Signaling by NODAL (Homo sapiens)

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25, 322, 6, 20, 31, 3611, 15, 21, 22, 33...53, 10, 139, 12, 14, 23, 2619, 272, 7, 24, 36281, 17, 18, 29, 30, 3416nucleoplasmcytosolLEFTY1,2:NODALACVR1B TDGF1P3 SMAD4 TDGF1P3 FOXO3 N-aspartyl-glycosylphosphatidylinositolethanolamine-TDGF1(31-188) SMAD2,3:SMAD4:FOXH1:Activin Response ElementACVR1C TDGF1P3 ACVR1C LEFTY1 GDF1 ADPNODAL Ligand:NODALReceptorACVR2B N-aspartyl-glycosylphosphatidylinositolethanolamine-CFC1 p-2S-SMAD2/3:SMAD4TDGF1P3 NODAL N-aspartyl-glycosylphosphatidylinositolethanolamine-TDGF1(31-188) NODAL(27-347) CER1 p-T175,S177,S179,S181,T194-ACVR1C N-aspartyl-glycosylphosphatidylinositolethanolamine-CFC1 ACVR2B LEFTY1 TDGF1P3 LEFTY2(22-366) N-aspartyl-glycosylphosphatidylinositolethanolamine-TDGF1(31-188) LEFTY2(22-366) Activin Response Element NODAL TDGF1P3 LEFTY2(22-366) ACVR2B NODAL ATPACVR2B ADPCER1 SMAD2/3ACVR2A NODAL p-S423,S425-SMAD3 N-aspartyl-glycosylphosphatidylinositolethanolamine-TDGF1(31-188) N-aspartyl-glycosylphosphatidylinositolethanolamine-CFC1 p-S465,S467-SMAD2 ACVR1C ATPFOXH1:DRAP1FoxO3a-binding Element SMAD4 p-S423,S425-SMAD3 NODAL dimerSMAD2 N-aspartyl-glycosylphosphatidylinositolethanolamine-TDGF1(31-188) DAND5 N-aspartyl-glycosylphosphatidylinositolethanolamine-TDGF1(31-188) FOXH1 ACVR2A ACVR1B LEFTY1,2:NODALReceptorSMAD4 GDF1 NODAL:ACVR1B:ACVR2A,B:EGF-CFCNODAL dimer,NODAL:GDF1N-aspartyl-glycosylphosphatidylinositolethanolamine-TDGF1(31-188) LEFTY1,2p-2S-SMAD2/3N-aspartyl-glycosylphosphatidylinositolethanolamine-CFC1 SMAD4FOXH1 ACVR1B N-aspartyl-glycosylphosphatidylinositolethanolamine-TDGF1(31-188) NODAL CER1,2N-aspartyl-glycosylphosphatidylinositolethanolamine-CFC1 PCSK6 GDF1 NODAL N-aspartyl-glycosylphosphatidylinositolethanolamine-CFC1 NODAL:p-NODALReceptorDAND5 ACVR1C Activin ResponseElementGDF1 GDF1 p-S423,S425-SMAD3 p-T175,S177,S179,S181,T194-ACVR1C NODAL SMAD3 GDF1 LEFTY1 TDGF1P3 p-S465,S467-SMAD2 p-S423,S425-SMAD3 NODAL ACVR2A p-S465,S467-SMAD2 DRAP1 p-4S,T188,T206-ACVR1B p-S465,S467-SMAD2 FoxO3a-bindingElementN-aspartyl-glycosylphosphatidylinositolethanolamine-CFC1 TDGF1P3 FOXH1p-4S,T188,T206-ACVR1B NODAL(27-347) dimerNODAL SMAD2,3:SMAD4:FOXO3:FoxO3a-binding ElementSMAD4 FOXO3ACVR2B FURIN, PACE4NODAL:p-ACVR1B:ACVR2:EGF-CFCFURIN GDF1 ACVR2B ACVR2A N-aspartyl-glycosylphosphatidylinositolethanolamine-CFC1 CERBERUS:NODALNODAL:p-ACVR1C:ACVR2B:EGF-CFCNODAL Receptorp-S423,S425-SMAD3 ADPACVR2B NODAL p-2S-SMAD2/3:SMAD4NODAL:ACVR1C:ACVR2B:EGF-CFCATPACVR1B p-S465,S467-SMAD2 ACVR2B ACVR2A ACVR2A 2726548265265


Signaling by NODAL is essential for patterning of the axes of the embryo and formation of mesoderm and endoderm (reviewed in Schier 2009, Shen 2007). The NODAL proprotein is secreted and cleaved extracellularly to yield mature NODAL. Mature NODAL homodimerizes and can also form heterodimers with LEFTY1, LEFTY2, or CERBERUS, which negatively regulate NODAL signaling. NODAL also forms heterodimers with GDF1, which increases NODAL activity. NODAL dimers bind the NODAL receptor comprising a type I Activin receptor (ACVR1B or ACVR1C), a type II Activin receptor (ACVR2A or ACVR2B), and an EGF-CFC coreceptor (CRIPTO or CRYPTIC). After binding NODAL, the type II activin receptor phosphorylates the type I activin receptor which then phosphorylates SMAD2 and SMAD3 (R-SMADs). Phosphorylated SMAD2 and SMAD3 form hetero-oligomeric complexes with SMAD4 (CO-SMAD) and transit from the cytosol to the nucleus. Within the nucleus the SMAD complexes interact with transcription factors such as FOXH1 to activate transcription of target genes. View original pathway at:Reactome.


