Termination of TGF-β Superfamily Signaling Through SMAD Dephosphorylation—A Functional Genomic View

Xia Lin; Yeguang Chen; Anming Meng; Xinhua Feng

doi:10.1016/S1673-8527(07)60001-0

Volume 34 Issue 1

Jan. 2007

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Termination of TGF-β Superfamily Signaling Through SMAD Dephosphorylation—A Functional Genomic View

doi: 10.1016/S1673-8527(07)60001-0

Xia Lin^{a, c},
Yeguang Chen^d,
Anming Meng^d,
Xinhua Feng^{a, b, c}

a
Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston TX 77030, USA
b
Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston TX 77030, USA
c
Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston TX 77030, USA
d
State Key Laboratory of Biomembrane and Membrane Biotechnology, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, China

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Corresponding author: E-mail address: xfeng@bcm.edu (Xinhua Feng)
Received Date: 2006-09-25
Accepted Date: 2006-10-31

Available Online: 2007-04-18

Publish Date: 2007-01-20

Abstract

Abstract

The transforming growth factor-β (TGF-β) and related growth factors activate a broad range of cellular responses in metazoan organisms via autocrine, paracrine, and endocrine modes. They play key roles in the pathogenesis of many diseases especially cancer, fibrotic diseases, autoimmune diseases and cardiovascular diseases. TGF-β receptor-mediated phosphorylation of R-SMADs represents the most critical step in the TGF-β signaling pathways that triggers a cascade of intracellular events from SMAD complex assembly in the cytoplasm to transcriptional control in the nucleus. Conversely, dephosphorylation of R-SMADs is a key mechanism for terminating TGF-β signaling. Our labs have recently taken an integrated approach combining functional genomics, biochemistry and development biology to describe the isolation and functional characterization of protein phosphatase PPM1A in controlling TGF-β signaling. This article briefly reviews how dynamic phosphorylation and dephosphorylation of SMADs control or fine-tune the signaling strength and duration and ultimately the physiological consequences in TGF-β signaling.
- transforming growth factor-β (TGF-β),
- SMADs,
- dephosphorylation

