Reactome | TGF-beta receptor signaling activates SMADs

TGF-beta receptor signaling activates SMADs

Stable Identifier

R-HSA-2173789

Type

Pathway

Species

Homo sapiens

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TGF-beta receptor signaling activates SMADs

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Binding of transforming growth factor beta 1 (TGF beta 1, i.e. TGFB1) to TGF beta receptor type 2 (TGFBR2) activates TGF beta receptor signaling cascade. TGFB1 is posttranslationally processed by furin (Dubois et al. 1995) to form a homodimer and secreted to the extracellular space as part of the large latent complex (LLC). After the LLC disassembles in the extracellular space, dimeric TGFB1 becomes capable of binding to TGFBR2 (Annes et al. 2003, Keski Oja et al. 2004). Formation of TGFB1:TGFBR2 complex creates a binding pocket for TGF-beta receptor type-1 (TGFBR1) and TGFBR1 is recruited to the complex by binding to both TGFB1 and TGFBR2. This results in an active heterotetrameric TGF-beta receptor complex that consists of TGFB1 homodimer bound to two heterodimers of TGFBR1 and TGFBR2 (Wrana et al. 1992, Moustakas et al. 1993, Franzen et al. 1993). TGF-beta signaling can also occur through a single heterodimer of TGFBR1 and TGFBR2, although with decreased efficiency (Huang et al. 2011). TGFBR1 and TGFBR2 interact through their extracellular domains, which brings their cytoplasmic domains together. Ligand binding to extracellular receptor domains is cooperative, but no conformational change is seen from crystal structures of either TGFB1- or TGFB3-bound heterotetrameric receptor complexes (Groppe et al. 2008, Radaev et al. 2010).

Activation of TGFBR1 by TGFBR2 in the absence of ligand is prevented by FKBP1A (FKBP12), a peptidyl-prolyl cis-trans isomerase. FKBP1A forms a complex with inactive TGFBR1 and dissociates from it only after TGFBR1 is recruited by TGFB1-bound TGFBR2 (Chen et al. 1997).

Both TGFBR1 and TGFBR2 are receptor serine/threonine kinases. Formation of the hetero-tetrameric TGF-beta receptor complex (TGFBR) in response to TGFB1 binding induces receptor rotation, so that TGFBR2 and TGFBR1 cytoplasmic kinase domains face each other in a catalytically favourable configuration. TGFBR2 trans-phosphorylates serine residues at the conserved Gly-Ser-rich juxtapositioned domain (GS domain) of TGFBR1 (Wrana et al. 1994, Souchelnytskyi et al. 1996), activating TGFBR1.
In addition to phosphorylation, TGFBR1 may also be sumoylated in response to TGF-beta stimulation. Sumoylation enhances TGFBR1 kinase activity (Kang et al. 2008).

The activated TGFBR complex is internalized by clathrin-mediated endocytosis into early endosomes. With the assistance of SARA, an early endosome membrane protein, phosphorylated TGFBR1 within TGFBR complex recruits SMAD2 and/or SMAD3 , i.e. R-SMADs (Tsukazaki et al. 1998). TGFBR1 phosphorylates recruited SMAD2/3 on two C-terminal serine residues (Souchelnytskyi et al. 2001). The phosphorylation changes the conformation of SMAD2/3 MH2 domain, promoting dissociation of SMAD2/3 from SARA and TGFBR1 (Souchelnytskyi et al. 1997, Macias-Silva et al. 1996, Nakao et al. 1997) and formation of SMAD2/3 trimers (Chacko et al. 2004). The phosphorylated C-terminal tail of SMAD2/3 has high affinity for SMAD4 (Co-SMAD), inducing formation of SMAD2/3:SMAD4 heterotrimers, composed of two phosphorylated R-SMADs (SMAD2 and/or SMAD3) and SMAD4 (Co-SMAD). SMAD2/3:SMAD4 heterotrimers are energetically favored over R-SMAD trimers (Nakao et al. 1997, Qin et al. 2001, Kawabata et al. 1998, Chacko et al. 2004).
SMAD2/3:SMAD4 heterotrimers translocate to the nucleus where they act as transcriptional regulators.

