Degradation of ubiquitinated SMAD2 Degradation of ubiquitinated SMAD3 Degradation of TGF-beta receptor complex PathwayStep5451 PathwayStep5452 PathwayStep5450 PathwayStep5455 PathwayStep5456 PathwayStep5453 PathwayStep5454 PathwayStep5464 PathwayStep5465 PathwayStep5466 PathwayStep5467 PathwayStep5460 PathwayStep5461 PathwayStep5462 PathwayStep5463 PathwayStep5458 PathwayStep5457 PathwayStep5459 PathwayStep5470 PathwayStep5477 PathwayStep5475 PathwayStep5476 PathwayStep5473 PathwayStep5474 PathwayStep5471 PathwayStep5472 PathwayStep5469 PathwayStep5468 SMAD7 binds to SMURF1 SMAD7:SMURF2 complex translocates to the cytosol SMAD7:SMURF1 complex is exported to the cytosol SMAD7:SMURF1 complex binds XPO1 (CRM1) STRAP binds phosphorylated TGF-beta receptor complex STRAP binds unphosphorylated TGF-beta receptor complex STRAP stabilizes interaction of activated TGF-beta receptor complex with SMAD7 SMAD7 recruits GADD34:PP1 to phosphorylated TGFBR PP1 dephosphorylates TGFBR1 SMAD7 binds to SMURF2 I-SMAD competes with SMAD2/3 for type I receptor (TGFBR1) PMEPA1 sequesters unphosphorylated SMAD2/3 PMEPA1 sequesters phosphorylated SMAD2/3 MTMR4 dephosphorylates SMAD2/3 MTMR4 binds phosphorylated SMAD2/3 STUB1 (CHIP) ubiquitinates SMAD3 SMURF2 ubiquitinates SMAD2 SMAD3 binds STUB1 (CHIP) SMURF2 binds SMAD2 UCHL5 or USP15 deubiquitinates TGFBR1 UCHL5 binds SMAD7 in complex with ubiquitinated TGFBR1 SMURFs/NEDD4L ubiquitinate phosphorylated TGFBR1 and SMAD7 SMAD7:SMURF complex binds to phosphorylated TGFBR1 SMAD7:NEDD4L complex translocates to the cytosol NEDD4L ubiquitin ligase binds SMAD7 Downregulation of TGF-beta receptor signaling Authored: Orlic-Milacic, M, 2012-04-04 Edited: Jassal, B, 2012-04-10 GENE ONTOLOGYGO:0030512 Pubmed10757800 Pubmed11158580 Pubmed11163210 Pubmed11278251 Pubmed12151385 Pubmed12519765 Pubmed14701756 Pubmed14718519 Pubmed15496141 Pubmed15781469 Pubmed16027725 Pubmed16061177 Pubmed20061380 Pubmed20129061 Pubmed20937913 Pubmed22045334 Pubmed22344298 Pubmed9215638 Pubmed9335507 Reactome Database ID Release 432173788 Reactome, http://www.reactome.org ReactomeREACT_120727 Reviewed: Huang, Tao, 2012-05-14 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. <br> <br>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). Biding of SMAD7 to TGBR1 can be stabilized by STRAP, a protein that simultanously binds SMAD7 and TGFBR1 (Datta et al. 2000). <br> <br>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). <br> <br>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). <br> <br>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). <br>