| Structural highlights
Disease
[SMAD7_HUMAN] Genetic variations in SMAD7 influence susceptibility to colorectal cancer type 3 (CRCS3) [MIM:612229]. Colorectal cancer consists of tumors or cancer of either the colon or rectum or both. Cancers of the large intestine are the second most common form of cancer found in males and females. Symptoms include rectal bleeding, occult blood in stools, bowel obstruction and weight loss. Treatment is based largely on the extent of cancer penetration into the intestinal wall. Surgical cures are possible if the malignancy is confined to the intestine. Risk can be reduced when following a diet which is low in fat and high in fiber.[1]
Function
[NED4L_HUMAN] E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Inhibits TGF-beta signaling by triggering SMAD2 and TGFBR1 ubiquitination and proteasome-dependent degradation. Promotes ubiquitination and internalization of various plasma membrane channels such as ENaC, Nav1.2, Nav1.3, Nav1.5, Nav1.7, Nav1.8, Kv1.3, EAAT1 or CLC5. Promotes ubiquitination and degradation of SGK1 and TNK2.[2] [3] [4] [5] [6] [7] [8] [SMAD7_HUMAN] Antagonist of signaling by TGF-beta (transforming growth factor) type 1 receptor superfamily members; has been shown to inhibit TGF-beta (Transforming growth factor) and activin signaling by associating with their receptors thus preventing SMAD2 access. Functions as an adapter to recruit SMURF2 to the TGF-beta receptor complex. Also acts by recruiting the PPP1R15A-PP1 complex to TGFBR1, which promotes its dephosphorylation. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator (By similarity).[9] [10] [11] [12] [13]
Publication Abstract from PubMed
Transforming growth factor (TGF)-beta and BMP signaling is mediated by Smads 1-5 (R-Smads and Co-Smads) and inhibited by Smad7, a major hub of regulation of TGF-beta and BMP receptors by negative feedback and antagonistic signals. The transcription coactivator YAP and the E3 ubiquitin ligases Smurf1/2 and Nedd4L target R-Smads for activation or degradation, respectively. Pairs of WW domain in these regulators bind PY motifs and adjacent CDK/MAPK and GSK3 phosphorylation sites in R-Smads in a selective and regulated manner. In contrast, here we show that Smad7 binds YAP, Smurf1, Smurf2, and Nedd4L constitutively, the binding involving a PY motif in Smad7 and no phosphorylation. We also provide a structural basis for how regulators that use WW domain pairs for selective interactions with R-Smads, resort to one single versatile WW domain for binding Smad7 to centralize regulation in the TGF-beta and BMP pathways.
Structural Basis for the Versatile Interactions of Smad7 with Regulator WW Domains in TGF-beta Pathways.,Aragon E, Goerner N, Xi Q, Gomes T, Gao S, Massague J, Macias MJ Structure. 2012 Oct 10;20(10):1726-36. doi: 10.1016/j.str.2012.07.014. Epub 2012 , Aug 23. PMID:22921829[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Broderick P, Carvajal-Carmona L, Pittman AM, Webb E, Howarth K, Rowan A, Lubbe S, Spain S, Sullivan K, Fielding S, Jaeger E, Vijayakrishnan J, Kemp Z, Gorman M, Chandler I, Papaemmanuil E, Penegar S, Wood W, Sellick G, Qureshi M, Teixeira A, Domingo E, Barclay E, Martin L, Sieber O, Kerr D, Gray R, Peto J, Cazier JB, Tomlinson I, Houlston RS. A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nat Genet. 2007 Nov;39(11):1315-7. Epub 2007 Oct 14. PMID:17934461 doi:ng.2007.18
- ↑ Boehmer C, Henke G, Schniepp R, Palmada M, Rothstein JD, Broer S, Lang F. Regulation of the glutamate transporter EAAT1 by the ubiquitin ligase Nedd4-2 and the serum and glucocorticoid-inducible kinase isoforms SGK1/3 and protein kinase B. J Neurochem. 2003 Sep;86(5):1181-8. PMID:12911626
- ↑ van Bemmelen MX, Rougier JS, Gavillet B, Apotheloz F, Daidie D, Tateyama M, Rivolta I, Thomas MA, Kass RS, Staub O, Abriel H. Cardiac voltage-gated sodium channel Nav1.5 is regulated by Nedd4-2 mediated ubiquitination. Circ Res. 2004 Aug 6;95(3):284-91. Epub 2004 Jun 24. PMID:15217910 doi:10.1161/01.RES.0000136816.05109.89
- ↑ Hryciw DH, Ekberg J, Lee A, Lensink IL, Kumar S, Guggino WB, Cook DI, Pollock CA, Poronnik P. Nedd4-2 functionally interacts with ClC-5: involvement in constitutive albumin endocytosis in proximal tubule cells. J Biol Chem. 2004 Dec 31;279(53):54996-5007. Epub 2004 Oct 15. PMID:15489223 doi:M411491200
- ↑ Henke G, Maier G, Wallisch S, Boehmer C, Lang F. Regulation of the voltage gated K+ channel Kv1.3 by the ubiquitin ligase Nedd4-2 and the serum and glucocorticoid inducible kinase SGK1. J Cell Physiol. 2004 May;199(2):194-9. PMID:15040001 doi:10.1002/jcp.10430
- ↑ 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 doi:BJ20040738
- ↑ Zhou R, Snyder PM. Nedd4-2 phosphorylation induces serum and glucocorticoid-regulated kinase (SGK) ubiquitination and degradation. J Biol Chem. 2005 Feb 11;280(6):4518-23. Epub 2004 Dec 2. PMID:15576372 doi:10.1074/jbc.M411053200
- ↑ Chan W, Tian R, Lee YF, Sit ST, Lim L, Manser E. Down-regulation of active ACK1 is mediated by association with the E3 ubiquitin ligase Nedd4-2. J Biol Chem. 2009 Mar 20;284(12):8185-94. doi: 10.1074/jbc.M806877200. Epub 2009 , Jan 14. PMID:19144635 doi:10.1074/jbc.M806877200
- ↑ Lebrun JJ, Takabe K, Chen Y, Vale W. Roles of pathway-specific and inhibitory Smads in activin receptor signaling. Mol Endocrinol. 1999 Jan;13(1):15-23. PMID:9892009
- ↑ 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. PMID:11163210
- ↑ Liu X, Nagarajan RP, Vale W, Chen Y. Phosphorylation regulation of the interaction between Smad7 and activin type I receptor. FEBS Lett. 2002 May 22;519(1-3):93-8. PMID:12023024
- ↑ 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. Epub 2004 Jan 12. PMID:14718519 doi:10.1083/jcb.200307151
- ↑ Seong HA, Jung H, Kim KT, Ha H. 3-Phosphoinositide-dependent PDK1 negatively regulates transforming growth factor-beta-induced signaling in a kinase-dependent manner through physical interaction with Smad proteins. J Biol Chem. 2007 Apr 20;282(16):12272-89. Epub 2007 Feb 27. PMID:17327236 doi:10.1074/jbc.M609279200
- ↑ Aragon E, Goerner N, Xi Q, Gomes T, Gao S, Massague J, Macias MJ. Structural Basis for the Versatile Interactions of Smad7 with Regulator WW Domains in TGF-beta Pathways. Structure. 2012 Oct 10;20(10):1726-36. doi: 10.1016/j.str.2012.07.014. Epub 2012 , Aug 23. PMID:22921829 doi:http://dx.doi.org/10.1016/j.str.2012.07.014
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