Literature References

PubMed ID	Title	Journal	Year
1333888	TGF beta signals through a heteromeric protein kinase receptor complex Wrana, JL, Attisano, L, Carcamo, J, Zentella, A, Doody, J, Laiho, M, Wang, XF, Massague, J	Cell	1992
11100470	Phosphorylation of Smad signaling proteins by receptor serine/threonine kinases Souchelnytskyi, S, Rönnstrand, L, Heldin, CH, ten Dijke, P	Methods Mol Biol	2001
9346966	Phosphorylation of Ser465 and Ser467 in the C terminus of Smad2 mediates interaction with Smad4 and is required for transforming growth factor-beta signaling Souchelnytskyi, S, Tamaki, K, Engstrom, U, Wernstedt, C, ten Dijke, P, Heldin, CH	J Biol Chem	1997
7693660	The transforming growth factor beta receptors types I, II, and III form hetero-oligomeric complexes in the presence of ligand Moustakas, A, Lin, HY, Henis, YI, Plamondon, J, O'Connor-McCourt, MD, Lodish, HF	J Biol Chem	1993
8980228	MADR2 is a substrate of the TGFbeta receptor and its phosphorylation is required for nuclear accumulation and signaling Macias-Silva, M, Abdollah, S, Hoodless, PA, Pirone, R, Attisano, L, Wrana, JL	Cell	1996
21423151	TGF-? signalling is mediated by two autonomously functioning T?RI:T?RII pairs Huang, T, David, L, Mendoza, V, Yang, Y, Villarreal, M, De, K, Sun, L, Fang, X, López-Casillas, F, Wrana, JL, Hinck, AP	EMBO J.	2011
9865696	SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor Tsukazaki, T, Chiang, TA, Davison, AF, Attisano, L, Wrana, JL	Cell	1998
11779505	Structural basis of Smad1 activation by receptor kinase phosphorylation Qin, BY, Chacko, BM, Lam, SS, de Caestecker, MP, Correia, JJ, Lin, K	Mol Cell	2001
8242743	Cloning of a TGF beta type I receptor that forms a heteromeric complex with the TGF beta type II receptor Franzen, P, ten Dijke, P, Ichijo, H, Yamashita, H, Schulz, P, Heldin, CH, Miyazono, K	Cell	1993
9311995	TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4 Nakao, A, Souchelnytskyi, S, Kawabata, M, Ishisaki, A, Oeda, E, Tamaki, K, Hanai, J, Heldin, CH, Miyazono, K, ten Dijke, P	EMBO J	1997
9233797	Mechanism of TGFbeta receptor inhibition by FKBP12 Chen, YG, Liu, F, Massague, J	EMBO J	1997
20207738	Ternary complex of transforming growth factor-beta1 reveals isoform-specific ligand recognition and receptor recruitment in the superfamily Radaev, S, Zou, Z, Huang, T, Lafer, EM, Hinck, AP, Sun, PD	J. Biol. Chem.	2010
18243111	Cooperative assembly of TGF-beta superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding Groppe, J, Hinck, CS, Samavarchi-Tehrani, P, Zubieta, C, Schuermann, JP, Taylor, AB, Schwarz, PM, Wrana, JL, Hinck, AP	Mol. Cell	2008
15564041	TGF-beta activation by traction? Keski-Oja, J, Koli, K, von Melchner, H	Trends Cell Biol	2004
8047140	Mechanism of activation of the TGF-beta receptor Wrana, JL, Attisano, L, Wieser, R, Ventura, F, Massague, J	Nature	1994
12482908	Making sense of latent TGFbeta activation Annes, JP, Munger, JS, Rifkin, DB	J Cell Sci	2003
15350224	Structural basis of heteromeric smad protein assembly in TGF-beta signaling Chacko, BM, Qin, BY, Tiwari, A, Shi, G, Lam, S, Hayward, LJ, De Caestecker, M, Lin, K	Mol Cell	2004
7737999	Processing of transforming growth factor beta 1 precursor by human furin convertase Dubois, CM, Laprise, MH, Blanchette, F, Gentry, LE, Leduc, R	J Biol Chem	1995
9670020	Smad proteins exist as monomers in vivo and undergo homo- and hetero-oligomerization upon activation by serine/threonine kinase receptors Kawabata, M, Inoue, H, Hanyu, A, Imamura, T, Miyazono, K	EMBO J	1998
8947046	Phosphorylation of Ser165 in TGF-beta type I receptor modulates TGF-beta1-induced cellular responses Souchelnytskyi, S, ten Dijke, P, Miyazono, K, Heldin, CH	EMBO J	1996