ALK1-Smad1/5 signaling pathway in fibrosis development: Friend or foe?

Cytokine and Growth Factor Reviews

Volumn 24, Issue 6, 2013, Pages 523-537

  Muñoz Félix, José M ^a,b,c   González Núñez, María ^a,b,c   López Novoa, José M ^a,b,c  

^a UNIVERSITY OF SALAMANCA   (Spain)

^b INSTITUTO DE INVESTIGACIÓN BIOMÉDICA DE SALAMANCA IBSAL   (Spain)

^c Institute Queen Sophie for Renal Research   (Spain)

Author keywords

Cirrhosis; Collagen; Extracellular matrix; Fibrosis; Smad

Indexed keywords

4 [4 (1,3 BENZODIOXOL 5 YL) 5 (2 PYRIDINYL) 1H IMIDAZOL 2 YL]BENZAMIDE; ACTIVIN RECEPTOR LIKE KINASE 1; ALPHA SMOOTH MUSCLE ACTIN; ANTIFIBROTIC AGENT; BONE MORPHOGENETIC PROTEIN RECEPTOR 1A; BONE MORPHOGENETIC PROTEIN RECEPTOR 1B; COLLAGEN; COMPOUND 861; CONNECTIVE TISSUE GROWTH FACTOR; DALANTERCEPT; DESMOCOLLIN; ENDOGLIN; IMATINIB; INHIBITOR OF DIFFERENTIATION 1; INTERSTITIAL COLLAGENASE; OLMESARTAN; OSTEOGENIC PROTEIN 1; PF 3446962; PLASMINOGEN ACTIVATOR INHIBITOR 1; RECOMBINANT OSTEOGENIC PROTEIN 1; SMAD1 PROTEIN; SMAD2 PROTEIN; SMAD3 PROTEIN; SMAD5 PROTEIN; THR 123; TRANSFORMING GROWTH FACTOR BETA; TRANSFORMING GROWTH FACTOR BETA RECEPTOR 1; TRANSFORMING GROWTH FACTOR BETA1; UNCLASSIFIED DRUG; UNINDEXED DRUG; UVOMORULIN;

BLOOD VESSEL; CARTILAGE CELL; DIABETIC NEPHROPATHY; DRUG EFFECT; DRUG TARGETING; ENDOTHELIUM CELL; ENZYME STRUCTURE; EPITHELIAL MESENCHYMAL TRANSITION; EXTRACELLULAR MATRIX; FIBROBLAST; FIBROSIS; HUMAN; KIDNEY FIBROSIS; LIVER CELL; LIVER FIBROSIS; LUNG FIBROSIS; NONHUMAN; OSTEOARTHRITIS; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN SYNTHESIS; RENAL PROTECTION; REVIEW; SCLERODERMA; SIGNAL TRANSDUCTION; SKIN FIBROSIS; SYSTEMIC SCLEROSIS;

CIRRHOSIS; COLLAGEN; EXTRACELLULAR MATRIX; FIBROSIS; SMAD;

ACTIVIN RECEPTORS, TYPE II; ANIMALS; EXTRACELLULAR MATRIX PROTEINS; FIBROSIS; HUMANS; SMAD1 PROTEIN; SMAD5 PROTEIN; TRANSFORMING GROWTH FACTOR BETA;

EID: 84888295679     PISSN: 13596101     EISSN: 18790305     Source Type: Journal    
DOI: 10.1016/j.cytogfr.2013.08.002     Document Type: Review

References (189)