Pathway is converted from Reactome ID: 1181150
Reactome version: 66
Reactome Author 
Reactome Author: May, Bruce

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  1. Xiao Z, Latek R, Lodish HF.; ''An extended bipartite nuclear localization signal in Smad4 is required for its nuclear import and transcriptional activity.''; PubMed Europe PMC Scholia
  2. Nadeem L, Munir S, Fu G, Dunk C, Baczyk D, Caniggia I, Lye S, Peng C.; ''Nodal signals through activin receptor-like kinase 7 to inhibit trophoblast migration and invasion: implication in the pathogenesis of preeclampsia.''; PubMed Europe PMC Scholia
  3. Kumar A, Novoselov V, Celeste AJ, Wolfman NM, ten Dijke P, Kuehn MR.; ''Nodal signaling uses activin and transforming growth factor-beta receptor-regulated Smads.''; PubMed Europe PMC Scholia
  4. Bianco C, Adkins HB, Wechselberger C, Seno M, Normanno N, De Luca A, Sun Y, Khan N, Kenney N, Ebert A, Williams KP, Sanicola M, Salomon DS.; ''Cripto-1 activates nodal- and ALK4-dependent and -independent signaling pathways in mammary epithelial Cells.''; PubMed Europe PMC Scholia
  5. Fu G, Peng C.; ''Nodal enhances the activity of FoxO3a and its synergistic interaction with Smads to regulate cyclin G2 transcription in ovarian cancer cells.''; PubMed Europe PMC Scholia
  6. Munir S, Xu G, Wu Y, Yang B, Lala PK, Peng C.; ''Nodal and ALK7 inhibit proliferation and induce apoptosis in human trophoblast cells.''; PubMed Europe PMC Scholia
  7. Zhong Y, Xu G, Ye G, Lee D, Modica-Amore J, Peng C.; ''Nodal and activin receptor-like kinase 7 induce apoptosis in human breast cancer cell lines: Role of caspase 3.''; PubMed Europe PMC Scholia
  8. Constam DB.; ''Regulation of TGFβ and related signals by precursor processing.''; PubMed Europe PMC Scholia
  9. Yeo CY, Chen X, Whitman M.; ''The role of FAST-1 and Smads in transcriptional regulation by activin during early Xenopus embryogenesis.''; PubMed Europe PMC Scholia
  10. Bondestam J, Huotari MA, Morén A, Ustinov J, Kaivo-Oja N, Kallio J, Horelli-Kuitunen N, Aaltonen J, Fujii M, Moustakas A, Ten Dijke P, Otonkoski T, Ritvos O.; ''cDNA cloning, expression studies and chromosome mapping of human type I serine/threonine kinase receptor ALK7 (ACVR1C).''; PubMed Europe PMC Scholia
  11. 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.''; PubMed Europe PMC Scholia
  12. Chen X, Weisberg E, Fridmacher V, Watanabe M, Naco G, Whitman M.; ''Smad4 and FAST-1 in the assembly of activin-responsive factor.''; PubMed Europe PMC Scholia
  13. DaCosta Byfield S, Major C, Laping NJ, Roberts AB.; ''SB-505124 is a selective inhibitor of transforming growth factor-beta type I receptors ALK4, ALK5, and ALK7.''; PubMed Europe PMC Scholia
  14. Chen X, Rubock MJ, Whitman M.; ''A transcriptional partner for MAD proteins in TGF-beta signalling.''; PubMed Europe PMC Scholia
  15. 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.''; PubMed Europe PMC Scholia
  16. Chen C, Shen MM.; ''Two modes by which Lefty proteins inhibit nodal signaling.''; PubMed Europe PMC Scholia
  17. Schmierer B, Hill CS.; ''Kinetic analysis of Smad nucleocytoplasmic shuttling reveals a mechanism for transforming growth factor beta-dependent nuclear accumulation of Smads.''; PubMed Europe PMC Scholia
