Signaling by Activin (Homo sapiens)

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15, 23, 32, 393, 6, 14, 25, 31...4, 16, 24, 27, 387, 15, 21, 3617, 18, 28, 34, 37...2, 5, 9, 20, 291, 11, 22, 30, 352, 8, 10, 267, 12, 13, 15, 39ACVR2A/B [plasmamembrane]Activin AB/B[extracellularregion]INHBB dimer[extracellularregion]INHBA dimer[extracellularregion]Activin AB/B[extracellularregion]ActivinA/AB/B:ACVR2A/B:ACVR1B[plasma membrane]ActivinAB/B:ACVR2A/B:p-ACVR1C[plasma membrane]INHBA dimer[extracellularregion]INHBB dimer[extracellularregion]ActivinAB/B:ACVR2A/B:ACVR1C[plasma membrane]Activin A/AB/B[extracellularregion]Activin A/AB/B[extracellularregion]p-2S-SMAD2/3:SMAD4[cytosol]INHBB dimer[extracellularregion]ActivinA/AB/B:ACVR2A/B:p-ACVR1B[plasma membrane]INHBA:INHBB[extracellularregion]ACVR2A/B [plasmamembrane]FOXH1:DRAP1[nucleoplasm]Activin:ACVR2A/B:p-ACVR1B/C[plasma membrane]INHBB dimer[extracellularregion]INHBA dimer[extracellularregion]ACVR2A/B [plasmamembrane]INHBB dimer[extracellularregion]INHBB dimer[extracellularregion]nucleoplasmcytosolINHBA:INHBB[extracellularregion]Activin A/AB/B[extracellularregion]INHBA:INHBB[extracellularregion]INHBA:INHBB[extracellularregion]p-2S-SMAD2/3:SMAD4[nucleoplasm]INHBA:INHBB[extracellularregion]Activin AB/B[extracellularregion]ACVR2A/B [plasmamembrane]INHBA dimer[extracellularregion]ActivinA/AB/B:ACVR2A/B:p-ACVR1B[plasma membrane]p-2S-SMAD2/3:SMAD4[nucleoplasm]ActivinAB/B:ACVR2A/B:p-ACVR1C[plasma membrane]INHBA:INHBB[extracellularregion]Activin A/AB/B[extracellularregion]INHBA dimer[extracellularregion]Activin AB/B[extracellularregion]Activin A/AB/B:FSTL3[extracellularregion]p-2S-SMAD2/3[nucleoplasm]p-2S-SMAD2/3[nucleoplasm]INHBB dimer[extracellularregion]Activin A/AB/B[extracellularregion]Activin A/AB/B[extracellularregion]Activin A/AB/B:FST[extracellularregion]ACVR2A/B [plasmamembrane]INHBB dimer[extracellularregion]INHBA:INHBB[extracellularregion]p-2S-SMAD2/3[cytosol]SMAD2/3:SMAD4:FOXH1:ActivinResponse Element[nucleoplasm]INHBB dimer[extracellularregion]INHBA dimer[extracellularregion]INHBA:INHBB[extracellularregion]INHBA:INHBB[extracellularregion]FOXH1INHBB [extracellularregion]INHBB [extracellularregion]Activin A/AB/Bp-S465,S467-SMAD2[nucleoplasm]INHBB [extracellularregion]INHBA [extracellularregion]SMAD4FSTL3ActivinAB/B:ACVR2A/B:p-ACVR1CACVR2A/BATPINHBB [extracellularregion]INHBA [extracellularregion]ACVR1Cp-4S,T188,T206-ACVR1B[plasma membrane]INHBA [extracellularregion]FST [extracellularregion]INHBB [extracellularregion]ACVR1BFSTL3 [extracellularregion]SMAD4 [cytosol]ActivinA/AB/B:ACVR2A/B:p-ACVR1Bp-2S-SMAD2/3ACVR2A [plasmamembrane]Activin ResponseElementActivinA/AB/B:ACVR2A/B:ACVR1BSMAD2/3:SMAD4:FOXH1:ActivinResponse Elementp-2S-SMAD2/3:SMAD4Activin AB/BFOXH1 [nucleoplasm]ATPINHBA [extracellularregion]DRAP1 [nucleoplasm]p-T175,S177,S179,S181,T194-ACVR1C[plasma membrane]ACVR2B [plasmamembrane]Activin A/AB/B:FSTINHBA [extracellularregion]FOXH1 [nucleoplasm]ACVR2B [plasmamembrane]SMAD4 [nucleoplasm]INHBA [extracellularregion]p-S423,S425-SMAD3[cytosol]SMAD4 [nucleoplasm]ACVR2B [plasmamembrane]ActivinAB/B:ACVR2A/B:ACVR1CACVR2A [plasmamembrane]INHBA [extracellularregion]Activin:ACVR2A/B:p-ACVR1B/CINHBA [extracellularregion]ACVR1B [plasmamembrane]p-4S,T188,T206-ACVR1B[plasma membrane]INHBB [extracellularregion]ACVR2A [plasmamembrane]INHBA [extracellularregion]ADPp-2S-SMAD2/3:SMAD4ADPACVR2A [plasmamembrane]INHBB [extracellularregion]FOXH1:DRAP1SMAD2/3p-S465,S467-SMAD2[cytosol]ACVR2B [plasmamembrane]Activin A/AB/B:FSTL3ACVR2B [plasmamembrane]INHBB [extracellularregion]p-S423,S425-SMAD3[nucleoplasm]ACVR2A [plasmamembrane]p-S465,S467-SMAD2[nucleoplasm]p-S423,S425-SMAD3[nucleoplasm]p-T175,S177,S179,S181,T194-ACVR1C[plasma membrane]ATPINHBB [extracellularregion]FSTADPACVR1C [plasmamembrane]112, 5, 9, 20, 297, 12, 21192, 10, 267, 12, 15, 21, 391911