1. Lopez-Hernandez F.J., Lopez-Novoa J.M. Role of TGF-beta in chronic kidney disease: an integration of tubular, glomerular and vascular effects. Cell Tissue Res 2012, 347:141-154.
2. Meng X.M., Chung A.C., Lan H.Y. Role of the TGF-beta/BMP-7/Smad pathways in renal diseases. Clin Sci (Lond) 2013, 124:243-254.
3. Dooley S., ten Dijke P. TGF-beta in progression of liver disease. Cell Tissue Res 2012, 347:245-256.
4. Wiercinska E., Wickert L., Denecke B., et al. Id1 is a critical mediator in TGF-beta-induced transdifferentiation of rat hepatic stellate cells. Hepatology 2006, 43:1032-1041.
5. Fernandez I.E., Eickelberg O. The impact of TGF-beta on lung fibrosis: from targeting to biomarkers. Proc Am Thorac Soc 2012, 9:111-116.
6. Maring J.A., Trojanowska M., ten Dijke P. Role of endoglin in fibrosis and scleroderma. Int Rev Cell Mol Biol 2012, 297:295-308.
7. Pannu J., Nakerakanti S., Smith E., ten Dijke P., Trojanowska M. Transforming growth factor-beta receptor type I-dependent fibrogenic gene program is mediated via activation of Smad1 and ERK1/2 pathways. J Biol Chem 2007, 282:10405-10413.
8. Pannu J., Asano Y., Nakerakanti S., et al. Smad1 pathway is activated in systemic sclerosis fibroblasts and is targeted by imatinib mesylate. Arthritis Rheum 2008, 58:2528-2537.
9. Morris E., Chrobak I., Bujor A., et al. Endoglin promotes TGF-beta/Smad1 signaling in scleroderma fibroblasts. J Cell Physiol 2011, 226:3340-3348.
10. Bujak M., Frangogiannis N.G. The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res 2007, 74:184-195.
11. Dobaczewski M., Chen W., Frangogiannis N.G. Transforming growth factor (TGF)-beta signaling in cardiac remodeling. J Mol Cell Cardiol 2011, 51:600-606.
12. Toma I., McCaffrey T.A. Transforming growth factor-beta and atherosclerosis: interwoven atherogenic and atheroprotective aspects. Cell Tissue Res 2012, 347:155-175.
13. Moon J.A., Kim H.T., Cho I.S., Sheen Y.Y., Kim D.K. IN-1130 a novel transforming growth factor-beta type I receptor kinase (ALK5) inhibitor, suppresses renal fibrosis in obstructive nephropathy. Kidney Int 2006, 70:1234-1243.
14. Matsubara T., Abe H., Arai H., et al. Expression of Smad1 is directly associated with mesangial matrix expansion in rat diabetic nephropathy. Lab Invest 2006, 86:357-368.
15. Jakowlew S.B., Mathias A., Lillehoj H.S. Transforming growth factor-beta isoforms in the developing chicken intestine and spleen: increase in transforming growth factor-beta 4 with coccidia infection. Vet Immunol Immunopathol 1997, 55:321-339.
16. Vempati U.D., Kondaiah P. Characterization of the 5' flanking region of the Xenopus laevis transforming growth factor-beta 5 (TGF-beta 5) gene. Gene 1998, 208:323-329.
17. Santibanez J.F., Quintanilla M., Bernabeu C. TGF-beta/TGF-beta receptor system and its role in physiological and pathological conditions. Clin Sci (Lond) 2011, 121:233-251.
18. Miyazawa K., Shinozaki M., Hara T., Furuya T., Miyazono K. Two major Smad pathways in TGF-beta superfamily signalling. Genes Cells 2002, 7:1191-1204.
19. Ikushima H., Komuro A., Isogaya K., et al. An Id-like molecule, HHM, is a synexpression group-restricted regulator of TGF-beta signalling. EMBO J 2008, 27:2955-2965.
20. Dennler S., Goumans M.J., ten Dijke P. Transforming growth factor beta signal transduction. J Leukoc Biol 2002, 71:731-740.
21. Liu I.M., Schilling S.H., Knouse K.A., Choy L., Derynck R., Wang X.F. TGFbeta-stimulated Smad1/5 phosphorylation requires the ALK5 L45 loop and mediates the pro-migratory TGFbeta switch. EMBO J 2009, 28:88-98.
22. Mu Y., Gudey S.K., Landstrom M. Non-Smad signaling pathways. Cell Tissue Res 2012, 347:11-20.
23. Choi M.E., Ding Y., Kim S.I. TGF-beta signaling via TAK1 pathway: role in kidney fibrosis. Semin Nephrol 2012, 32:244-252.
24. Miyazono K., Kamiya Y., Morikawa M. Bone morphogenetic protein receptors and signal transduction. J Biochem 2010, 147:35-51.
25. Rider C.C., Mulloy B. Bone morphogenetic protein and growth differentiation factor cytokine families and their protein antagonists. Biochem J 2010, 429:1-12.
26. Rifkin D.B. Latent transforming growth factor-beta (TGF-beta) binding proteins: orchestrators of TGF-beta availability. J Biol Chem 2005, 280:7409-7412.
27. Itoh S., ten Dijke P. Negative regulation of TGF-beta receptor/Smad signal transduction. Curr Opin Cell Biol 2007, 19:176-184.
28. Di Guglielmo G.M., Le Roy C., Goodfellow A.F., Wrana J.L. Distinct endocytic pathways regulate TGF-beta receptor signalling and turnover. Nat Cell Biol 2003, 5:410-421.
29. Derynck R., Zhang Y.E., Smad-dependent Smad-independent pathways in TGF-beta family signalling. Nature 2003, 425:577-584.
30. Lin S.J., Lerch T.F., Cook R.W., Jardetzky T.S., Woodruff T.K. The structural basis of TGF-beta, bone morphogenetic protein, and activin ligand binding. Reproduction 2006, 132:179-190.