  18. Dai F, Duan X, Liang YY, Lin X, Feng XH.; ''Coupling of dephosphorylation and nuclear export of Smads in TGF-beta signaling.''; PubMed Europe PMC Scholia
  19. Piccolo S, Agius E, Leyns L, Bhattacharyya S, Grunz H, Bouwmeester T, De Robertis EM.; ''The head inducer Cerberus is a multifunctional antagonist of Nodal, BMP and Wnt signals.''; PubMed Europe PMC Scholia
  20. ''''; PubMed Europe PMC Scholia
  21. Qin BY, Chacko BM, Lam SS, de Caestecker MP, Correia JJ, Lin K.; ''Structural basis of Smad1 activation by receptor kinase phosphorylation.''; PubMed Europe PMC Scholia
  22. 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.''; PubMed Europe PMC Scholia
  23. 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.''; PubMed Europe PMC Scholia
  24. Reissmann E, Jörnvall H, Blokzijl A, Andersson O, Chang C, Minchiotti G, Persico MG, Ibáñez CF, Brivanlou AH.; ''The orphan receptor ALK7 and the Activin receptor ALK4 mediate signaling by Nodal proteins during vertebrate development.''; PubMed Europe PMC Scholia
  25. Shen MM.; ''Nodal signaling: developmental roles and regulation.''; PubMed Europe PMC Scholia
  26. Zhou S, Zawel L, Lengauer C, Kinzler KW, Vogelstein B.; ''Characterization of human FAST-1, a TGF beta and activin signal transducer.''; PubMed Europe PMC Scholia
  27. Aykul S, Ni W, Mutatu W, Martinez-Hackert E.; ''Human Cerberus prevents nodal-receptor binding, inhibits nodal signaling, and suppresses nodal-mediated phenotypes.''; PubMed Europe PMC Scholia
  28. Yeo C, Whitman M.; ''Nodal signals to Smads through Cripto-dependent and Cripto-independent mechanisms.''; PubMed Europe PMC Scholia
  29. 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.''; PubMed Europe PMC Scholia
  30. Xu L, Chen YG, Massagué J.; ''The nuclear import function of Smad2 is masked by SARA and unmasked by TGFbeta-dependent phosphorylation.''; PubMed Europe PMC Scholia
  31. Xu G, Zhong Y, Munir S, Yang BB, Tsang BK, Peng C.; ''Nodal induces apoptosis and inhibits proliferation in human epithelial ovarian cancer cells via activin receptor-like kinase 7.''; PubMed Europe PMC Scholia
  32. Schier AF.; ''Nodal morphogens.''; PubMed Europe PMC Scholia
  33. 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.''; PubMed Europe PMC Scholia
  34. Hill CS.; ''Nucleocytoplasmic shuttling of Smad proteins.''; PubMed Europe PMC Scholia
  35. 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.''; PubMed Europe PMC Scholia
  36. Jörnvall H, Reissmann E, Andersson O, Mehrkash M, Ibáñez CF.; ''ALK7, a receptor for nodal, is dispensable for embryogenesis and left-right patterning in the mouse.''; PubMed Europe PMC Scholia


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101202view11:10, 1 November 2018ReactomeTeamreactome version 66
100740view20:34, 31 October 2018ReactomeTeamreactome version 65
100284view19:11, 31 October 2018ReactomeTeamreactome version 64
99830view15:55, 31 October 2018ReactomeTeamreactome version 63
99387view14:33, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99085view12:39, 31 October 2018ReactomeTeamreactome version 62
93877view13:42, 16 August 2017ReactomeTeamreactome version 61
93444view11:23, 9 August 2017ReactomeTeamreactome version 61
87178view19:55, 18 July 2016EgonwOntology Term : 'signaling pathway' added !
