title: Smad linker region phosphorylation in the regulation of extracellular matrix synthesis.
abstract: The canonical TGF-β signalling pathway involves Smad transcription factors through direct serine phosphorylation of the carboxy termini, nuclear translocation and regulation of transcription by receptor-regulated (R)-Smad complexes. Smads can also be phosphorylated in the linker region most prominently by the action of mitogen-activated protein (MAP) kinases, which in turn have been activated by TGF-β or a multitude of other growth factors and hormones. Linker region phosphorylation can prevent nuclear translocation of Smads and inhibit TGF-β signalling, potentially leading to oncogenesis. However, some evidence has revealed that linker region phosphorylated Smads can be translocated to the nucleus where they regulate transcription particularly of the synthesis of extracellular matrix molecules. Matrix molecules such as collagen and proteoglycans are involved in diseases such a fibrosis and atherosclerosis, respectively, and the involvement of linker region phosphorylation may represent a new therapeutic target.
authors.affiliation: Diabetes and Cell Biology Laboratory, BakerIDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia. micah.burch@bakeridi.edu.au
authors.forename: Micah L
authors.initials: ML
authors.lastname: Burch
authors.forename: Wenhua
authors.initials: W
authors.lastname: Zheng
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Little
mesh_terms: D000818:Animals; D003094:Collagen / Q000096:biosynthesis; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology; D011509:Proteoglycans / Q000096:biosynthesis; D051381:Rats; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology; D051785:Smad Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat
references.citation: Open Biochem J. 2008;2:135-42
references.pmid: 19238187
references.citation: Genes Dev. 2003 Dec 15;17(24):2993-7
references.pmid: 14701870
references.citation: Arterioscler Thromb Vasc Biol. 2002 Jan;22(1):55-60
references.pmid: 11788461
references.citation: J Biol Chem. 2001 Apr 27;276(17):14466-73
references.pmid: 11278290
references.citation: J Biol Chem. 2006 Dec 29;281(52):39870-80
references.pmid: 17074756
references.citation: Circulation. 2007 Oct 16;116(16):1832-44
references.pmid: 17938300
references.citation: Genes Dev. 2000 Oct 15;14(20):2610-22
references.pmid: 11040215
references.citation: Cell Signal. 2002 Sep;14(9):733-43
references.pmid: 12034354
references.citation: Am J Pathol. 2005 Apr;166(4):1029-39
references.pmid: 15793284
references.citation: Nature. 2003 Oct 9;425(6958):577-84
references.pmid: 14534577
references.citation: J Cell Mol Med. 2010 Jun;14(6B):1408-18
references.pmid: 19754668
references.citation: Am J Pathol. 2002 Dec;161(6):2111-21
references.pmid: 12466127
references.citation: Nat Rev Mol Cell Biol. 2007 Nov;8(11):857-69
references.pmid: 17895899
references.citation: J Allergy Clin Immunol. 2009 Aug;124(2):253-9, 259.e1-2
references.pmid: 19500825
references.citation: Genes Dev. 1999 Apr 1;13(7):804-16
references.pmid: 10197981
references.citation: Genes Dev. 2005 Dec 1;19(23):2783-810
references.pmid: 16322555
references.citation: EMBO J. 2007 Sep 5;26(17):3957-67
references.pmid: 17673906
references.citation: Cell Growth Differ. 1997 Jul;8(7):821-7
references.pmid: 9218876
references.citation: Curr Vasc Pharmacol. 2005 Jan;3(1):55-61
references.pmid: 15638782
references.citation: Cell Mol Life Sci. 2004 Jun;61(11):1296-306
references.pmid: 15170508
references.citation: FASEB J. 2003 Aug;17(11):1576-8
references.pmid: 12824291
references.citation: Cell. 1996 May 17;85(4):489-500
references.pmid: 8653785
references.citation: Arterioscler Thromb Vasc Biol. 1995 May;15(5):551-61
references.pmid: 7749869
references.citation: Clin Sci (Lond). 2008 Oct;115(7):203-18
references.pmid: 18752467
references.citation: Atherosclerosis. 2002 May;162(1):119-29
references.pmid: 11947905
references.citation: Mol Cell. 2009 Nov 13;36(3):457-68