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References

[1]	Derynck, R, Choy, et al.
[2]	Whitman, M Smads and early developmental signaling by the TGFbeta superfamily Genes Dev, 12 (1998),pp. 2445-2462
[3]	Hill, CS TGF-beta signalling pathways in early Xenopus development Curr Opin Genet Dev, 11 (2001),pp. 533-540
[4]	von Bubnoff, A, Cho, et al. Intracellular BMP signaling regulation in vertebrates: pathway or network? Dev Biol, 239 (2001),pp. 1-14
[5]	Blobe, GC, Schiemann, et al. Role of transforming growth factor beta in human disease N Engl J Med, 342 (2000),pp. 1350-1358
[6]	Derynck, R, Feng, et al. TGF-β receptor signaling Biochim Biophys Acta, 1333 (1997),pp. F105-F150
[7]	Freeman, JW, deArmond, et al. Alterations of cell signaling pathways in pancreatic cancer Front Biosci, 9 (2004),pp. 1889-1898
[8]	Rich, J, Borton, et al. Transforming growth factor-beta signaling in cancer Microsc Res Tech, 52 (2001),pp. 363-373
[9]	Siegel, PM, Massague, et al. Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer Nat Rev Cancer, 3 (2003),pp. 807-821
[10]	Varga, J Antifibrotic therapy in scleroderma: extracellular or intracellular targeting of activated fibroblasts? Curr Rheumatol Rep, 6 (2004),pp. 164-170
[11]	Wakefield, LM, Roberts, et al. TGF-beta signaling: positive and negative effects on tumorigenesis Curr Opin Genet Dev, 12 (2002),pp. 22-29
[12]	Byfield, SD, Roberts, et al. Lateral signaling enhances TGF-beta response complexity Trends Cell Biol, 14 (2004),pp. 107-111
[13]	Derynck, R, Zhang, et al. Smad-dependent and Smad-independent pathways in TGF-beta family signalling Nature, 425 (2003),pp. 577-584
[14]	Feng, XH, Derynck, et al. Specificity and versatility in -β signaling through Smads Ann Rev Cell Dev Biol,, 21 (2005),pp. 659-693
[15]	Massagué, J, Wotton, et al. Transcriptional control by the TGF-beta/Smad signaling system Embo J, 19 (2000),pp. 1745-1754
[16]	Shi, Y, Massague, et al. Mechanisms of TGF-beta signaling from cell membrane to the nucleus Cell, 113 (2003),pp. 685-700
[17]	ten Dijke, P, Hill, et al. New insights into TGF-beta-Smad signalling Trends Biochem Sci, 29 (2004),pp. 265-273
[18]	Liu, F, Hata, et al. A human Mad protein acting as a BMP-regulated transcriptional activator Nature, 381 (1996),pp. 620-623
[19]	Watanabe, M, Masuyama, et al. Regulation of inracellular dynamics of Smad4 by its leucine-rich nuclear export signal EMBO Reports, 1 (2000),pp. 176-182
[20]	Xiao, Z, Liu, et al. A distinct nuclear localization signal in the N terminus of Smad 3 determines its ligand-induced nuclear translocation Proc Natl Acad Sci USA, 97 (2000),pp. 7853-7858
[21]	Xu, L, Chen, et al. The nuclear import function of Smad2 is masked by SARA and unmasked by TGFb-dependent phosphorylation Nat Cell Biol, 2 (2000),pp. 559-562
[22]	ten Dijke, P, Miyazono, et al. Signaling inputs converge on nuclear effectors in TGF-beta signaling Trends Biochem Sci, 25 (2000),pp. 64-70
[23]	Roberts, AB TGF-beta signaling from receptors to the nucleus Microbes Infect, 1 (1999),pp. 1265-1273
[24]	Feng, XH, Zhang, et al. The tumor suppressor Smad4/DPC4 and transcriptional adaptor CBP/p300 are coactivators for Smad3 in TGF-β -induced transcriptional activation Genes Dev, 12 (1998),pp. 2153-2163
[25]	Janknecht, R, Wells, et al. TGF-beta-stimulated cooperation of Smad proteins with the coactivators CBP/p300 Genes Dev, 12 (1998),pp. 2114-2119
[26]	Shen, X, Hu, et al. TGF-beta-induced phosphorylation of Smad3 regulates its interaction with coactivator p300/CREB-binding protein Mol Biol Cell, 9 (1998),pp. 3309-3319
[27]	Akiyoshi, S, Inoue, et al. c-Ski acts as a transcriptional corepressor in transforming growth factor-beta signaling through interaction with Smads J Biol Chem, 274 (1999),pp. 35269-35277