86535view09:20, 11 July 2016ReactomeTeamreactome version 56
83277view10:37, 18 November 2015ReactomeTeamVersion54
81396view12:55, 21 August 2015ReactomeTeamVersion53
76863view08:13, 17 July 2014ReactomeTeamFixed remaining interactions
76568view11:55, 16 July 2014ReactomeTeamFixed remaining interactions
75901view09:55, 11 June 2014ReactomeTeamRe-fixing comment source
75602view10:45, 10 June 2014ReactomeTeamReactome 48 Update
74957view13:48, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74601view08:39, 30 April 2014ReactomeTeamNew pathway

External references


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NameTypeDatabase referenceComment
ACVR1B ProteinP36896 (Uniprot-TrEMBL)
ACVR1C ProteinQ8NER5 (Uniprot-TrEMBL)
ACVR2A ProteinP27037 (Uniprot-TrEMBL)
ACVR2B ProteinQ13705 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activin Response ElementR-ALL-1225892 (Reactome) The inferred consensus sequence of the activin response element is TGT(G/T)(G/T)ATT (Zhou et al. 1998).
Activin Response Element R-ALL-1225892 (Reactome) The inferred consensus sequence of the activin response element is TGT(G/T)(G/T)ATT (Zhou et al. 1998).
CER1 ProteinO95813 (Uniprot-TrEMBL)
CER1,2ComplexR-HSA-8932534 (Reactome)
CERBERUS:NODALComplexR-HSA-1181341 (Reactome)
DAND5 ProteinQ8N907 (Uniprot-TrEMBL)
DRAP1 ProteinQ14919 (Uniprot-TrEMBL)
FOXH1 ProteinO75593 (Uniprot-TrEMBL)
FOXH1:DRAP1ComplexR-HSA-1226031 (Reactome)
FOXH1ProteinO75593 (Uniprot-TrEMBL)
FOXO3 ProteinO43524 (Uniprot-TrEMBL)
FOXO3ProteinO43524 (Uniprot-TrEMBL)
FURIN ProteinP09958 (Uniprot-TrEMBL)
FURIN, PACE4ComplexR-HSA-1181135 (Reactome)
FoxO3a-binding ElementR-ALL-1535904 (Reactome) The consensus sequence bound by FoxO3a is TTGTTTCA.
FoxO3a-binding Element R-ALL-1535904 (Reactome) The consensus sequence bound by FoxO3a is TTGTTTCA.
GDF1 ProteinP27539 (Uniprot-TrEMBL)
LEFTY1 ProteinO75610 (Uniprot-TrEMBL)
LEFTY1,2:NODAL ReceptorComplexR-HSA-1181346 (Reactome)
LEFTY1,2:NODALComplexR-HSA-1181340 (Reactome)
LEFTY1,2ComplexR-HSA-1181332 (Reactome)
LEFTY2(22-366) ProteinO00292 (Uniprot-TrEMBL)
N-aspartyl-glycosylphosphatidylinositolethanolamine-CFC1 ProteinP0CG37 (Uniprot-TrEMBL)
N-aspartyl-glycosylphosphatidylinositolethanolamine-TDGF1(31-188) ProteinP13385 (Uniprot-TrEMBL)
NODAL Ligand:NODAL ReceptorComplexR-HSA-1181133 (Reactome)
NODAL ProteinQ96S42 (Uniprot-TrEMBL)
NODAL ReceptorComplexR-HSA-1181125 (Reactome)
NODAL dimer, NODAL:GDF1ComplexR-HSA-1226027 (Reactome)
NODAL dimerComplexR-HSA-1181130 (Reactome)
NODAL(27-347) ProteinQ96S42 (Uniprot-TrEMBL)
NODAL(27-347) dimerComplexR-HSA-6788947 (Reactome)
NODAL:ACVR1B:ACVR2A,B:EGF-CFCComplexR-HSA-1225875 (Reactome)
