Regulation of TGF-β receptor activity

Transforming growth factor-β (TGF-β) family, including TGF-β, activin, Nodal, bone morphogenetic proteins (BMPs) and others, play vital roles in development, tissue homeostasis and some diseases development [1-3]. TGF-β signaling is initiated by the binding of TGF-β to its serine and threonine kinase receptors, the type II (TβRII) and type I (TβRI) receptors on the cell membrane. Ligand binding leads to formation of the receptor heterocomplex, in which TβRII phosphorylates threonine and serine residues in the TTSGSGSG motif of TβRI and thus activates TβRI [2,4]. The activated TβRI recruits and phosphorylates the R-Smad proteins, Smad2/3 for TGF-β and activin signaling while Smad1/5/8 for BMP signaling, which then form a heterocomplex with the Co-Smad Smad4 [5,6]. The Smad complexes are then translocated into the nucleus to regulate transcription of the target genes in cooperation with other co-factors [5,7,8]. For each member of the TGF-β family, they have their own type I and type II receptors. Among the seven type I receptors, which are also called as activin receptor-like kinases (ALKs), TβRI/ALK5 can mediate TGF-β signaling with the TGF-β type II receptor TβRII to activate Smad2/3 in universal cell types, while in endothelial cells ALK1 functions with TβRII to activate Smad1/5/8 for TGF-β signaling [8-10]. In response to BMPs, ALK2/3/6 can activate Smad1/5/8 with the type II receptors BMPRII, ActRII and ActRIIB [11,12]. ALK4/7 can activate Smad2/3 with ActRII and ActRIIB to mediate activin/Nodal signaling [13]. In this review, we mainly discuss the regulation mechanisms of TGF-β signaling receptors.In addition to activating Smad2/3, TGF-β can also activate mitogen-activating protein kinases (MAPKs) (ERK, p38 and JNK), phosphatidylinositol 3 kinase (PI3K)/Akt and small GTPases in a context-dependent manner [14-17]. Furthermore, despite the fact that TGF-β can activate Smad1/5/8 in endothelial cells which requires ALK1 [18,19], it can also activate Smad1/5/8 in ot