[28]	Stroschein, SL, Wang, et al. Negative feedback regulation of TGF-beta signaling by the SnoN oncoprotein Science, 286 (1999),pp. 771-774
[29]	Sun, Y, Liu, et al. Interaction of the Ski oncoprotein with Smad3 regulates TGF-beta signaling Mol Cell, 4 (1999),pp. 499-509
[30]	Wotton, D, Lo, et al. A Smad transcriptional corepressor Cell, 97 (1999),pp. 29-39
[31]	Yahata, T, de Caestecker, et al. The MSG1 non-DNA-binding transactivator binds to the p300/CBP coactivators, enhancing their functional link to the Smad transcription factors J Biol Chem, 275 (2000),pp. 8825-8834
[32]	Kim, RH, Wang, et al. A novel smad nuclear interacting protein, SNIP1, suppresses p300-dependent TGF-beta signal transduction Genes Dev, 14 (2000),pp. 1605-1616
[33]	Hannon GJ, Beach D. p15null is a potential effector of TGF-β-induced cell cycle arrest. Nature, 371: 257 – 260.
[34]	Reynisdóttir, I, Polyak, et al. Kip/Cip and Ink4 cdk inhibitors cooperate to induce cell cycle arrest in response to -β Genes Dev, 9 (1995),pp. 1831-1845
[35]	Li, CY, Suardet, et al. Potential role of WAF1/Cip1/p21 as a mediator of TGF-beta cytoinhibitory effect J Biol Chem, 270 (1995),pp. 4971-4974
[36]	Feng, XH, Lin, et al. EMBO J, 19 (2000),pp. 5178-5193
[37]	Datto, MB, Li, et al. Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism Proc Natl Acad Sci USA, 92 (1995),pp. 5545-5549
[38]	Pardali, K, Kurisaki, et al. J Biol Chem, 275 (2000),pp. 29244-29256
[39]	Seoane, J p21(WAF1/CIP1) at the switch between the antioncogenic and oncogenic faces of TGFbeta Cancer Biol Ther, 3 (2004),pp. 226-227
[40]	Scandura, JM, Boccuni, et al. Transforming growth factor beta-induced cell cycle arrest of human hematopoietic cells requires p57KIP2 up-regulation Proc Natl Acad Sci USA, 101 (2004),pp. 15231-15236
[41]	Alexandrow, MG, Kawabata, et al. Over-expression of the c-Myc oncoprotein blocks the growth-inhibitory response but is required for the mitogenic effects of transforming growth factor beta 1 Proc Natl Acad Sci USA, 92 (1995),pp. 3239-3243
[42]	Chen, CR, Kang, et al. E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression Cell, 110 (2002),pp. 19-32
[43]	Frederick, JP, Liberati, et al. Transforming growth factor beta-mediated transcriptional repression of c-myc is dependent on direct binding of Smad3 to a novel repressive Smad binding element Mol Cell Biol, 24 (2004),pp. 2546-2559
[44]	Sasaki, T, Suzuki, et al. Lymphoid enhancer factor 1 makes cells resistant to transforming growth factor beta-induced repression of c-myc Cancer Res, 63 (2003),pp. 801-806
[45]	Warner, BJ, Blain, et al. Myc downregulation by transforming growth factor beta required for activation of the p15(Ink4b) G(1) arrest pathway Mol Cell Biol, 19 (1999),pp. 5913-5922
[46]	Eppert, K, Scherer, et al. MADR2 maps to 18q21 and encodes a TGFβ - regulated MAD-related protein that is functionally mutated in colorectal carcinoma Cell, 86 (1996),pp. 543-552
[47]	Hahn, SA, Schutte, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1 Science, 271 (1996),pp. 350-353
[48]	Riggins, GJ, Thiagalingam, et al. Mad-related genes in the human Nature Genet, 13 (1996),pp. 347-349
[49]	Schutte, M, Hiruban, et al. DPC4 gene in various tumor types Cancer Res, 56 (1996),pp. 2527-2530
[50]	Thiagalingam, S, Lengauer, et al. Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers Nat Genet, 13 (1996),pp. 343-346
[51]	Riggins, GJa, Kinzler, et al. Frequency of Smad gene mutations in human cancers Cancer Res, 57 (1997),pp. 2578-2580
[52]	Hoque, AT, Hahn, et al. DPC4 gene mutation in colitis associated neoplasia Gut, 40 (1997),pp. 120-122
[53]	Takagi, Y, Koumura, et al. Somatic alterations of the SMAD-2 gene in human colorectal cancers Br J Cancer, 78 (1998),pp. 1152-1155