NODAL:ACVR1C:ACVR2B:EGF-CFCComplexR-HSA-1225912 (Reactome)
NODAL:p-ACVR1B:ACVR2:EGF-CFCComplexR-HSA-1225883 (Reactome)
NODAL:p-ACVR1C:ACVR2B:EGF-CFCComplexR-HSA-1225915 (Reactome)
NODAL:p-NODAL ReceptorComplexR-HSA-1181134 (Reactome)
PCSK6 ProteinP29122 (Uniprot-TrEMBL)
SMAD2 ProteinQ15796 (Uniprot-TrEMBL)
SMAD2,3:SMAD4:FOXH1:Activin Response ElementComplexR-HSA-1225870 (Reactome)
SMAD2,3:SMAD4:FOXO3:FoxO3a-binding ElementComplexR-HSA-1535906 (Reactome)
SMAD2/3ComplexR-HSA-171172 (Reactome)
SMAD3 ProteinP84022 (Uniprot-TrEMBL)
SMAD4 ProteinQ13485 (Uniprot-TrEMBL)
SMAD4ProteinQ13485 (Uniprot-TrEMBL)
TDGF1P3 ProteinP51864 (Uniprot-TrEMBL)
p-2S-SMAD2/3:SMAD4ComplexR-HSA-171175 (Reactome)
p-2S-SMAD2/3:SMAD4ComplexR-HSA-173511 (Reactome)
p-2S-SMAD2/3ComplexR-HSA-171182 (Reactome)
p-4S,T188,T206-ACVR1B ProteinP36896 (Uniprot-TrEMBL)
p-S423,S425-SMAD3 ProteinP84022 (Uniprot-TrEMBL)
p-S465,S467-SMAD2 ProteinQ15796 (Uniprot-TrEMBL)
p-T175,S177,S179,S181,T194-ACVR1C ProteinQ8NER5 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-1181156 (Reactome)
ADPArrowR-HSA-1181355 (Reactome)
ADPArrowR-HSA-1225894 (Reactome)
ATPR-HSA-1181156 (Reactome)
ATPR-HSA-1181355 (Reactome)
ATPR-HSA-1225894 (Reactome)
Activin Response ElementR-HSA-1225919 (Reactome)
CER1,2R-HSA-1181354 (Reactome)
CER1,2TBarR-HSA-1181155 (Reactome)
CERBERUS:NODALArrowR-HSA-1181354 (Reactome)
FOXH1:DRAP1TBarR-HSA-1225919 (Reactome)
FOXH1R-HSA-1225919 (Reactome)
FOXO3R-HSA-1535903 (Reactome)
FURIN, PACE4mim-catalysisR-HSA-1181152 (Reactome)
FoxO3a-binding ElementR-HSA-1535903 (Reactome)
LEFTY1,2:NODAL ReceptorArrowR-HSA-1181351 (Reactome)
LEFTY1,2:NODALArrowR-HSA-1181352 (Reactome)
LEFTY1,2R-HSA-1181351 (Reactome)
LEFTY1,2R-HSA-1181352 (Reactome)
LEFTY1,2TBarR-HSA-1181155 (Reactome)
NODAL Ligand:NODAL ReceptorArrowR-HSA-1181155 (Reactome)
NODAL ReceptorR-HSA-1181155 (Reactome)
NODAL ReceptorR-HSA-1181351 (Reactome)
NODAL dimer, NODAL:GDF1R-HSA-1181155 (Reactome)
NODAL dimerArrowR-HSA-1181152 (Reactome)
NODAL dimerR-HSA-1181352 (Reactome)
NODAL dimerR-HSA-1181354 (Reactome)
NODAL(27-347) dimerR-HSA-1181152 (Reactome)
NODAL:ACVR1B:ACVR2A,B:EGF-CFCmim-catalysisR-HSA-1181156 (Reactome)
NODAL:ACVR1C:ACVR2B:EGF-CFCmim-catalysisR-HSA-1225894 (Reactome)
NODAL:p-ACVR1B:ACVR2:EGF-CFCArrowR-HSA-1181156 (Reactome)
NODAL:p-ACVR1C:ACVR2B:EGF-CFCArrowR-HSA-1225894 (Reactome)
NODAL:p-NODAL Receptormim-catalysisR-HSA-1181355 (Reactome)
R-HSA-1181152 (Reactome) Either FURIN or PACE4 endoproteases cleave the 321 amino acid NODAL proprotein to yield the 110 amino acid NODAL mature protein. In cultured mouse cells the CRIPTO coreceptor at the plasma membrane recruits both NODAL proprotein and FURIN or PACE4 endoprotease.
