Signaling by NODAL (Homo sapiens)

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1. 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
2. Constam DB.; ''Regulation of TGFβ and related signals by precursor processing.''; PubMed Europe PMC Scholia
3. 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
4. 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
5. 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
6. 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
7. 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
8. Yeo C, Whitman M.; ''Nodal signals to Smads through Cripto-dependent and Cripto-independent mechanisms.''; PubMed Europe PMC Scholia
9. Schier AF.; ''Nodal morphogens.''; PubMed Europe PMC Scholia
10. 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
11. 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
12. 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
13. 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
14. 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
15. 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
16. 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
17. 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
18. 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
19. 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
20. Chen X, Rubock MJ, Whitman M.; ''A transcriptional partner for MAD proteins in TGF-beta signalling.''; PubMed Europe PMC Scholia
21. 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
22. Chen C, Shen MM.; ''Two modes by which Lefty proteins inhibit nodal signaling.''; PubMed Europe PMC Scholia
23. 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
24. 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
25. ''''; PubMed Europe PMC Scholia
26. Shen MM.; ''Nodal signaling: developmental roles and regulation.''; PubMed Europe PMC Scholia
27. 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
28. 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
29. 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
30. 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
31. 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
32. Hill CS.; ''Nucleocytoplasmic shuttling of Smad proteins.''; PubMed Europe PMC Scholia
33. 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
34. 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
35. 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
36. 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

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External references

DataNodes

Name	Type	Database reference	Comment
ACVR1B [plasma membrane]	Protein	P36896 (Uniprot-TrEMBL)
ACVR1C [plasma membrane]	Protein	Q8NER5 (Uniprot-TrEMBL)
ACVR2A [plasma membrane]	Protein	P27037 (Uniprot-TrEMBL)
ACVR2B [plasma membrane]	Protein	Q13705 (Uniprot-TrEMBL)
ADP	Metabolite	CHEBI:16761 (ChEBI)
ATP	Metabolite	CHEBI:15422 (ChEBI)
Activin Response Element		REACT_111540 (Reactome)	The inferred consensus sequence of the activin response element is TGT(G/T)(G/T)ATT (Zhou et al. 1998).
CER1 [extracellular region]	Protein	O95813 (Uniprot-TrEMBL)
CER1	Protein	O95813 (Uniprot-TrEMBL)
CERBERUS:NODAL	Complex	REACT_111457 (Reactome)
DRAP1 [nucleoplasm]	Protein	Q14919 (Uniprot-TrEMBL)
FOXH1 [nucleoplasm]	Protein	O75593 (Uniprot-TrEMBL)
FOXH1:DRAP1	Complex	REACT_111401 (Reactome)
FOXH1	Protein	O75593 (Uniprot-TrEMBL)
FOXO3(1-673) [nucleoplasm]	Protein	O43524 (Uniprot-TrEMBL)
FOXO3(1-673)	Protein	O43524 (Uniprot-TrEMBL)
FURIN and PACE4		REACT_111765 (Reactome)
FoxO3a-binding Element		REACT_111770 (Reactome)	The consensus sequence bound by FoxO3a is TTGTTTCA.
GDF1 [extracellular region]	Protein	P27539 (Uniprot-TrEMBL)
LEFTY1 [extracellular region]	Protein	O75610 (Uniprot-TrEMBL)
LEFTY2(22-366) [extracellular region]	Protein	O00292 (Uniprot-TrEMBL)
LEFTY:EGF-CFC:NODAL Receptor	Complex	REACT_111462 (Reactome)
LEFTY:NODAL	Complex	REACT_111269 (Reactome)
LEFTY	Protein	REACT_111534 (Reactome)
N-aspartyl-glycosylphosphatidylinositolethanolamine-CFC1 [plasma membrane]	Protein	P0CG37 (Uniprot-TrEMBL)
N-aspartyl-glycosylphosphatidylinositolethanolamine-TDGF1(31-188) [plasma membrane]	Protein	P13385 (Uniprot-TrEMBL)
NODAL Ligand:NODAL Receptor	Complex	REACT_111368 (Reactome)
NODAL Ligands (Agonists)	Complex	REACT_111841 (Reactome)
NODAL Receptor	Complex	REACT_111355 (Reactome)
NODAL [extracellular region]	Protein	Q96S42 (Uniprot-TrEMBL)
NODAL(27-347)	Protein	Q96S42 (Uniprot-TrEMBL)
NODAL:ACVR1B:ACVR2:EGF-CFC	Complex	REACT_111526 (Reactome)
NODAL:ACVR1C:ACVR2B:EGF-CFC	Complex	REACT_111650 (Reactome)
NODAL:p-ACVR1B:ACVR2:EGF-CFC	Complex	REACT_111458 (Reactome)
NODAL:p-ACVR1C:ACVR2B:EGF-CFC	Complex	REACT_111276 (Reactome)
NODAL:p-NODAL Receptor	Complex	REACT_111362 (Reactome)
NODAL	Protein	Q96S42 (Uniprot-TrEMBL)
SMAD2/3:SMAD4:FOXH1:Activin Response Element	Complex	REACT_111692 (Reactome)
SMAD2/3:SMAD4:FOXO3:FoxO3a-binding Element	Complex	REACT_111746 (Reactome)
SMAD2/3	Protein	REACT_7451 (Reactome)
SMAD4 [cytosol]	Protein	Q13485 (Uniprot-TrEMBL)
SMAD4 [nucleoplasm]	Protein	Q13485 (Uniprot-TrEMBL)
SMAD4	Protein	Q13485 (Uniprot-TrEMBL)
p-2S-SMAD2/3:SMAD4	Complex	REACT_7344 (Reactome)
p-2S-SMAD2/3:SMAD4	Complex	REACT_7382 (Reactome)
p-2S-SMAD2/3	Protein	REACT_7364 (Reactome)
p-4S,T188,T206-ACVR1B [plasma membrane]	Protein	P36896 (Uniprot-TrEMBL)
p-S423,S425-SMAD3 [cytosol]	Protein	P84022 (Uniprot-TrEMBL)
p-S423,S425-SMAD3 [nucleoplasm]	Protein	P84022 (Uniprot-TrEMBL)
p-S465,S467-SMAD2 [cytosol]	Protein	Q15796 (Uniprot-TrEMBL)
p-S465,S467-SMAD2 [nucleoplasm]	Protein	Q15796 (Uniprot-TrEMBL)
p-T175,S177,S179,S181,T194-ACVR1C [plasma membrane]	Protein	Q8NER5 (Uniprot-TrEMBL)