Description

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.Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=1502540

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Bibliography

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History

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101384view11:27, 1 November 2018ReactomeTeamreactome version 66
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100462view19:37, 31 October 2018ReactomeTeamreactome version 64
100008view16:21, 31 October 2018ReactomeTeamreactome version 63
99561view14:54, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
94007view13:51, 16 August 2017ReactomeTeamreactome version 61
93622view11:29, 9 August 2017ReactomeTeamreactome version 61
87118view18:36, 18 July 2016EgonwOntology Term : 'signaling pathway' added !
86732view09:25, 11 July 2016ReactomeTeamreactome version 56
83227view10:26, 18 November 2015ReactomeTeamVersion54
81622view13:10, 21 August 2015ReactomeTeamVersion53
77082view08:38, 17 July 2014ReactomeTeamFixed remaining interactions
76787view12:15, 16 July 2014ReactomeTeamFixed remaining interactions
76110view10:17, 11 June 2014ReactomeTeamRe-fixing comment source
75822view11:37, 10 June 2014ReactomeTeamReactome 48 Update
75172view14:12, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74819view08:55, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ACVR1B [plasma membrane]ProteinP36896 (Uniprot-TrEMBL)
ACVR1BProteinP36896 (Uniprot-TrEMBL)
ACVR1C [plasma membrane]ProteinQ8NER5 (Uniprot-TrEMBL)
ACVR1CProteinQ8NER5 (Uniprot-TrEMBL)
ACVR2A [plasma membrane]ProteinP27037 (Uniprot-TrEMBL)
ACVR2A/BProteinREACT_111501 (Reactome)
ACVR2B [plasma membrane]ProteinQ13705 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activin A/AB/B:ACVR2A/B:ACVR1BComplexREACT_111481 (Reactome)
Activin A/AB/B:ACVR2A/B:p-ACVR1BComplexREACT_111303 (Reactome)
Activin AB/B:ACVR2A/B:ACVR1CComplexREACT_151591 (Reactome)
Activin AB/B:ACVR2A/B:p-ACVR1CComplexREACT_150570 (Reactome)
Activin A/AB/B:FSTL3ComplexREACT_152075 (Reactome)
Activin A/AB/B:FSTComplexREACT_150737 (Reactome)
Activin A/AB/BComplexREACT_151143 (Reactome)
Activin AB/BComplexREACT_152049 (Reactome)
Activin Response ElementREACT_111540 (Reactome) The inferred consensus sequence of the activin response element is TGT(G/T)(G/T)ATT (Zhou et al. 1998).
Activin:ACVR2A/B:p-ACVR1B/CComplexREACT_150543 (Reactome)
DRAP1 [nucleoplasm]ProteinQ14919 (Uniprot-TrEMBL)
FOXH1 [nucleoplasm]ProteinO75593 (Uniprot-TrEMBL)
FOXH1:DRAP1ComplexREACT_111401 (Reactome)
FOXH1ProteinO75593 (Uniprot-TrEMBL)
FST [extracellular region]ProteinP19883 (Uniprot-TrEMBL)
FSTL3 [extracellular region]ProteinO95633 (Uniprot-TrEMBL)
FSTL3ProteinO95633 (Uniprot-TrEMBL)
FSTProteinP19883 (Uniprot-TrEMBL)
INHBA [extracellular region]ProteinP08476 (Uniprot-TrEMBL)
INHBB [extracellular region]ProteinP09529 (Uniprot-TrEMBL)
SMAD2/3:SMAD4:FOXH1:Activin Response ElementComplexREACT_111692 (Reactome)
SMAD2/3ProteinREACT_7451 (Reactome)
SMAD4 [cytosol]ProteinQ13485 (Uniprot-TrEMBL)
SMAD4 [nucleoplasm]ProteinQ13485 (Uniprot-TrEMBL)