R-HSA-1181155 (Reactome) NODAL binds a receptor comprising a type I activin receptor (ACVR1B or ACVR1C), a type II activin receptor (ACVR2 or ACVR2B), and a EGF-CFC coreceptor (CRIPTO or CRYPTIC). Though NODAL is able to signal via the ACVR1C (ALK7) receptor (Reissman et al. 2001), experiments in mouse indicate NODAL signaling via ALK7 is dispensable during embryogenesis (Jornvall et al. 2004).
R-HSA-1181156 (Reactome) As inferred from the response of the activin receptor to activin, the type II component of the NODAL receptor phosphorylates the type I component in response to NODAL binding. Experiments with human proteins in frog oocytes show NODAL can signal via the CRIPTO:ACVR1B(ALK4):ACVR2 complex (Yeo and Whitman 2001).
R-HSA-1181351 (Reactome) LEFTY1 and LEFTY2 are able to inhibit NODAL signaling by binding the EGF-CFC coreceptor (CRIPTO or CRYPTIC) and thereby preventing the coreceptor from interacting with other components of the NODAL receptor.
R-HSA-1181352 (Reactome) As inferred from mouse (Chen and Shen 2004) both LEFTY1 and LEFTY2 can bind NODAL and inhibit NODAL signaling. The stoichiometry of the resulting LEFTY:NODAL complex is unknown.
R-HSA-1181354 (Reactome) As inferred from Xenopus (Piccolo 1999) and as observed in human cells (Aykul et al. 2015) CERBERUS binds NODAL and inhibits NODAL signaling. CERBERUS and NODAL are believed to bind as dimer to form a tetrameric complex (Aykul et al. 2015)
R-HSA-1181355 (Reactome) NODAL receptors signal by phosphorylating SMAD2 and SMAD3 (Bondestam et al. 2001, Kumar et al. 2001, DaCosta Byfield et al. 2004). As in TGF-beta signaling, Smad anchor for receptor activation (SARA) may bind and present SMAD2 and SMAD3 for phosphorylation but this has not yet been demonstrated in NODAL signaling.
R-HSA-1225894 (Reactome) As inferred from the response of the activin receptor to activin, the type II component of the NODAL receptor phosphorylates the type I component in response to NODAL binding. As inferred from mouse and frog (Xenopus) NODAL can signal via the ACVR1C (ALK7) type I activin receptor (Reissman et al. 2001) though this may be dispensable for development in mouse (Jornvall et al. 2004).
R-HSA-1225919 (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.
R-HSA-1535903 (Reactome) FOXO3 (FOXO3A) interacts with phospho-SMAD2 and phospho-SMAD3 complexed with CO-SMAD (SMAD4) at a promoter containing the FoxO3a-binding Element (Fu and Peng 20110).
R-HSA-170847 (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).
R-HSA-173488 (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).
SMAD2,3:SMAD4:FOXH1:Activin Response ElementArrowR-HSA-1225919 (Reactome)
SMAD2,3:SMAD4:FOXO3:FoxO3a-binding ElementArrowR-HSA-1535903 (Reactome)
SMAD2/3R-HSA-1181355 (Reactome)
SMAD4R-HSA-170847 (Reactome)
p-2S-SMAD2/3:SMAD4ArrowR-HSA-170847 (Reactome)
p-2S-SMAD2/3:SMAD4ArrowR-HSA-173488 (Reactome)
p-2S-SMAD2/3:SMAD4R-HSA-1225919 (Reactome)
p-2S-SMAD2/3:SMAD4R-HSA-1535903 (Reactome)
p-2S-SMAD2/3:SMAD4R-HSA-173488 (Reactome)
p-2S-SMAD2/3ArrowR-HSA-1181355 (Reactome)
p-2S-SMAD2/3R-HSA-170847 (Reactome)
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