Downregulation of TGF-beta receptor signaling

Eichhorn PJ, Rodón L, Gonzàlez-Juncà A, Dirac A, Gili M, Martínez-Sáez E, Aura C, Barba I, Peg V, Prat A, Cuartas I, Jimenez J, García-Dorado D, Sahuquillo J, Bernards R, Baselga J, Seoane J. USP15 stabilizes TGF-ß receptor I and promotes oncogenesis through the activation of TGF-ß signaling in glioblastoma. Nat Med. 2012 Feb 19;18(3):429–35. doi: 10.1038/nm.2619. PMID: 22344298.; Tang LY, Yamashita M, Coussens NP, Tang Y, Wang X, Li C, Deng CX, Cheng SY, Zhang YE. Ablation of Smurf2 reveals an inhibition in TGF-ß signalling through multiple mono-ubiquitination of Smad3. EMBO J. 2011 Nov 01;30(23):4777–89. PMID: 22045334; PMCID: PMC3243605.; Chong PA, Lin H, Wrana JL, Forman-Kay JD. Coupling of tandem Smad ubiquitination regulatory factor (Smurf) WW domains modulates target specificity. Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18404–9. PMID: 20937913; PMCID: PMC2972958.; Yu J, Pan L, Qin X, Chen H, Xu Y, Chen Y, Tang H. MTMR4 Attenuates Transforming Growth Factor ß (TGFß) Signaling by Dephosphorylating R-Smads in Endosomes. Journal of Biological Chemistry. 2010 Mar;285(11):8454–62. doi: 10.1074/jbc.m109.075036.; Watanabe Y, Itoh S, Goto T, Ohnishi E, Inamitsu M, Itoh F, Satoh K, Wiercinska E, Yang W, Shi L, Tanaka A, Nakano N, Mommaas AM, Shibuya H, Ten Dijke P, Kato M. TMEPAI, a transmembrane TGF-beta-inducible protein, sequesters Smad proteins from active participation in TGF-beta signaling. Mol Cell. 2010 Jan 15;37(1):123–34. doi: 10.1016/j.molcel.2009.10.028. PMID: 20129061.; Yan X, Lin Z, Chen F, Zhao X, Chen H, Ning Y, Chen Y. Human BAMBI Cooperates with Smad7 to Inhibit Transforming Growth Factor-ß Signaling. Journal of Biological Chemistry. 2009 Oct;284(44):30097–104. doi: 10.1074/jbc.m109.049304.; Ogunjimi AA, Briant DJ, Pece-Barbara N, Le Roy C, Di Guglielmo GM, Kavsak P, Rasmussen RK, Seet BT, Sicheri F, Wrana JL. Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain. Mol Cell. 2005 Aug 05;19(3):297–308. doi: 10.1016/j.molcel.2005.06.028. PMID: 16061177.; Wicks SJ, Haros K, Maillard M, Song L, Cohen RE, Dijke PT, Chantry A. The deubiquitinating enzyme UCH37 interacts with Smads and regulates TGF-beta signalling. Oncogene. 2005 Dec 01;24(54):8080–4. doi: 10.1038/sj.onc.1208944. PMID: 16027725.; Xin H, Xu X, Li L, Ning H, Rong Y, Shang Y, Wang Y, Fu XY, Chang Z. CHIP controls the sensitivity of transforming growth factor-beta signaling by modulating the basal level of Smad3 through ubiquitin-mediated degradation. J Biol Chem. 2005 May 27;280(21):20842–50. doi: 10.1074/jbc.m412275200. PMID: 15781469.; Kuratomi G, Komuro A, Goto K, Shinozaki M, Miyazawa K, Miyazono K, Imamura T. 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. Biochem J. 2005 Mar 15;386(Pt 3):461–70. PMID: 15496141; PMCID: PMC1134864.; Shi W, Sun C, He B, Xiong W, Shi X, Yao D, Cao X. GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor. J Cell Biol. 2004 Jan 19;164(2):291–300. PMID: 14718519; PMCID: PMC2172339.; Li L, Xin H, Xu X, Huang M, Zhang X, Chen Y, Zhang S, Fu X, Chang Z. CHIP Mediates Degradation of Smad Proteins and Potentially Regulates Smad-Induced Transcription. Molecular and Cellular Biology. 