title: Ligand-dependent ubiquitination of Smad3 is regulated by casein kinase 1 gamma 2, an inhibitor of TGF-beta signaling.
abstract: Transforming growth factor-beta (TGF-beta) elicits a variety of cellular activities primarily through a signaling cascade mediated by two key transcription factors, Smad2 and Smad3. Numerous regulatory mechanisms exist to control the activity of Smad3, thereby modulating the strength and specificity of TGF-beta responses. In search for potential regulators of Smad3 through a yeast two-hybrid screen, we identified casein kinase 1 gamma 2 (CKIgamma2) as a novel Smad3-interacting protein. In mammalian cells, CKIgamma2 selectively and constitutively binds Smad3 but not Smad1, -2 or -4. Functionally, CKIgamma2 inhibits Smad3-mediated TGF-beta responses including induction of target genes and cell growth arrest, and this inhibition is dependent on CKIgamma2 kinase activity. Mechanistically, CKIgamma2 does not affect the basal levels of Smad proteins or activity of the receptors. Rather, CKIgamma2 preferentially promotes the ubiquitination and degradation of activated Smad3 through direct phosphorylation of its MH2 domain at Ser418. Importantly, mutation of Ser418 to alanine or aspartic acid causes an increase or decrease of Smad3 activity, respectively, in the presence of TGF-beta. CKIgamma2 is the first kinase known to mark activated Smad3 for destruction. Given its negative function in TGF-beta signaling and its reported overexpression in human cancers, CKIgamma2 may act as an oncoprotein during tumorigenesis.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27710, USA.
authors.forename: X
authors.initials: X
authors.lastname: Guo
authors.forename: D S
authors.initials: DS
authors.lastname: Waddell
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.forename: N T
authors.initials: NT
authors.lastname: Liberati
authors.forename: S
authors.initials: S
authors.lastname: Yong
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.forename: X-F
authors.initials: XF
authors.lastname: Wang
mesh_terms: D047389:Casein Kinase I / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008024:Ligands; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D020798:Two-Hybrid System Techniques; D054875:Ubiquitination
chemical_list: D008024:Ligands; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D047389:Casein Kinase I
references.citation: Nat Cell Biol. 1999 Dec;1(8):E195-7
references.pmid: 10587654
references.citation: Genes Dev. 2005 Dec 1;19(23):2783-810
references.pmid: 16322555
references.citation: FEBS Lett. 2005 May 23;579(13):2853-62
references.pmid: 15907489
references.citation: J Biol Chem. 2000 Dec 29;275(52):40710-7
references.pmid: 11018029
references.citation: Mol Cell. 2002 Aug;10(2):271-82
references.pmid: 12191473
references.citation: Genomics. 1997 Nov 15;46(1):133-7
references.pmid: 9403068
references.citation: Cell Signal. 1998 Nov;10(10):699-711
references.pmid: 9884021
references.citation: Oncogene. 1999 Feb 25;18(8):1643-8
references.pmid: 10102636
references.citation: Cytokine Growth Factor Rev. 2006 Feb-Apr;17(1-2):19-27
references.pmid: 16290023
references.citation: Genes Dev. 2005 Jan 1;19(1):152-63
references.pmid: 15630024
references.citation: Nat Cell Biol. 1999 Dec;1(8):472-8
references.pmid: 10587642
references.citation: J Biol Chem. 1999 Jan 8;274(2):703-9
references.pmid: 9873005
references.citation: J Biol Chem. 2004 Jul 9;279(28):29236-46
references.pmid: 15133026
references.citation: J Biol Chem. 2001 Jun 22;276(25):22595-603
references.pmid: 11306568
references.citation: Cell. 2002 Mar 22;108(6):823-35
references.pmid: 11955435
references.citation: Nat Rev Mol Cell Biol. 2000 Dec;1(3):169-78
references.pmid: 11252892
references.citation: Genes Dev. 2006 Feb 15;20(4):399-410
references.pmid: 16481469
references.citation: Cell. 2006 Jun 2;125(5):838-40
references.pmid: 16751094
references.citation: Mol Cell Biol. 2005 Nov;25(22):9845-58
references.pmid: 16260601
references.citation: J Biol Chem. 1995 May 26;270(21):12717-24
references.pmid: 7759525
references.citation: J Biol Chem. 2007 May 25;282(21):15534-40
references.pmid: 17400544
references.citation: Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):4844-9
references.pmid: 10220381
references.citation: Cell. 2003 Jun 13;113(6):685-700
references.pmid: 12809600
references.citation: Cell Signal. 2005 Jun;17(6):675-89
references.pmid: 15722192
references.citation: J Biol Chem. 2001 Jun 8;276(23):19945-53
references.pmid: 11262418
references.citation: Nature. 2005 Dec 8;438(7069):867-72
references.pmid: 16341016
references.citation: Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):99-104
references.pmid: 14691252
references.citation: Nat Rev Cancer. 2006 Jul;6(7):506-20
references.pmid: 16794634
references.citation: J Biol Chem. 2000 Nov 24;275(47):36818-22
references.pmid: 11016919
references.citation: Mol Cell. 2002 Aug;10(2):283-94
references.pmid: 12191474
references.citation: Cell. 1998 Sep 4;94(5):585-94
references.pmid: 9741623
references.citation: Cytokine Growth Factor Rev. 2000 Mar-Jun;11(1-2):49-58
references.pmid: 10708952
references.citation: Nephrology (Carlton). 2005 Feb;10(1):48-56
references.pmid: 15705182
references.citation: IUBMB Life. 2001 Feb;51(2):73-8
references.pmid: 11463166
references.citation: Cell. 2002 Mar 22;108(6):837-47
references.pmid: 11955436
references.citation: Cell. 2006 Jun 2;125(5):915-28
references.pmid: 16751101
references.citation: Neoplasia. 2006 Aug;8(8):677-88
references.pmid: 16925950
references.citation: Nature. 1997 Dec 4;390(6659):465-71
references.pmid: 9393997
references.citation: Nature. 1999 Sep 23;401(6751):345-50
references.pmid: 10517632
references.citation: Oncogene. 2004 Sep 9;23(41):6914-23
references.pmid: 15221015
references.citation: Trends Cell Biol. 2003 May;13(5):216-20
references.pmid: 12742164
references.citation: Mol Biol Cell. 2001 May;12(5):1431-43
references.pmid: 11359933
references.citation: Oncogene. 2003 Oct 2;22(43):6748-63
references.pmid: 14555988
references.citation: Cell. 2000 Oct 13;103(2):295-309
references.pmid: 11057902
references.citation: Nature. 2005 Dec 8;438(7069):873-7
references.pmid: 16341017
references.citation: Genes Dev. 2008 Jan 1;22(1):106-20
references.pmid: 18172167