31. Groppe J., Hinck C.S., Samavarchi-Tehrani P., et al. Cooperative assembly of TGF-beta superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding. Mol Cell 2008, 29:157-168.
32. Roelen B.A., van Rooijen M.A., Mummery C.L. Expression of ALK-1, a type 1 serine/threonine kinase receptor, coincides with sites of vasculogenesis and angiogenesis in early mouse development. Dev Dyn 1997, 209:418-430.
33. Panchenko M.P., Williams M.C., Brody J.S., Yu Q. Type I receptor serine-threonine kinase preferentially expressed in pulmonary blood vessels. Am J Physiol 1996, 270:L547-L558.
34. ten Dijke P., Ichijo H., Franzen P., et al. Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity. Oncogene 1993, 8:2879-2887.
35. Mahmoud M., Borthwick G.M., Hislop A.A., Arthur H.M. Endoglin and activin receptor-like-kinase 1 are co-expressed in the distal vessels of the lung: implications for two familial vascular dysplasias, HHT and PAH. Lab Invest 2009, 89:15-25.
36. Seki T., Yun J., Oh S.P. Arterial endothelium-specific activin receptor-like kinase 1 expression suggests its role in arterialization and vascular remodeling. Circ Res 2003, 93:682-689.
37. Torsney E., Charlton R., Parums D., Collis M., Arthur H.M. Inducible expression of human endoglin during inflammation and wound healing in vivo. Inflamm Res 2002, 51:464-470.
38. van Laake L.W., van den Driesche S., Post S., et al. Endoglin has a crucial role in blood cell-mediated vascular repair. Circulation 2006, 114:2288-2297.
39. Sanz-Rodriguez F., Fernandez L.A., Zarrabeitia R., et al. Mutation analysis in Spanish patients with hereditary hemorrhagic telangiectasia: deficient endoglin up-regulation in activated monocytes. Clin Chem 2004, 50:2003-2011.
40. Konig H.G., Kogel D., Rami A., Prehn J.H. TGF-{beta}1 activates two distinct type I receptors in neurons: implications for neuronal NF-{kappa}B signaling. J Cell Biol 2005, 168:1077-1086.
41. Beger B., Robertson K., Evans A., Grant A., Berg J. Expression of endoglin and the activin receptor-like kinase 1 in skin suggests a role for these receptors in normal skin function and skin tumorigenesis. Br J Dermatol 2006, 154:379-382.
42. Finnson K.W., Parker W.L., ten Dijke P., Thorikay M., Philip A. ALK1 opposes ALK5/Smad3 signaling and expression of extracellular matrix components in human chondrocytes. J Bone Miner Res 2008, 23:896-906.
43. Mancini M.L., Verdi J.M., Conley B.A., et al. Endoglin is required for myogenic differentiation potential of neural crest stem cells. Dev Biol 2007, 308:520-533.
44. Velasco S., Alvarez-Munoz P., Pericacho M., et al. L- and S-endoglin differentially modulate TGFbeta1 signaling mediated by ALK1 and ALK5 in L6E9 myoblasts. J Cell Sci 2008, 121:913-919.
45. Blaney Davidson E.N., Remst D.F., Vitters E.L., et al. Increase in ALK1/ALK5 ratio as a cause for elevated MMP-13 expression in osteoarthritis in humans and mice. J Immunol 2009, 182:7937-7945.
46. Attisano L., Carcamo J., Ventura F., Weis F.M., Massague J., Wrana J.L. Identification of human activin and TGF beta type I receptors that form heteromeric kinase complexes with type II receptors. Cell 1993, 75:671-680.
47. ten Dijke P., Yamashita H., Sampath T.K., et al. Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4. J Biol Chem 1994, 269:16985-16988.
48. Oh S.P., Seki T., Goss K.A., et al. Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis. Proc Natl Acad Sci U S A 2000, 97:2626-2631.
49. Upton P.D., Davies R.J., Trembath R.C., Morrell N.W. Bone morphogenetic protein (BMP) and activin type II receptors balance BMP9 signals mediated by activin receptor-like kinase-1 in human pulmonary artery endothelial cells. J Biol Chem 2009, 284:15794-15804.
50. Scharpfenecker M., van Dinther M., Liu Z., et al. BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis. J Cell Sci 2007, 120:964-972.
51. David L., Mallet C., Mazerbourg S., Feige J.J., Bailly S. Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells. Blood 2007, 109:1953-1961.
52. Brown M.A., Zhao Q., Baker K.A., et al. Crystal structure of BMP-9 and functional interactions with pro-region and receptors. J Biol Chem 2005, 280:25111-25118.
53. Townson S.A., Martinez-Hackert E., Greppi C., et al. Specificity and structure of a high affinity activin receptor-like kinase 1 (ALK1) signaling complex. J Biol Chem 2012, 287:27313-27325.
54. Goumans M.J., Valdimarsdottir G., Itoh S., et al. Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFbeta/ALK5 signaling. Mol Cell 2003, 12:817-828.
55. Wrana J.L., Tran H., Attisano L., et al. Two distinct transmembrane serine/threonine kinases from Drosophila melanogaster form an activin receptor complex. Mol Cell Biol 1994, 14:944-950.