[54]	Zhu, Y, Richardson, et al. Smad3 mutant mice develop metastatic colorectal cancer Cell, 94 (1998),pp. 703-714
[55]	Kim, BG, Li, et al. Smad4 signalling in T cells is required for suppression of gastrointestinal cancer Nature, 441 (2006),pp. 1015-1019
[56]	Izzi, L, Attisano, et al. Regulation of the TGF-beta signalling pathway by ubiquitin-mediated degradation Oncogene, 23 (2004),pp. 2071-2078
[57]	Mulder, KM Role of Ras and Mapks in TGF-beta signaling Cytokine Growth Factor Rev, 11 (2000),pp. 23-35
[58]	Massague, J Integration of Smad and MAPK pathways: a link and a linker revisited Genes Dev, 17 (2003),pp. 2993-2997
[59]	Liu, F, Matsuura, et al. Inhibition of Smad antiproliferative function by CDK phosphorylation Cell, Cycle, 4 (2005)
[60]	Brown, JD, DiChiara, et al. MEKK-1, a component of the stress (stress-activated protein kinase/c-Jun N-terminal kinase) pathway, can selectively activate Smad2-mediated transcriptional activation in endothelial cells J Biol Chem, 274 (1999),pp. 8797-8805
[61]	de Caestecker, M, Parks, et al. Smad2 transduces common signals from receptor serine-threonine and tyrosine kinases Genes Dev, 12 (1998),pp. 1587-1592
[62]	Engel, ME, McDonnell, et al. Interdependent SMAD and JNK signaling in transforming growth factor-beta-mediated transcription J Biol Chem, 274 (1999),pp. 37413-37420
[63]	Kretzschmar, M, Doody, et al. Opposing BMP and EGF signalling pathways converge on the TGF-β family mediator Smad1 Nature, 389 (1997),pp. 618-622
[64]	Kretzschmar, M, Doody, et al. A mechanism of repression of TGF-beta/Smad signaling by oncogenic Ras Genes Dev, 13 (1999),pp. 804-816
[65]	Pera, EM, Ikeda, et al. Integration of IGF, FGF, and anti-BMP signals via Smad1 phosphorylation in neural induction Genes Dev, 17 (2003),pp. 3023-3028
[66]	Kamaraju, AK, Roberts, et al. J Biol Chem, 280 (2005),pp. 1024-1036
[67]	Matsuura, I, Denissova, et al. Cyclin-dependent kinases regulate the antiproliferative function of Smads Nature, 430 (2004),pp. 226-231
[68]	Griswold-Prenner, I, Kamibayashi, et al. Physical and functional interactions between type I transforming growth factor beta receptors and Balpha, a WD-40 repeat subunit of phosphatase 2A Mol Cell Biol, 18 (1998),pp. 6595-6604
[69]	Shi, W, Sun, et al. GADD34-PP1c recruited by Smad7 dephosphorylates TGF-beta type I receptor J Cell Biol, 164 (2004),pp. 291-300
[70]	Lin, X, Liang, et al. Smurf2 is a ubiquitin E3 ligase mediating proteasome-dependent degradation of Smad2 in TGF-beta signaling J Biol Chem, 275 (2000),pp. 36818-36822
[71]	Liang, YY, Lin, et al. dSmurf selectively degrades decapentaplegic-activated MAD, and its overexpression disrupts imaginal disc development J Biol Chem, 278 (2003),pp. 26307-26310
[72]	Kavsak, P, Rasmussen, et al. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation Mol Cell, 6 (2000),pp. 1365-1375
[73]	Komuro, A, Imamura, et al. Negative regulation of transforming growth factor-beta (TGF-beta) signaling by WW domain-containing protein 1 (WWP1) Oncogene, 23 (2004),pp. 6914-6923
[74]	Kuratomi, G, Komuro, et al. 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, 386 (2005),pp. 461-470
[75]	Seo, SR, Lallemand, et al. The novel E3 ubiquitin ligase Tiul1 associates with TGIF to target Smad2 for degradation Embo J, 23 (2004),pp. 3780-3792
[76]	Zhang, Y, Chang, et al. Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase Proc Natl Acad Sci USA, 98 (2001),pp. 974-979
[77]	Zhu, H, Kavsak, et al. A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation Nature, 400 (1999),pp. 687-693
[78]	Feng, XH, Lin, et al.
[79]	Liang, M, Melchior, et al. Regulation of Smad4 sumoylation and transforming growth factor-beta signaling by protein inhibitor of activated STAT1 J Biol Chem, 279 (2004),pp. 22857-22865