2004 Jan 01;24(2):856–64. doi: 10.1128/mcb.24.2.856-864.2004.; Tajima Y, Goto K, Yoshida M, Shinomiya K, Sekimoto T, Yoneda Y, Miyazono K, Imamura T. 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. J Biol Chem. 2003 Mar 21;278(12):10716–21. doi: 10.1074/jbc.m212663200. PMID: 12519765.; Suzuki C, Murakami G, Fukuchi M, Shimanuki T, Shikauchi Y, Imamura T, Miyazono K. Smurf1 Regulates the Inhibitory Activity of Smad7 by Targeting Smad7 to the Plasma Membrane. Journal of Biological Chemistry. 2002 Oct;277(42):39919–25. doi: 10.1074/jbc.m201901200.; Ebisawa T, Fukuchi M, Murakami G, Chiba T, Tanaka K, Imamura T, Miyazono K. Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation. J Biol Chem. 2001 Apr 20;276(16):12477–80. doi: 10.1074/jbc.c100008200. PMID: 11278251.; Zhang Y, Chang C, Gehling DJ, Hemmati-Brivanlou A, Derynck R. Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase. Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):974–9. PMID: 11158580; PMCID: PMC14694.; Kavsak P, Rasmussen RK, Causing CG, Bonni S, Zhu H, Thomsen GH, Wrana JL. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. Mol Cell. 2000 Dec;6(6):1365–75. doi: 10.1016/s1097-2765(00)00134-9. PMID: 11163210.; Datta PK, Moses HL. STRAP and Smad7 Synergize in the Inhibition of Transforming Growth Factor ß Signaling. Mol Cell Biol. 2000 May;20(9):3157–67. doi: 10.1128/mcb.20.9.3157-3167.2000.; Onichtchouk D, Chen YG, Dosch R, Gawantka V, Delius H, Massagué J, Niehrs C. Silencing of TGF-beta signalling by the pseudoreceptor BAMBI. Nature. 1999 Sep 30;401(6752):480–5. doi: 10.1038/46794. PMID: 10519551.; Nakao A, Afrakhte M, Morén A, Nakayama T, Christian JL, Heuchel R, Itoh S, Kawabata M, Heldin NE, Heldin CH, ten Dijke P. Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling. Nature. 1997 Oct 09;389(6651):631–5. doi: 10.1038/39369. PMID: 9335507.; Hayashi H, Abdollah S, Qiu Y, Cai J, Xu YY, Grinnell BW, Richardson MA, Topper JN, Gimbrone MA, Wrana JL, Falb D. The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell. 1997 Jun 27;89(7):1165–73. doi: 10.1016/s0092-8674(00)80303-7. PMID: 9215638.

Metabolites

H2O

Formula: H2O (18.0105642)

CAS ID: 7732-18-5



Enzyme

EC Number name full name note
2.3.2.26 HECT-type E3 ubiquitin transferase [E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine:[acceptor protein] ubiquitin transferase (isopeptide bond-forming)
2.3.2.27 RING-type E3 ubiquitin transferase [E2 ubiquitin-conjugating enzyme]-S-ubiquitinyl-L-cysteine:[acceptor protein] ubiquitin transferase (isopeptide bond-forming; RING-type)
2.7.11.30 receptor protein serine/threonine kinase ATP:[receptor-protein] phosphotransferase
3.1.3.95 phosphatidylinositol-3,5-bisphosphate 3-phosphatase 1-phosphatidyl-1D-myo-inositol-3,5-bisphosphate 3-phosphohydrolase


Proteins

Protein ID name full name