56. Garrido-Martin E.M., Blanco F.J., Fernandez L.A., et al. Characterization of the human Activin-A receptor type II-like kinase 1 (ACVRL1) promoter and its regulation by Sp1. BMC Mol Biol 2010, 11:51.
57. Lopez-Novoa J.M., Bernabeu C. The physiological role of endoglin in the cardiovascular system. Am J Physiol Heart Circ Physiol 2010, 299:H959-H974.
58. Lebrin F., Goumans M.J., Jonker L., et al. Endoglin promotes endothelial cell proliferation and TGF-beta/ALK1 signal transduction. EMBO J 2004, 23:4018-4028.
59. Lee N.Y., Ray B., How T., Blobe G.C. Endoglin promotes transforming growth factor beta-mediated Smad 1/5/8 signaling and inhibits endothelial cell migration through its association with GIPC. J Biol Chem 2008, 283:32527-32533.
60. Scherner O., Meurer S.K., Tihaa L., Gressner A.M., Weiskirchen R. Endoglin differentially modulates antagonistic transforming growth factor-beta1 and BMP-7 signaling. J Biol Chem 2007, 282:13934-13943.
61. Eikmans M., Baelde J.J., de Heer E., Bruijn J.A. ECM homeostasis in renal diseases: a genomic approach. J Pathol 2003, 200:526-536.
62. Border W.A., Ruoslahti E. Transforming growth factor-beta in disease: the dark side of tissue repair. J Clin Invest 1992, 90:1-7.
63. Leask A., Abraham D.J. TGF-beta signaling and the fibrotic response. FASEB J 2004, 18:816-827.
64. Verrecchia F., Mauviel A. Transforming growth factor-beta signaling through the Smad pathway: role in extracellular matrix gene expression and regulation. J Invest Dermatol 2002, 118:211-215.
65. Fan H., Derynck R. Ectodomain shedding of TGF-alpha and other transmembrane proteins is induced by receptor tyrosine kinase activation and MAP kinase signaling cascades. EMBO J 1999, 18:6962-6972.
66. Xu J., Lamouille S., Derynck R. TGF-beta-induced epithelial to mesenchymal transition. Cell Res 2009, 19:156-172.
67. Wang W., Koka V., Lan H.Y. Transforming growth factor-beta and Smad signalling in kidney diseases. Nephrology (Carlton) 2005, 10:48-56.
68. Yang C., Dai L., Liu X.G., Chen Q., Zhang X.R., Guo M.Y. [Effect of transforming growth factor beta1/Smad signaling pathway on the expression and enzymatic activity of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 in cultured rat mesangial cells]. Zhonghua Bing Li Xue Za Zhi 2003, 32:553-557.
69. Yang Y.C., Piek E., Zavadil J., et al. Hierarchical model of gene regulation by transforming growth factor beta. Proc Natl Acad Sci U S A 2003, 100:10269-10274.
70. Chen S.J., Yuan W., Mori Y., Levenson A., Trojanowska M., Varga J. Stimulation of type I collagen transcription in human skin fibroblasts by TGF-beta: involvement of Smad 3. J Invest Dermatol 1999, 112:49-57.
71. Vindevoghel L., Lechleider R.J., Kon A., et al. SMAD3/4-dependent transcriptional activation of the human type VII collagen gene (COL7A1) promoter by transforming growth factor beta. Proc Natl Acad Sci U S A 1998, 95:14769-14774.
72. Vindevoghel L., Kon A., Lechleider R.J., Uitto J., Roberts A.B., Mauviel A. Smad-dependent transcriptional activation of human type VII collagen gene (COL7A1) promoter by transforming growth factor-beta. J Biol Chem 1998, 273:13053-13057.
73. Verrecchia F., Vindevoghel L., Lechleider R.J., Uitto J., Roberts A.B., Mauviel A. Smad3/AP-1 interactions control transcriptional responses to TGF-beta in a promoter-specific manner. Oncogene 2001, 20:3332-3340.
74. Ruiz-Ortega M., Rodriguez-Vita J., Sanchez-Lopez E., Carvajal G., Egido J. TGF-beta signaling in vascular fibrosis. Cardiovasc Res 2007, 74:196-206.
75. Laping N.J. ALK5 inhibition in renal disease. Curr Opin Pharmacol 2003, 3:204-208.
76. Tang Y., Yang X., Friesel R.E., Vary C.P., Liaw L. Mechanisms of TGF-beta-induced differentiation in human vascular smooth muscle cells. J Vasc Res 2011, 48:485-494.
77. Finnson K.W., Parker W.L., Chi Y., et al. Endoglin differentially regulates TGF-beta-induced Smad2/3 and Smad1/5 signalling and its expression correlates with extracellular matrix production and cellular differentiation state in human chondrocytes. Osteoarthritis Cartilage 2010, 18:1518-1527.
78. Weng H.L., Ciuclan L., Liu Y., et al. Profibrogenic transforming growth factor-beta/activin receptor-like kinase 5 signaling via connective tissue growth factor expression in hepatocytes. Hepatology 2007, 46:1257-1270.
79. Gressner O.A., Lahme B., Siluschek M., Rehbein K., Weiskirchen R., Gressner A.M. Connective tissue growth factor is a Smad2 regulated amplifier of transforming growth factor beta actions in hepatocytes-but without modulating bone morphogenetic protein 7 signaling. Hepatology 2009, 49:2021-2030.
80. Shen H., Fan J., Burczynski F., Minuk G.Y., Cattini P., Gong Y. Increased Smad1 expression and transcriptional activity enhances trans-differentiation of hepatic stellate cells. J Cell Physiol 2007, 212:764-770.