references.pmid: 19917253
references.citation: J Biol Chem. 2008 Mar 21;283(12):7844-52
references.pmid: 18223258
references.citation: Cardiovasc Res. 2008 Jul 1;79(1):14-23
references.pmid: 18430750
references.citation: J Biol Chem. 1987 Apr 15;262(11):5065-72
references.pmid: 3031038
references.citation: Biochem Biophys Res Commun. 2009 May 1;382(2):259-63
references.pmid: 19285964
references.citation: Nature. 2001 May 17;411(6835):355-65
references.pmid: 11357143
references.citation: Development. 2009 Nov;136(22):3691-7
references.pmid: 19855012
references.citation: Development. 2009 Nov;136(22):3699-714
references.pmid: 19855013
references.citation: Curr Opin Lipidol. 2008 Oct;19(5):448-54
references.pmid: 18769225
references.citation: Biochim Biophys Acta. 2008 Apr;1782(4):197-228
references.pmid: 18313409
references.citation: Thromb Res. 2008;123(2):288-97
references.pmid: 18571697
references.citation: Cell Res. 2009 Jan;19(1):89-102
references.pmid: 19050696
references.citation: Mol Cell Biol. 2000 Nov;20(21):8103-11
references.pmid: 11027280
references.citation: Arch Pharm Res. 2007 Jun;30(6):739-42
references.pmid: 17679552
references.citation: J Lipid Res. 2002 Jan;43(1):149-57
references.pmid: 11792734
references.citation: Vasc Health Risk Manag. 2007;3(1):117-24
references.pmid: 17583182
references.citation: Dev Dyn. 2009 Jul;238(7):1688-700
references.pmid: 19517569
references.citation: Biochem Biophys Res Commun. 1992 Mar 16;183(2):694-700
references.pmid: 1550575
references.citation: Atherosclerosis. 2009 Aug;205(2):451-7
references.pmid: 19217622
references.citation: Cell Mol Life Sci. 2010 Jun;67(12):2077-90
references.pmid: 20213272
references.citation: Nature. 1996 Feb 8;379(6565):557-60
references.pmid: 8596637
references.citation: Biochem Biophys Res Commun. 2009 Aug 21;386(2):289-93
references.pmid: 19465000
references.citation: J Biol Chem. 1997 Jan 31;272(5):2896-900
references.pmid: 9006934
references.citation: Expert Opin Pharmacother. 2009 Jul;10(10):1587-603
references.pmid: 19527187
references.citation: Carcinogenesis. 2008 Feb;29(2):244-51
references.pmid: 18174260
references.citation: Arthritis Rheum. 2009 Jul;60(7):2142-55
references.pmid: 19565505
references.citation: Genes Cells. 2009 Jan;14(1):17-28
references.pmid: 19032343
references.citation: Atherosclerosis. 2008 Aug;199(2):237-47
references.pmid: 18436225
references.citation: Nature. 1997 Dec 4;390(6659):465-71
references.pmid: 9393997
references.citation: FASEB J. 2008 Jun;22(6):1769-77
references.pmid: 18218921
references.citation: Oncogene. 2007 May 14;26(22):3100-12
references.pmid: 17496909
references.citation: Science. 1995 Dec 22;270(5244):2008-11
references.pmid: 8533096
references.citation: Cancer Res. 2008 Nov 15;68(22):9107-11
references.pmid: 19010878
references.citation: J Biol Chem. 2009 Apr 10;284(15):9663-73
references.pmid: 19218245
references.citation: J Clin Invest. 1993 Dec;92(6):3003-7
references.pmid: 8254054
references.citation: Expert Rev Gastroenterol Hepatol. 2009 Feb;3(1):1-3
references.pmid: 19210106
references.citation: Biochem J. 2005 Feb 15;386(Pt 1):e1-e3
references.pmid: 15702493
references.citation: J Biol Chem. 2003 Mar 28;278(13):11041-9
references.pmid: 12538652
references.citation: Am J Physiol. 1990 Mar;258(3 Pt 1):C408-15
references.pmid: 1690514
references.citation: Cell. 2009 Nov 13;139(4):757-69
references.pmid: 19914168
references.citation: Am J Pathol. 1998 Feb;152(2):533-46
references.pmid: 9466580
references.citation: Annu Rev Biochem. 1998;67:753-91
references.pmid: 9759503
references.citation: Nature. 1997 Oct 9;389(6651):618-22
references.pmid: 9335504
references.citation: Arch Physiol Biochem. 2009 Jul;115(3):147-54
references.pmid: 19580379
references.citation: J Mol Cell Cardiol. 2001 Jan;33(1):3-7
references.pmid: 11133218
references.citation: Cell. 2000 Oct 13;103(2):295-309
references.pmid: 11057902
references.citation: Zhonghua Yi Xue Za Zhi. 2004 Apr 2;84(7):574-7
references.pmid: 15144593