[80]	Lin, X, Liang, et al. Activation of transforming growth factor-beta signaling by SUMO-1 modification of tumor suppressor Smad4/DPC4 J Biol Chem, 278 (2003),pp. 18714-18719
[81]	Lin, X, Liang, et al. SUMO-1/Ubc9 promotes nuclear accumulation and metabolic stability of tumor suppressor Smad4 J Biol Chem, 278 (2003),pp. 31043-31048
[82]	Ohshima, T, Shimotohno, et al. Transforming growth factor-beta-mediated signaling via the p38 MAP kinase pathway activates Smad-dependent transcription through SUMO-1 modification of Smad4 J Biol Chem, 278 (2003),pp. 50833-50842
[83]	Long, J, Wang, et al. Repression of Smad4 transcriptional activity by SUMO modification Biochem J, 379 (2004),pp. 23-29
[84]	Lee, PS, Chang, et al. Sumoylation of Smad4, the common Smad mediator of transforming growth factor-beta family signaling J Biol Chem, 278 (2003),pp. 27853-27863
[85]	Imoto, S, Sugiyama, et al. The RING domain of PIASy is involved in the suppression of bone morphogenetic protein-signaling pathway Biochem Biophys Res Commun, 319 (2004),pp. 275-282
[86]	Liang, M, Liang, et al. Ubiquitination and proteolysis of cancer-derived Smad4 mutants by SCFSkp2 Mol Cell Biol, 24 (2004),pp. 7524-7537
[87]	Inman, GJ, Nicolas, et al. Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity Mol Cell, 10 (2002),pp. 283-294
[88]	Nicolas, FJ, De Bosscher, et al. Analysis of Smad nucleocytoplasmic shuttling in living cells J Cell Sci, 117 (2004),pp. 4113-4125
[89]	Pierreux, CE, Nicolas, et al. Transforming growth factor beta-independent shuttling of Smad4 between the cytoplasm and nucleus Mol Cell Biol, 20 (2000),pp. 9041-9054
[90]	Xiao, Z, Liu, et al. Importin β mediates nuclear translocation of Smad 3 J Biol Chem, 275 (2000),pp. 23425-23428
[91]	Xiao, Z, Watson, et al. Nucleocytoplasmic shuttling of Smad1 conferred by its nuclear localization and nuclear export signals J Biol Chem, 276 (2001),pp. 39404-39410
[92]	Xiao, Z, Brownawell, et al. A novel nuclear export signal in Smad1 is essential for its signaling activity J Biol Chem, 278 (2003),pp. 34245-34252
[93]	Xiao, Z, Latek, et al. An extended bipartite nuclear localization signal in Smad4 is required for its nuclear import and transcriptional activity Oncogene, 22 (2003),pp. 1057-1069
[94]	Xu, L, Kang, et al. Smad2 nucleocytoplasmic shuttling by nucleoporins CAN/Nup214 and Nup153 feeds TGFbeta signaling complexes in the cytoplasm and nucleus Mol Cell, 10 (2002),pp. 271-282
[95]	Xu, L, Alarcon, et al. Distinct domain utilization by Smad3 and Smad4 for nucleoporin interaction and nuclear import J Biol Chem, 278 (2003),pp. 42569-42577
[96]	Reguly, T, Wrana, et al. In or out? The dynamics of Smad nucleocytoplasmic shuttling Trends Cell Biol, 13 (2003),pp. 216-220
[97]	Xu, L, Massague, et al. Nucleocytoplasmic shuttling of signal transducers Nat Rev Mol Cell Biol, 5 (2004),pp. 209-219
[98]	Alonso, A, Sasin, et al. Protein tyrosine phosphatases in the human genome Cell, 117 (2004),pp. 699-711
[99]	Cohen, PTW
[100]	Gallego, M, Virshup, et al. Protein serine/threonine phosphatases: life, death, and sleeping Curr Opin Cell Biol, 17 (2005),pp. 197-202
[101]	Lin, X, Duan, et al. PPM1A functions as a Smad phosphatase to terminate TGFβ signaling Cell, 125 (2006),pp. 915-928
[102]	Akhurst, RJ TGF beta signaling in health and disease Nat Genet, 36 (2004),pp. 790-792
[103]	Boileau, C, Jondeau, et al. Molecular genetics of Marfan sydrome Curr Opin Cardiol, 20 (2005),pp. 194-200
[104]	Roberts, AB, Wakefield, et al. The two faces of transforming growth factor beta in carcinogenesis Proc Natl Acad Sci USA, 100 (2003),pp. 8621-8623
[105]	Waite, KA, Eng, et al. From developmental disorder to heritable cancer: it's all in the BMP/TGF-beta family Nat Rev Genet, 4 (2003),pp. 763-773