81. Li L., Zhao X.Y., Wang B.E. Down-regulation of transforming growth factor beta 1/activin receptor-like kinase 1 pathway gene expression by herbal compound 861 is related to deactivation of LX-2 cells. World J Gastroenterol 2008, 14:2894-2899.
82. Wang L., Wang B.E., Wang J., Xiao P.G., Tan X.H. Herbal compound 861 regulates mRNA expression of collagen synthesis- and degradation-related genes in human hepatic stellate cells. World J Gastroenterol 2008, 14:1790-1794.
83. Datto M.B., Frederick J.P., Pan L., Borton A.J., Zhuang Y., Wang X.F. Targeted disruption of Smad3 reveals an essential role in transforming growth factor beta-mediated signal transduction. Mol Cell Biol 1999, 19:2495-2504.
84. Piek E., Ju W.J., Heyer J., et al. Functional characterization of transforming growth factor beta signaling in Smad2- and Smad3-deficient fibroblasts. J Biol Chem 2001, 276:19945-19953.
85. Jinnin M., Ihn H., Tamaki K. Characterization of SIS3, a novel specific inhibitor of Smad3, and its effect on transforming growth factor-beta1-induced extracellular matrix expression. Mol Pharmacol 2006, 69:597-607.
86. Muñoz-Félix J.M. Heterozygous disruption of Activin receptor-like kinase 1 is associated with increased renal fibrosis in a mouse model of obstructive nephropathy. Kidney Int 2013.
87. Davies M., Robinson M., Smith E., Huntley S., Prime S., Paterson I. Induction of an epithelial to mesenchymal transition in human immortal and malignant keratinocytes by TGF-beta1 involves MAPK, Smad and AP-1 signalling pathways. J Cell Biochem 2005, 95:918-931.
88. Nieto M.A. The ins and outs of the epithelial to mesenchymal transition in health and disease. Annu Rev Cell Dev Biol 2011, 27:347-376.
89. Lopez-Novoa J.M., Nieto M.A., Inflammation EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med 2009, 1:303-314.
90. Thiery J.P., Acloque H., Huang R.Y., Nieto M.A. Epithelial-mesenchymal transitions in development and disease. Cell 2009, 139:871-890.
91. Chevalier R.L., Forbes M.S., Thornhill B.A. Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy. Kidney Int 2009, 75:1145-1152.
92. Zeisberg M., Duffield J.S. Resolved EMT produces fibroblasts in the kidney. J Am Soc Nephrol 2010, 21:1247-1253.
93. Kriz W., Kaissling B., Le Hir M. Epithelial-mesenchymal transition (EMT) in kidney fibrosis: fact or fantasy. J Clin Invest 2011, 121:468-474.
94. Derynck R., Akhurst R.J. Differentiation plasticity regulated by TGF-beta family proteins in development and disease. Nat Cell Biol 2007, 9:1000-1004.
95. Garrod D., Chidgey M. Desmosome structure, composition and function. Biochim Biophys Acta 2008, 1778:572-587.
96. De Craene B., Gilbert B., Stove C., Bruyneel E., van Roy F., Berx G. The transcription factor snail induces tumor cell invasion through modulation of the epithelial cell differentiation program. Cancer Res 2005, 65:6237-6244.
97. Heldin C.H., Vanlandewijck M., Moustakas A. Regulation of EMT by TGFbeta in cancer. FEBS Lett 2012, 586:1959-1970.
98. Jordan N.V., Johnson G.L., Abell A.N. Tracking the intermediate stages of epithelial-mesenchymal transition in epithelial stem cells and cancer. Cell Cycle 2011, 10:2865-2873.
99. Miettinen P.J., Ebner R., Lopez A.R., Derynck R. TGF-beta induced transdifferentiation of mammary epithelial cells to mesenchymal cells: involvement of type I receptors. J Cell Biol 1994, 127:2021-2036.
100. Piek E., Moustakas A., Kurisaki A., Heldin C.H., ten Dijke P. TGF-(beta) type I receptor/ALK-5 and Smad proteins mediate epithelial to mesenchymal transdifferentiation in NMuMG breast epithelial cells. J Cell Sci 1999, 112(Pt 24):4557-4568.
101. Valcourt U., Kowanetz M., Niimi H., Heldin C.H., Moustakas A. TGF-beta and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. Mol Biol Cell 2005, 16:1987-2002.
102. Thuault S., Tan E.J., Peinado H., Cano A., Heldin C.H., Moustakas A. HMGA2 and Smads co-regulate SNAIL1 expression during induction of epithelial-to-mesenchymal transition. J Biol Chem 2008, 283:33437-33446.
103. Portella G., Cumming S.A., Liddell J., et al. Transforming growth factor beta is essential for spindle cell conversion of mouse skin carcinoma in vivo: implications for tumor invasion. Cell Growth Differ 1998, 9:393-404.
104. Sato M., Muragaki Y., Saika S., Roberts A.B., Ooshima A. Targeted disruption of TGF-beta1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction. J Clin Invest 2003, 112:1486-1494.
105. Kocic J., Bugarski D., Santibanez J.F. SMAD3 is essential for transforming growth factor-beta1-induced urokinase type plasminogen activator expression and migration in transformed keratinocytes. Eur J Cancer 2012, 48:1550-1557.
106. Frey R.S., Mulder K.M. Involvement of extracellular signal-regulated kinase 2 and stress-activated protein kinase/Jun N-terminal kinase activation by transforming growth factor beta in the negative growth control of breast cancer cells. Cancer Res 1997, 57:628-633.