Annotated Interactions

Source	Target	Type	Database reference	Comment
	ADP	Arrow	REACT_111130 (Reactome)
	ADP	Arrow	REACT_111131 (Reactome)
	ADP	Arrow	REACT_111138 (Reactome)
ATP			REACT_111130 (Reactome)
ATP			REACT_111131 (Reactome)
ATP			REACT_111138 (Reactome)
Activin Response Element			REACT_111132 (Reactome)
CER1			REACT_111227 (Reactome)
	CERBERUS:NODAL	Arrow	REACT_111227 (Reactome)
FOXH1:DRAP1		TBar	REACT_111132 (Reactome)
FOXH1			REACT_111132 (Reactome)
FOXO3(1-673)			REACT_111216 (Reactome)
FURIN and PACE4		mim-catalysis	REACT_111228 (Reactome)
FoxO3a-binding Element			REACT_111216 (Reactome)
	LEFTY:EGF-CFC:NODAL Receptor	Arrow	REACT_111240 (Reactome)
	LEFTY:NODAL	Arrow	REACT_111188 (Reactome)
LEFTY			REACT_111188 (Reactome)
LEFTY			REACT_111240 (Reactome)
	NODAL Ligand:NODAL Receptor	Arrow	REACT_111250 (Reactome)
NODAL Ligands (Agonists)			REACT_111250 (Reactome)
NODAL Receptor			REACT_111240 (Reactome)
NODAL Receptor			REACT_111250 (Reactome)
NODAL(27-347)			REACT_111228 (Reactome)
NODAL:ACVR1B:ACVR2:EGF-CFC			REACT_111131 (Reactome)
NODAL:ACVR1B:ACVR2:EGF-CFC		mim-catalysis	REACT_111131 (Reactome)
NODAL:ACVR1C:ACVR2B:EGF-CFC			REACT_111130 (Reactome)
NODAL:ACVR1C:ACVR2B:EGF-CFC		mim-catalysis	REACT_111130 (Reactome)
	NODAL:p-ACVR1B:ACVR2:EGF-CFC	Arrow	REACT_111131 (Reactome)
	NODAL:p-ACVR1C:ACVR2B:EGF-CFC	Arrow	REACT_111130 (Reactome)
NODAL:p-NODAL Receptor		mim-catalysis	REACT_111138 (Reactome)
	NODAL	Arrow	REACT_111228 (Reactome)
NODAL			REACT_111188 (Reactome)
NODAL			REACT_111227 (Reactome)
			REACT_111130 (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).
			REACT_111131 (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).
			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_111138 (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.
			REACT_111188 (Reactome)	As inferred from mouse (Chen and Shen 2004) both LEFTY1 and LEFTY2 can bind NODAL and inhibit NODAL signaling.
			REACT_111216 (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).
			REACT_111227 (Reactome)	As inferred from Xenopus (Piccolo 1999) CERBERUS binds NODAL and inhibits NODAL signaling.
			REACT_111228 (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.
			REACT_111240 (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.
			REACT_111250 (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).
			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 Element	Arrow	REACT_111132 (Reactome)
	SMAD2/3:SMAD4:FOXO3:FoxO3a-binding Element	Arrow	REACT_111216 (Reactome)
SMAD2/3			REACT_111138 (Reactome)
SMAD4			REACT_6760 (Reactome)
	p-2S-SMAD2/3:SMAD4	Arrow	REACT_6726 (Reactome)
	p-2S-SMAD2/3:SMAD4	Arrow	REACT_6760 (Reactome)
p-2S-SMAD2/3:SMAD4			REACT_111132 (Reactome)
p-2S-SMAD2/3:SMAD4			REACT_111216 (Reactome)
p-2S-SMAD2/3:SMAD4			REACT_6726 (Reactome)
	p-2S-SMAD2/3	Arrow	REACT_111138 (Reactome)
p-2S-SMAD2/3			REACT_6760 (Reactome)