Reactome | Downregulation of TGF-beta receptor signaling

Downregulation of TGF-beta receptor signaling

Stable Identifier

R-HSA-2173788

Type

Pathway

Species

Homo sapiens

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Downregulation of TGF-beta receptor signaling

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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
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
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
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
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