107. Hocevar B.A., Brown T.L., Howe P.H. TGF-beta induces fibronectin synthesis through a c-Jun N-terminal kinase-dependent, Smad4-independent pathway. EMBO J 1999, 18:1345-1356.
108. Hanafusa H., Ninomiya-Tsuji J., Masuyama N., et al. Involvement of the p38 mitogen-activated protein kinase pathway in transforming growth factor-beta-induced gene expression. J Biol Chem 1999, 274:27161-27167.
109. Bhowmick N.A., Ghiassi M., Bakin A., et al. Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol Biol Cell 2001, 12:27-36.
110. Yu L., Hebert M.C., Zhang Y.E. TGF-beta receptor-activated p38 MAP kinase mediates Smad-independent TGF-beta responses. EMBO J 2002, 21:3749-3759.
111. Yamashita M., Fatyol K., Jin C., Wang X., Liu Z., Zhang Y.E. TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-beta. Mol Cell 2008, 31:918-924.
112. Kimura N., Matsuo R., Shibuya H., Nakashima K., Taga T. BMP2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6. J Biol Chem 2000, 275:17647-17652.
113. Edlund S., Bu S., Schuster N., et al. Transforming growth factor-beta1 (TGF-beta)-induced apoptosis of prostate cancer cells involves Smad7-dependent activation of p38 by TGF-beta-activated kinase 1 and mitogen-activated protein kinase kinase 3. Mol Biol Cell 2003, 14:529-544.
114. Lamouille S., Derynck R. Cell size and invasion in TGF-beta-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway. J Cell Biol 2007, 178:437-451.
115. Jonson T., Albrechtsson E., Axelson J., et al. Altered expression of TGFB receptors and mitogenic effects of TGFB in pancreatic carcinomas. Int J Oncol 2001, 19:71-81.
116. Ungefroren H., Schniewind B., Groth S., et al. Antitumor activity of ALK1 in pancreatic carcinoma cells. Int J Cancer 2007, 120:1641-1651.
117. Zeisberg M., Hanai J., Sugimoto H., et al. BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 2003, 9:964-968.
118. Manson S.R., Niederhoff R.A., Hruska K.A., Austin P.F. The BMP-7-Smad1/5/8 pathway promotes kidney repair after obstruction induced renal injury. J Urol 2011, 185:2523-2530.
119. Sugimoto H., LeBleu V.S., Bosukonda D., et al. Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis. Nat Med 2012, 18:396-404.
120. Li Q., Gu X., Weng H., et al. Bone morphogenetic protein-9 induces epithelial to mesenchymal transition in hepatocellular carcinoma cells. Cancer Sci 2013.
121. Li M.X., Liu B.C. Epithelial to mesenchymal transition in the progression of tubulointerstitial fibrosis. Chin Med J (Engl) 2007, 120:1925-1930.
122. Zeisberg M., Kalluri R. Reversal of experimental renal fibrosis by BMP7 provides insights into novel therapeutic strategies for chronic kidney disease. Pediatr Nephrol 2008, 23:1395-1398.
123. Wetzel P., Haag J., Campean V., et al. Bone morphogenetic protein-7 expression and activity in the human adult normal kidney is predominantly localized to the distal nephron. Kidney Int 2006, 70:717-723.
124. Wang S., de Caestecker M., Kopp J., Mitu G., Lapage J., Hirschberg R. Renal bone morphogenetic protein-7 protects against diabetic nephropathy. J Am Soc Nephrol 2006, 17:2504-2512.
125. Mitu G.M., Wang S., Hirschberg R. BMP7 is a podocyte survival factor and rescues podocytes from diabetic injury. Am J Physiol Renal Physiol 2007, 293:F1641-F1648.
126. Zeisberg M., Shah A.A., Kalluri R. Bone morphogenic protein-7 induces mesenchymal to epithelial transition in adult renal fibroblasts and facilitates regeneration of injured kidney. J Biol Chem 2005, 280:8094-8100.
127. Zeisberg E.M., Potenta S.E., Sugimoto H., Zeisberg M., Kalluri R. Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition. J Am Soc Nephrol 2008, 19:2282-2287.
128. Veerasamy M., Nguyen T.Q., Motazed R., Pearson A.L., Goldschmeding R., Dockrell M.E. Differential regulation of E-cadherin and alpha-smooth muscle actin by BMP 7 in human renal proximal tubule epithelial cells and its implication in renal fibrosis. Am J Physiol Renal Physiol 2009, 297:F1238-F1248.
129. Gould S.E., Day M., Jones S.S., Dorai H. BMP-7 regulates chemokine, cytokine, and hemodynamic gene expression in proximal tubule cells. Kidney Int 2002, 61:51-60.
130. Miyazono K., Maeda S., Imamura T. BMP receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk. Cytokine Growth Factor Rev 2005, 16:251-263.
131. Bosukonda D., Shih M.S., Sampath K.T., Vukicevic S. Characterization of receptors for osteogenic protein-1/bone morphogenetic protein-7 (OP-1/BMP-7) in rat kidneys. Kidney Int 2000, 58:1902-1911.
132. Li Y., Yang J., Luo J.H., Dedhar S., Liu Y. Tubular epithelial cell dedifferentiation is driven by the helix-loop-helix transcriptional inhibitor Id1. J Am Soc Nephrol 2007, 18:449-460.
133. Lyden D., Young A.Z., Zagzag D., et al. Id1 and Id3 are required for neurogenesis, angiogenesis and vascularization of tumour xenografts. Nature 1999, 401:670-677.