SMAD4ProteinQ13485 (Uniprot-TrEMBL)
p-2S-SMAD2/3:SMAD4ComplexREACT_7344 (Reactome)
p-2S-SMAD2/3:SMAD4ComplexREACT_7382 (Reactome)
p-2S-SMAD2/3ProteinREACT_7364 (Reactome)
p-4S,T188,T206-ACVR1B [plasma membrane]ProteinP36896 (Uniprot-TrEMBL)
p-S423,S425-SMAD3 [cytosol]ProteinP84022 (Uniprot-TrEMBL)
p-S423,S425-SMAD3 [nucleoplasm]ProteinP84022 (Uniprot-TrEMBL)
p-S465,S467-SMAD2 [cytosol]ProteinQ15796 (Uniprot-TrEMBL)
p-S465,S467-SMAD2 [nucleoplasm]ProteinQ15796 (Uniprot-TrEMBL)
p-T175,S177,S179,S181,T194-ACVR1C [plasma membrane]ProteinQ8NER5 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ACVR1BREACT_150161 (Reactome)
ACVR1CREACT_150244 (Reactome)
ACVR2A/BREACT_150161 (Reactome)
ACVR2A/BREACT_150244 (Reactome)
ADPArrowREACT_111068 (Reactome)
ADPArrowREACT_150345 (Reactome)
ADPArrowREACT_150380 (Reactome)
ATPREACT_111068 (Reactome)
ATPREACT_150345 (Reactome)
ATPREACT_150380 (Reactome)
Activin A/AB/B:ACVR2A/B:ACVR1BArrowREACT_150161 (Reactome)
Activin A/AB/B:ACVR2A/B:ACVR1BREACT_111068 (Reactome)
Activin A/AB/B:ACVR2A/B:ACVR1Bmim-catalysisREACT_111068 (Reactome)
Activin A/AB/B:ACVR2A/B:p-ACVR1BArrowREACT_111068 (Reactome)
Activin AB/B:ACVR2A/B:ACVR1CArrowREACT_150244 (Reactome)
Activin AB/B:ACVR2A/B:ACVR1CREACT_150380 (Reactome)
Activin AB/B:ACVR2A/B:ACVR1Cmim-catalysisREACT_150380 (Reactome)
Activin AB/B:ACVR2A/B:p-ACVR1CArrowREACT_150380 (Reactome)
Activin A/AB/B:FSTArrowREACT_150395 (Reactome)
Activin A/AB/B:FSTL3ArrowREACT_150306 (Reactome)
Activin A/AB/BREACT_150161 (Reactome)
Activin A/AB/BREACT_150306 (Reactome)
Activin A/AB/BREACT_150395 (Reactome)
Activin AB/BREACT_150244 (Reactome)
Activin Response ElementREACT_111132 (Reactome)
Activin:ACVR2A/B:p-ACVR1B/Cmim-catalysisREACT_150345 (Reactome)
FOXH1:DRAP1TBarREACT_111132 (Reactome)
FOXH1REACT_111132 (Reactome)
FSTL3REACT_150306 (Reactome)
FSTREACT_150395 (Reactome)
REACT_111068 (Reactome) 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).
REACT_111132 (Reactome) 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.
REACT_150161 (Reactome) 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.
REACT_150244 (Reactome) 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.
REACT_150306 (Reactome) 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.
REACT_150345 (Reactome) 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.
REACT_150380 (Reactome) 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.
REACT_150395 (Reactome) 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.
REACT_6726 (Reactome) 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).
REACT_6760 (Reactome) 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).
SMAD2/3:SMAD4:FOXH1:Activin Response ElementArrowREACT_111132 (Reactome)
SMAD2/3REACT_150345 (Reactome)
SMAD4REACT_6760 (Reactome)
p-2S-SMAD2/3:SMAD4ArrowREACT_6726 (Reactome)
p-2S-SMAD2/3:SMAD4ArrowREACT_6760 (Reactome)
p-2S-SMAD2/3:SMAD4REACT_111132 (Reactome)
p-2S-SMAD2/3:SMAD4REACT_6726 (Reactome)
p-2S-SMAD2/3ArrowREACT_150345 (Reactome)
p-2S-SMAD2/3REACT_6760 (Reactome)
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