Downregulation of TGF-beta receptor signaling

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Homo sapiens
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TGF-beta receptor signaling is downregulated by proteasome and lysosome-mediated degradation of ubiquitinated TGFBR1, SMAD2 and SMAD3, as well as by dephosphorylation of TGFBR1, SMAD2 and SMAD3.

In the nucleus, SMAD2/3:SMAD4 complex stimulates transcription of SMAD7, an inhibitory SMAD (I-SMAD). SMAD7 binds phosphorylated TGFBR1 and competes with the binding of SMAD2 and SMAD3 (Hayashi et al. 1997, Nakao et al. 1997). Binding of SMAD7 to TGBR1 can be stabilized by STRAP, a protein that simultaneously binds SMAD7 and TGFBR1 (Datta et al. 2000). BAMBI simultaneously binds SMAD7 and activated TGFBR1, leading to downregulation of TGF-beta receptor complex signaling (Onichtchouk et al. 1999, Yan et al. 2009).

In addition to competing with SMAD2/3 binding to TGFBR1, SMAD7 recruits protein phosphatase PP1 to phosphorylated TGFBR1, by binding to the PP1 regulatory subunit PPP1R15A (GADD34). PP1 dephosphorylates TGFBR1, preventing the activation of SMAD2/3 and propagation of TGF-beta signal (Shi et al. 2004).

SMAD7 associates with several ubiquitin ligases, SMURF1 (Ebisawa et al. 2001, Suzuki et al. 2002, Tajima et al. 2003, Chong et al. 2010), SMURF2 (Kavsak et al. 2000, Ogunjimi et al. 2005), and NEDD4L (Kuratomi et al. 2005), and recruits them to phosphorylated TGFBR1 within TGFBR complex. SMURF1, SMURF2 and NEDD4L ubiquitinate TGFBR1 (and SMAD7), targeting TGFBR complex for proteasome and lysosome-dependent degradation (Ebisawa et al. 2001, Kavsak et al. 2000, Kuratomi et al. 2005). The ubiquitination of TGFBR1 can be reversed by deubiquitinating enzymes, UCHL5 (UCH37) and USP15, which may be recruited to ubiquitinated TGFBR1 by SMAD7 (Wicks et al. 2005, Eichhorn et al. 2012).

Basal levels of SMAD2 and SMAD3 are maintained by SMURF2 and STUB1 ubiquitin ligases. SMURF2 is able to bind and ubiquitinate SMAD2, leading to SMAD2 degradation (Zhang et al. 2001), but this has been questioned by a recent study of Smurf2 knockout mice (Tang et al. 2011). STUB1 (CHIP) binds and ubiquitinates SMAD3, leading to SMAD3 degradation (Li et al. 2004, Xin et al. 2005). PMEPA1 can bind and sequester unphosphorylated SMAD2 and SMAD3, preventing their activation in response to TGF-beta signaling. In addition, PMEPA1 can bind and sequester phosphorylated SMAD2 and SMAD3, preventing formation of SMAD2/3:SMAD4 heterotrimer complexes (Watanabe et al. 2010). A protein phosphatase MTMR4, residing in the membrane of early endosomes, can dephosphorylate activated SMAD2 and SMAD3, preventing formation of SMAD2/3:SMAD4 complexes (Yu et al. 2010).
Literature References
PubMed ID Title Journal Year
22045334 Ablation of Smurf2 reveals an inhibition in TGF-? signalling through multiple mono-ubiquitination of Smad3

Zhang, YE, Coussens, NP, Tang, LY, Li, C, Tang, Y, Deng, CX, Yamashita, M, Cheng, SY, Wang, X

EMBO J 2011
11278251 Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation

Tanaka, K, Chiba, T, Miyazono, K, Murakami, G, Fukuchi, M, Ebisawa, T, Imamura, T

J Biol Chem 2001
11158580 Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase

Zhang, Y, Gehling, DJ, Chang, C, Hemmati-Brivanlou, A, Derynck, R

Proc Natl Acad Sci U S A 2001
14718519 GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor

Shi, X, Sun, C, Cao, X, Yao, D, He, B, Shi, W, Xiong, W

J Cell Biol 2004
20937913 Coupling of tandem Smad ubiquitination regulatory factor (Smurf) WW domains modulates target specificity

Wrana, JL, Lin, H, Chong, PA, Forman-Kay, JD

Proc Natl Acad Sci U S A 2010
12151385 Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane

Miyazono, K, Murakami, G, Shimanuki, T, Fukuchi, M, Shikauchi, Y, Imamura, T, Suzuki, C

J Biol Chem 2002
10757800 STRAP and Smad7 synergize in the inhibition of transforming growth factor beta signaling

Datta, PK, Moses, HL

Mol Cell Biol 2000
16061177 Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain

Briant, DJ, Wrana, JL, Pece-Barbara, N, Sicheri, F, Di Guglielmo, GM, Rasmussen, RK, Ogunjimi, AA, Seet, BT, Le Roy, C, Kavsak, P

Mol Cell 2005
15496141 NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) negatively regulates TGF-beta (transforming growth factor-beta) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-beta type I receptor

Miyazono, K, Goto, K, Kuratomi, G, Shinozaki, M, Imamura, T, Komuro, A, Miyazawa, K

Biochem J 2005
9215638 The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling

Richardson, MA, Wrana, JL, Gimbrone MA, Jr, Topper, JN, Hayashi, H, Xu, YY, Grinnell, BW, Qiu, Y, Abdollah, S, Falb, D, Cai, J

Cell 1997
20061380 MTMR4 attenuates transforming growth factor beta (TGFbeta) signaling by dephosphorylating R-Smads in endosomes

Xu, Y, Yu, J, Chen, Y, Pan, L, Tang, H, Chen, H, Qin, X

J Biol Chem 2010
14701756 CHIP mediates degradation of Smad proteins and potentially regulates Smad-induced transcription

Zhang, S, Fu, XY, Xin, H, Li, L, Zhang, X, Chang, Z, Chen, Y, Xu, X, Huang, M

Mol Cell Biol 2004
10519551 Silencing of TGF-beta signalling by the pseudoreceptor BAMBI

Dosch, R, Onichtchouk, D, Delius, H, Gawantka, V, Niehrs, C, Massagué, J, Chen, YG

Nature 1999
9335507 Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling

Nakao, A, Christian, JL, Itoh, S, Nakayama, T, Heldin, NE, Kawabata, M, Moren, A, ten Dijke, P, Afrakhte, M, Heuchel, R, Heldin, CH

Nature 1997
15781469 CHIP controls the sensitivity of transforming growth factor-beta signaling by modulating the basal level of Smad3 through ubiquitin-mediated degradation

Fu, XY, Xin, H, Li, L, Chang, Z, Rong, Y, Xu, X, Ning, H, Shang, Y, Wang, Y

J Biol Chem 2005
12519765 Chromosomal region maintenance 1 (CRM1)-dependent nuclear export of Smad ubiquitin regulatory factor 1 (Smurf1) is essential for negative regulation of transforming growth factor-beta signaling by Smad7

Yoshida, M, Miyazono, K, Yoneda, Y, Tajima, Y, Shinomiya, K, Goto, K, Sekimoto, T, Imamura, T

J Biol Chem 2003
20129061 TMEPAI, a transmembrane TGF-beta-inducible protein, sequesters Smad proteins from active participation in TGF-beta signaling

Yang, W, Shibuya, H, Itoh, S, Shi, L, Goto, T, Satoh, K, Kato, M, Tanaka, A, Inamitsu, M, Watanabe, Y, Wiercinska, E, ten Dijke, P, Ohnishi, E, Mommaas, AM, Nakano, N, Itoh, F

Mol Cell 2010
11163210 Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation

Thomsen, GH, Wrana, JL, Bonni, S, Causing, CG, Rasmussen, RK, Zhu, H, Kavsak, P

Mol Cell 2000
19758997 Human BAMBI cooperates with Smad7 to inhibit transforming growth factor-beta signaling

Yan, X, Chen, F, Zhao, X, Lin, Z, Ning, Y, Chen, YG, Chen, H

J Biol Chem 2009
16027725 The deubiquitinating enzyme UCH37 interacts with Smads and regulates TGF-beta signalling

Haros, K, Maillard, M, Song, L, Dijke, PT, Cohen, RE, Chantry, A, Wicks, SJ

Oncogene 2005
22344298 USP15 stabilizes TGF-? receptor I and promotes oncogenesis through the activation of TGF-? signaling in glioblastoma

Aura, C, Martínez-Sáez, E, Barba, I, Baselga, J, Eichhorn, PJ, Prat, A, Peg, V, García-Dorado, D, Bernards, R, Cuartas, I, Jimenez, J, Seoane, J, Gili, M, Dirac, A, Gonzàlez-Juncà, A, Sahuquillo, J, Rodón, L

Nat Med 2012
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