134. Liang Y.Y., Brunicardi F.C., Lin X. Smad3 mediates immediate early induction of Id1 by TGF-beta. Cell Res 2009, 19:140-148.
135. Boor P., Ostendorf T., Floege J. Renal fibrosis: novel insights into mechanisms and therapeutic targets. Nat Rev Nephrol 2010, 6:643-656.
136. Lopez-Novoa J.M., Martinez-Salgado C., Rodriguez-Pena A.B., Lopez-Hernandez F.J. Common pathophysiological mechanisms of chronic kidney disease: therapeutic perspectives. Pharmacol Ther 2010, 128:61-81.
137. Lopez-Novoa J.M., Rodriguez-Pena A.B., Ortiz A., Martinez-Salgado C., Lopez Hernandez F.J. Etiopathology of chronic tubular, glomerular and renovascular nephropathies: clinical implications. J Transl Med 2011, 9:13.
138. Zeisberg M., Neilson E.G. Mechanisms of tubulointerstitial fibrosis. J Am Soc Nephrol 2010, 21:1819-1834.
139. Strutz F., Zeisberg M. Renal fibroblasts and myofibroblasts in chronic kidney disease. J Am Soc Nephrol 2006, 17:2992-2998.
140. Strutz F., Muller G.A. Renal fibrosis and the origin of the renal fibroblast. Nephrol Dial Transplant 2006, 21:3368-3370.
141. Grande M.T., Lopez-Novoa J.M. Fibroblast activation and myofibroblast generation in obstructive nephropathy. Nat Rev Nephrol 2009, 5:319-328.
142. Kaissling B., Le Hir M. The renal cortical interstitium: morphological and functional aspects. Histochem Cell Biol 2008, 130:247-262.
143. Hinz B., Gabbiani G. Fibrosis: recent advances in myofibroblast biology and new therapeutic perspectives. F1000 Biol Rep 2010, 2:78.
144. Hinz B. The myofibroblast: paradigm for a mechanically active cell. J Biomech 2010, 43:146-155.
145. Steffes M.W., Osterby R., Chavers B., Mauer S.M. Mesangial expansion as a central mechanism for loss of kidney function in diabetic patients. Diabetes 1989, 38:1077-1081.
146. Kopp J.B., Factor V.M., Mozes M., et al. Transgenic mice with increased plasma levels of TGF-beta 1 develop progressive renal disease. Lab Invest 1996, 74:991-1003.
147. Ziyadeh F.N. Mediators of diabetic renal disease: the case for tgf-Beta as the major mediator. J Am Soc Nephrol 2004, 15(Suppl. 1):S55-S57.
148. Miyajima A., Chen J., Lawrence C., et al. Antibody to transforming growth factor-beta ameliorates tubular apoptosis in unilateral ureteral obstruction. Kidney Int 2000, 58:2301-2313.
149. Ketteler M., Noble N.A., Border W.A. Transforming growth factor-beta and angiotensin II: the missing link from glomerular hyperfiltration to glomerulosclerosis. Annu Rev Physiol 1995, 57:279-295.
150. Eddy A.A. Molecular insights into renal interstitial fibrosis. J Am Soc Nephrol 1996, 7:2495-2508.
151. Sharma K., Ziyadeh F.N. The transforming growth factor-beta system and the kidney. Semin Nephrol 1993, 13:116-128.
152. Haberstroh U., Zahner G., Disser M., Thaiss F., Wolf G., Stahl R.A. TGF-beta stimulates rat mesangial cell proliferation in culture: role of PDGF beta-receptor expression. Am J Physiol 1993, 264:F199-F205.
153. Border W.A., Noble N.A. TGF-beta in kidney fibrosis: a target for gene therapy. Kidney Int 1997, 51:1388-1396.
154. Inazaki K., Kanamaru Y., Kojima Y., et al. Smad3 deficiency attenuates renal fibrosis, inflammation,and apoptosis after unilateral ureteral obstruction. Kidney Int 2004, 66:597-604.
155. Meng X.M., Huang X.R., Chung A.C., et al. Smad2 protects against TGF-beta/Smad3-mediated renal fibrosis. J Am Soc Nephrol 2010, 21:1477-1487.
156. Chung A.C., Huang X.R., Zhou L., Heuchel R., Lai K.N., Lan H.Y. Disruption of the Smad7 gene promotes renal fibrosis and inflammation in unilateral ureteral obstruction (UUO) in mice. Nephrol Dial Transplant 2009, 24:1443-1454.
157. Lan H.Y., Mu W., Tomita N., et al. Inhibition of renal fibrosis by gene transfer of inducible Smad7 using ultrasound-microbubble system in rat UUO model. J Am Soc Nephrol 2003, 14:1535-1548.
158. Lan H.Y. Smad7 as a therapeutic agent for chronic kidney diseases. Front Biosci 2008, 13:4984-4992.
159. Takahashi T., Abe H., Arai H., et al. Activation of STAT3/Smad1 is a key signaling pathway for progression to glomerulosclerosis in experimental glomerulonephritis. J Biol Chem 2005, 280:7100-7106.
160. Abe H., Matsubara T., Iehara N., et al. Type IV collagen is transcriptionally regulated by Smad1 under advanced glycation end product (AGE) stimulation. J Biol Chem 2004, 279:14201-14206.
161. Mima A., Matsubara T., Arai H., et al. Angiotensin II-dependent Src and Smad1 signaling pathway is crucial for the development of diabetic nephropathy. Lab Invest 2006, 86:927-939.
162. Mima A., Arai H., Matsubara T., et al. Urinary Smad1 is a novel marker to predict later onset of mesangial matrix expansion in diabetic nephropathy. Diabetes 2008, 57:1712-1722.
