ) [14], Ecotropic viral integration site 1 ( Evi-1 ) [15] and LEM domain containing 3 ( MAN1 ) [16], [17] interact with SMAD s and inhibit them directly.

Activin A signal may be stimulated by different activators, such as, Forkhead box H1 ( FAST-1/2 ) [18] and Positive cofactor 2 ( PC2 (TIG1) ) [19]. FAST-1/2 -dependent transcription may be inhibited by Forkhead box G1 ( FKHL1 ) [20].

Another pathway regulated by Activin A signaling is acetylation/deacetylation of SMAD s and different Histone s at Activin A -dependent promoters. For example, V-ski sarcoma viral oncogene homolog ( Ski ) may inhibit SMAD3/ SMAD4 - dependent transcription by recruiting Histone deacetylase 1 ( HDAC1 ) [21], [2]. E1A binding protein p300 ( p300 )/ CREB binding protein ( CBP ) may activate Activin A signaling by acetylation of SMAD s and Histone s [6], [22]

References:

  1. Brown CW, Li L, Houston-Hawkins DE, Matzuk MM
    Activins are critical modulators of growth and survival. Molecular endocrinology (Baltimore, Md.) 2003 Dec;17(12):2404-17
  2. Abe Y, Minegishi T, Leung PC
    Activin receptor signaling. Growth factors (Chur, Switzerland) 2004 Jun;22(2):105-10
  3. Jones KL, de Kretser DM, Patella S, Phillips DJ
    Activin A and follistatin in systemic inflammation. Molecular and cellular endocrinology 2004 Oct 15;225(1-2):119-25
  4. Phillips DJ
    Activins, inhibins and follistatins in the large domestic species. Domestic animal endocrinology 2005 Jan;28(1):1-16
  5. Larsson J, Karlsson S
    The role of Smad signaling in hematopoiesis. Oncogene 2005 Aug 29;24(37):5676-92
  6. Miyazono K
    Positive and negative regulation of TGF-beta signaling. Journal of cell science 2000 Apr;113 ( Pt 7):1101-9
  7. Sidis Y, Tortoriello DV, Holmes WE, Pan Y, Keutmann HT, Schneyer AL
    Follistatin-related protein and follistatin differentially neutralize endogenous vs. exogenous activin. Endocrinology 2002 May;143(5):1613-24
  8. Kumanov P, Nandipati KC, Tomova A, Robeva R, Agarwal A
    Significance of inhibin in reproductive pathophysiology and current clinical applications. Reproductive biomedicine online 2005 Jun;10(6):786-812
  9. Lewis KA, Gray PC, Blount AL, MacConell LA, Wiater E, Bilezikjian LM, Vale W
    Betaglycan binds inhibin and can mediate functional antagonism of activin signalling. Nature 2000 Mar 23;404(6776):411-4
  10. Chapman SC, Woodruff TK
    Modulation of activin signal transduction by inhibin B and inhibin-binding protein (INhBP). Molecular endocrinology (Baltimore, Md.) 2001 Apr;15(4):668-79
  11. Onichtchouk D, Chen YG, Dosch R, Gawantka V, Delius H, Massague J, Niehrs C
    Silencing of TGF-beta signalling by the pseudoreceptor BAMBI. Nature 1999 Sep 30;401(6752):480-5
  12. Yamaguchi T, Kurisaki A, Yamakawa N, Minakuchi K, Sugino H
    FKBP12 functions as an adaptor of the Smad7-Smurf1 complex on activin type I receptor. Journal of molecular endocrinology 2006 Jun;36(3):569-79
  13. Liu X, Nagarajan RP, Vale W, Chen Y
    Phosphorylation regulation of the interaction between Smad7 and activin type I receptor. FEBS letters 2002 May 22;519(1-3):93-8
  14. Chiba S, Takeshita K, Imai Y, Kumano K, Kurokawa M, Masuda S, Shimizu K, Nakamura S, Ruddle FH, Hirai H
    Homeoprotein DLX-1 interacts with Smad4 and blocks a signaling pathway from activin A in hematopoietic cells. Proceedings of the National Academy of Sciences of the United States of America 2003 Dec 23;100(26):15577-82
  15. Alliston T, Ko TC, Cao Y, Liang YY, Feng XH, Chang C, Derynck R
    Repression of bone morphogenetic protein and activin-inducible transcription by Evi-1. The Journal of biological chemistry 2005 Jun 24;280(25):24227-37
  16. Pan D, Estevez-Salmeron LD, Stroschein SL, Zhu X, He J, Zhou S, Luo K
    The integral inner nuclear membrane protein MAN1 physically interacts with the R-Smad proteins to repress signaling by the transforming growth factor-{beta} superfamily of cytokines. The Journal of biological chemistry 2005 Apr 22;280(16):15992-6001
  17. Bengtsson L
    What MAN1 does to the Smads. TGFbeta/BMP signaling and the nuclear envelope. The FEBS journal 2007 Mar;274(6):1374-82
  18. Attisano L, Silvestri C, Izzi L, Labbe E
    The transcriptional role of Smads and FAST (FoxH1) in TGFbeta and activin signalling. Molecular and cellular endocrinology 2001 Jun 30;180(1-2):3-11
  19. Kato Y, Habas R, Katsuyama Y, Naar AM, He X
    A component of the ARC/Mediator complex required for TGF beta/Nodal signalling. Nature 2002 Aug 8;418(6898):641-6
  20. Dou C, Lee J, Liu B, Liu F, Massague J, Xuan S, Lai E
    BF-1 interferes with transforming growth factor beta signaling by associating with Smad partners. Molecular and cellular biology 2000 Sep;20(17):6201-11
  21. Takeda M, Mizuide M, Oka M, Watabe T, Inoue H, Suzuki H, Fujita T, Imamura T, Miyazono K, Miyazawa K
    Interaction with Smad4 is indispensable for suppression of BMP signaling by c-Ski. Molecular biology of the cell 2004 Mar;15(3):963-72
  22. Tu AW, Luo K
    Acetylation of Smad2 by the co-activator p300 regulates activin and TGFbeta response. The Journal of biological chemistry 2007 May 3;