PathwayStep6346 PathwayStep6341 PathwayStep6340 PathwayStep6342 PathwayStep6337 PathwayStep6338 PathwayStep6339 PathwayStep110 PathwayStep109 Phosphorylation of R-SMAD2/3 by NODAL Receptor Phospho R-SMAD(SMAD2/3):CO-SMAD(SMAD4):FOXO3 Binds FoxO3a-binding Elements Type II Activin Receptor (ActRII/ACVR2) Phosphorylates Type I Activin Receptor (ActRIB/ACVR1B) in Response to NODAL Type II Activin Receptor (ActRIIB/ACVR2B) Phosphorylates Type I Activin Receptor (ActRIC/ACVR1C) in Response to NODAL Cleavage of NODAL Proprotein The NODAL Receptor Binds NODAL Ligands Phosphorylated SMAD2 and SMAD3 form a complex with SMAD4 The SMAD2/3:SMAD4 complex transfers to the nucleus Phospho R-SMAD(SMAD2/3):CO-SMAD(SMAD4):FOXH1 Binds Activin Response Element PathwayStep5935 Signaling by NODAL Authored: May, B, 2011-01-23 Edited: May, B, 2011-01-23 Pubmed17287255 Pubmed20066122 Reactome Database ID Release 431181150 Reactome, http://www.reactome.org ReactomeREACT_111057 Reviewed: Peng, C, 2011-08-24 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. Regulation of Signaling by NODAL