163. Scharpfenecker M., Floot B., Korlaar R., Russell N.S., Stewart F.A. ALK1 heterozygosity delays development of late normal tissue damage in the irradiated mouse kidney. Radiother Oncol 2011, 99:349-355.
164. Wang S., Chen Q., Simon T.C., et al. Bone morphogenic protein-7 (BMP-7), a novel therapy for diabetic nephropathy. Kidney Int 2003, 63:2037-2049.
165. Klahr S., Morrissey J. Obstructive nephropathy and renal fibrosis: The role of bone morphogenic protein-7 and hepatocyte growth factor. Kidney Int Suppl 2003, S105-S112.
166. Finnson K.W., Philip A. Endoglin in liver fibrosis. J Cell Commun Signal 2012, 6:1-4.
167. Dooley S., Delvoux B., Lahme B., Mangasser-Stephan K., Gressner A.M. Modulation of transforming growth factor beta response and signaling during transdifferentiation of rat hepatic stellate cells to myofibroblasts. Hepatology 2000, 31:1094-1106.
168. Kawaguchi H. Endochondral ossification signals in cartilage degradation during osteoarthritis progression in experimental mouse models. Mol Cells 2008, 25:1-6.
169. Ferguson C.M., Schwarz E.M., Reynolds P.R., Puzas J.E., Rosier R.N., O'Keefe R.J. Smad2 and 3 mediate transforming growth factor-beta1-induced inhibition of chondrocyte maturation. Endocrinology 2000, 141:4728-4735.
170. Blaney Davidson E.N., Vitters E.L., van den Berg W.B., van der Kraan P.M. TGF beta-induced cartilage repair is maintained but fibrosis is blocked in the presence of Smad7. Arthritis Res Ther 2006, 8:R65.
171. Blaney Davidson E.N., van der Kraan P.M., van den Berg W.B. TGF-beta and osteoarthritis. Osteoarthr. Cartilage 2007, 15:597-604.
172. Scheja A., Hellmer G., Wollheim F.A., Akesson A. Carboxyterminal type I procollagen peptide concentrations in systemic sclerosis: higher levels in early diffuse disease. Br J Rheumatol 1993, 32:59-62.
173. Gabrielli A., Avvedimento E.V., Krieg T., Scleroderma N Engl J Med 2009, 360:1989-2003.
174. Chen Z.L., Wang D.M., Duan J.F., Wen S.Q., Tang Y.F., Li Z.X. Leptin enhances the release of cytokines by peripheral blood mononuclear cells from acute multiple sclerosis patients. Neurosci Bull 2006, 22:115-117.
175. Leask A., Abraham D.J., Finlay D.R., et al. Dysregulation of transforming growth factor beta signaling in scleroderma: overexpression of endoglin in cutaneous scleroderma fibroblasts. Arthritis Rheum 2002, 46:1857-1865.
176. Haines P., Hant F.N., Lafyatis R., Trojanowska M., Bujor A.M. Elevated expression of cav-1 in a subset of SSc fibroblasts contributes to constitutive Alk1/Smad1 activation. J Cell Mol Med 2012, 16:2238-2246.
177. Kayano K., Sakaida I., Uchida K., Okita K. Inhibitory effects of the herbal medicine Sho-saiko-to (TJ-9) on cell proliferation and procollagen gene expressions in cultured rat hepatic stellate cells. J Hepatol 1998, 29:642-649.
178. Wang L., Wang J., Wang B.E., Xiao P.G., Qiao Y.J., Tan X.H. Effects of herbal compound 861 on human hepatic stellate cell proliferation and activation. World J Gastroenterol 2004, 10:2831-2835.
179. Daniels C.E., Wilkes M.C., Edens M., et al. Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents bleomycin-mediated lung fibrosis. J Clin Invest 2004, 114:1308-1316.
180. Wang S., Wilkes M.C., Leof E.B., Hirschberg R. Imatinib mesylate blocks a non-Smad TGF-beta pathway and reduces renal fibrogenesis in vivo. FASEB J 2005, 19:1-11.
181. Distler J.H., Jungel A., Huber L.C., et al. Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis. Arthritis Rheum 2007, 56:311-322.
182. Leask A. Signaling in fibrosis: targeting the TGF beta, endothelin-1 and CCN2 axis in scleroderma. Front Biosci (Elite Ed) 2009, 1:115-122.
183. Trojanowska M. Noncanonical transforming growth factor beta signaling in scleroderma fibrosis. Curr Opin Rheumatol 2009, 21:623-629.
184. Cunha S.I., Pardali E., Thorikay M., et al. Genetic and pharmacological targeting of activin receptor-like kinase 1 impairs tumor growth and angiogenesis. J Exp Med 2010, 207:85-100.
185. Yan X., Lin Z., Chen F., et al. Human BAMBI cooperates with Smad7 to inhibit transforming growth factor-beta signaling. J Biol Chem 2009, 284:30097-30104.
186. Grotewold L., Plum M., Dildrop R., Peters T., Ruther U. Bambi is coexpressed with Bmp-4 during mouse embryogenesis. Mech Dev 2001, 100:327-330.
187. Guillot N., Kollins D., Gilbert V., et al. BAMBI regulates angiogenesis and endothelial homeostasis through modulation of alternative TGFbeta signaling. PLoS ONE 2012, 7:e39406.
188. Villar A.V., Garcia R., Llano M., et al. BAMBI (BMP and activin membrane-bound inhibitor) protects the murine heart from pressure-overload biomechanical stress by restraining TGF-beta signaling. Biochim Biophys Acta 2013, 1832:323-335.
189. Weiskirchen R., Meurer S.K., Gressner O.A., Herrmann J., Borkham-Kamphorst E., Gressner A.M. BMP-7 as antagonist of organ fibrosis. Front Biosci 2009, 14:4992-5012.