• type I receptors require type II receptors for ligand binding and signal.
• type II receptors bind ligands even in the absence of type I receptors but require type I receptors for signaling.
• receptorregulated (R) Smads are direct substrates of type I receptors
• activin/TGF-b-specific R-Smads (AR-Smads) : SMAD2 / MADH2 and SMAD3 / MADH3 are specifically activated by activin/nodal and TGF-b type I receptors
• BMP-specific R-Smads (BR-Smads) : SMAD1 / MADH1, SMAD5 / MADH5, SMAD8 / MADH8 and SMAD9 / MADH9 are activated by BMP type I receptors.
R-Smads form complexes with common-mediator Smad (Co-Smads) (SMAD4 / MADH4) and translocate into the nucleus, where they regulate the transcription of target genes : Id proteins (ID1, ID2, ID3, ID4) are induced by BR-Smads, and play important roles in exhibiting some biological effects of BMPs. Smad1 and Smad5 related with transcription factors included core binding factor A1 (CBFA1), smad-interacting protein 1 (SIP1), ornithine decarboxylase antizyme (OAZ), activating protein-1 (AP-1), xenopus ventralizing homeobox protein-2 (Xvent-2), sandostatin (Ski), antiproliferative proteins (Tob), and homeodomain-containing transcriptian factor-8 (Hoxc-8), et al. CBFA1 could interact with Smad1, Smad2, Smad3, and Smad5, so it was involved in TGF-b and BMP-2 signal transduction, and played an important role in the bone formation.
• 3 levels by which this signaling pathway is regulated could be distinguished :
• a control mechanism exists in the intracellular space, where inhibitory (I) Smads  (SMAD6 / MADH6 and SMAD7 / MADH7) and Smurfs (SMURF1, SMURF2) prevent further signaling and activation of target genes
• at the membrane site, the pseudoreceptor BAMBI/Nma is able to inhibit further signaling within the cells
• a range of extracellular mediators are identified which modulate the functioning of members of the TGF-b superfamily

receptor serine/threonine kinase name		expressed on ...	ligand(s)	agonists	antagonists
TGF-b-R type I receptor type II receptor type III receptor / accessory molecule b-glycan CD105 / endoglin, a homodimeric transmembrane glycoprotein highly expressed by endothelial cells. It is a component of the TGF-b receptor complex as it binds TGF-b1 and TGF-b3 with high affinity			TGF-b1 TGF-b2 TGF-b3		SD-208 (kinase inhibitor)
activins and inhibin receptor type I receptor I / ALK2 IB / ALK4 IC / ALK7 type II receptor II IIB  II-like 1 /ALK1			inhibin activin A activin AB NODAL
BMP receptor type I receptor IA / ALK3 IB / ALK6  type II receptor			BMP1 BMP2 BMP3 BMP4 BMP5 BMP6 BMP7 BMP8 BMP9 BMP10 BMP11 BMP15
decoy receptors	noggin (by diffusing through extracellular matrices more efficiently than members of the TGF-b superfamily, noggin may have a principal role in creating morphogenic gradients)
	chordin (a key developmental protein that dorsalizes early vertebrate embryonic tissues by binding to ventralizing TGF-b-like bone morphogenetic proteins and sequestering them in latent complexes)
	twisted gastrulation 1 (TWSG1)
	gremlin (moderates signaling by BMPs during limb outgrowth to maintain the signaling loop between the zone of polarizing activity (ZPA) and the apical ectodermal ridge (AER))
AMHR, type 2		mesenchymal cells adjacent to the Mullerian duct epithelium (temporally and spatially regulated during development : becomes restricted to the most caudal ends that fuse to form the prostatic utricle), normal prostate, human prostate adenocarcinomas, Sertoli and granulosa cells of the fetal and adult, male and female gonads	Mullerian inhibiting factor (MIF) / Mullerian inhibiting substance (MIS) / anti-Mullerian hormone (AMH)

Web resources :

• Attisano and Wrana Lab on signaling by the TGF-b superfamily
• The IFNg and TGFb signaling pathways

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