TGF-beta receptor signaling activates SMADs

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Homo sapiens
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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
11100470 Phosphorylation of Smad signaling proteins by receptor serine/threonine kinases

Souchelnytskyi, S, ten Dijke, P, Heldin, CH, Rönnstrand, L

Methods Mol Biol 2001
1333888 TGF beta signals through a heteromeric protein kinase receptor complex

Massague, J, Wrana, JL, Carcamo, J, Laiho, M, Attisano, L, Doody, J, Wang, XF, Zentella, A

Cell 1992
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, Engstrom, U, ten Dijke, P, Heldin, CH, Wernstedt, C, Tamaki, K

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

O'Connor-McCourt, MD, Lodish, HF, Plamondon, J, Henis, YI, Moustakas, A, Lin, HY

J Biol Chem 1993
8980228 MADR2 is a substrate of the TGFbeta receptor and its phosphorylation is required for nuclear accumulation and signaling

Wrana, JL, Attisano, L, Abdollah, S, Hoodless, PA, Pirone, R, Macias-Silva, M

Cell 1996
21423151 TGF-? signalling is mediated by two autonomously functioning T?RI:T?RII pairs

Mendoza, V, Wrana, JL, De, K, Hinck, AP, Villarreal, M, Sun, L, López-Casillas, F, Huang, T, Fang, X, David, L, Yang, Y

EMBO J. 2011
9865696 SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor

Wrana, JL, Attisano, L, Chiang, TA, Davison, AF, Tsukazaki, T

Cell 1998
11779505 Structural basis of Smad1 activation by receptor kinase phosphorylation

Lin, K, Correia, JJ, Chacko, BM, Lam, SS, Qin, BY, de Caestecker, MP

Mol Cell 2001
8242743 Cloning of a TGF beta type I receptor that forms a heteromeric complex with the TGF beta type II receptor

Miyazono, K, Schulz, P, Yamashita, H, Ichijo, H, ten Dijke, P, Heldin, CH, Franzen, P

Cell 1993
9311995 TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4

Nakao, A, Miyazono, K, Souchelnytskyi, S, Ishisaki, A, Kawabata, M, ten Dijke, P, Heldin, CH, Oeda, E, Hanai, J, Tamaki, K

EMBO J 1997
9233797 Mechanism of TGFbeta receptor inhibition by FKBP12

Massague, J, Liu, F, Chen, YG

EMBO J 1997
20207738 Ternary complex of transforming growth factor-beta1 reveals isoform-specific ligand recognition and receptor recruitment in the superfamily

Sun, PD, Lafer, EM, Hinck, AP, Radaev, S, Zou, Z, Huang, T

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

Wrana, JL, Groppe, J, Hinck, AP, Schuermann, JP, Samavarchi-Tehrani, P, Taylor, AB, Schwarz, PM, Zubieta, C, Hinck, CS

Mol. Cell 2008
15564041 TGF-beta activation by traction?

von Melchner, H, Keski-Oja, J, Koli, K

Trends Cell Biol 2004
8047140 Mechanism of activation of the TGF-beta receptor

Massague, J, Wrana, JL, Wieser, R, Attisano, L, Ventura, F

Nature 1994
12482908 Making sense of latent TGFbeta activation

Annes, JP, Rifkin, DB, Munger, JS

J Cell Sci 2003
15350224 Structural basis of heteromeric smad protein assembly in TGF-beta signaling

Shi, G, De Caestecker, M, Lin, K, Chacko, BM, Hayward, LJ, Tiwari, A, Qin, BY, Lam, S

Mol Cell 2004
7737999 Processing of transforming growth factor beta 1 precursor by human furin convertase

Leduc, R, Blanchette, F, Dubois, CM, Laprise, MH, Gentry, LE

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

Miyazono, K, Inoue, H, Kawabata, M, Imamura, T, Hanyu, A

EMBO J 1998
8947046 Phosphorylation of Ser165 in TGF-beta type I receptor modulates TGF-beta1-induced cellular responses

Miyazono, K, Souchelnytskyi, S, ten Dijke, P, Heldin, CH

EMBO J 1996
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