- •Accessory and pseudo receptors: betaglycan, endoglin, cripto, and BAMBI
- •Betaglycan
- •Cripto
- •BAMBI
- •Downstream signalling: Drosophila, Caenorhabitidis, and Smad
- •Smad proteins have multiple roles in signal transduction
- •Receptor-regulated Smads 1, 2, 3, 5 and 8: receptor recognition
- •Cytoplasmic retention of receptor-regulated Smad proteins
- •Common mediator Smad4
- •Hetero-oligomeric complex formation
- •Smad–Smad complexes
- •Nuclear import and export
- •SMAD transcriptional complexes
- •Activation of gene expression
- •Repression of gene expression
- •A self-enabling response: repression of myc is prerequisite for expression of cell cycle inhibitors
- •The Smad linker region: hotspot for kinases and an E3-ligase
- •Smurf-mediated Smad degradation
- •Inhibitory Smads
- •BAMBI, a signal inhibitory pseudo receptor
- •Smad phosphatases
- •References
Signal Transduction
Abbreviation |
Full name/description |
SwissProt |
Comments, Omim links |
|
|
Entry |
|
|
|
|
|
TGIF1 |
5 -TG-3 -interacting factor-1 |
Q15583 |
homeobox protein, |
|
|
|
MIM:142946, MIM:236100 |
|
|
|
|
TIF1 |
transcription intermediate factor 1-gamma |
Q9UPN9 |
tripartite motif containing |
|
|
|
protein 33 (TRIM33) |
|
|
|
|
TLP |
TRAP-like protein |
? |
|
|
|
|
|
TRAP-1 |
TGF-beta receptor associated protein-1 |
genbank |
|
|
|
AF022795 |
|
|
|
|
|
UbcH7 |
ubiquitin conjugation factor H7 |
P68036 |
ubiquitin-protein ligase L3, |
|
|
|
E2-F1 |
|
|
|
|
ZO-1 |
zona occludens protein-1 |
Q07157 |
tight-junction protein-1 |
|
|
|
|
References
1. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science. 2002;298:1912–1934.
2. Shi Y, Massagué J. Mechanisms of TGF signaling from cell membrane to the nucleus. Cell. 2003;113:685–700.
3. Massagué J, Seoane J, Wotton D. Smad transcription factors. Genes Dev. 2005;19:2783–2810.
4. McPherron AC, Lee SJ. Double muscling in cattle due to mutations in the myostatin gene. Proc Natl Acad Sci USA. 1997;94:12457–12461.
5. Oklu R, Hesketh R. The latent transforming growth factor binding protein (LTBP) family. Biochem J. 2000;352(pt 3):601–610.
6. Yang Z, Mu Z, Dabovic B, et al. Absence of integrin-mediated TGF 1 activation in vivo recapitulates the phenotype of TGF 1-null mice. J Cell Biol. 2007;176:787–793.
7. Shull MM, Ormsby I, Kier AB, et al. Targeted disruption of the mouse transforming growth factor- 1 gene results in multifocal inflammatory disease. Nature. 1992;359:693–699.
8. Mathews LS, Vale WW. Expression cloning of an activin receptor, a predicted transmembrane serine kinase. Cell. 1991;65:973–982.
9. Bassing CH, Yingling JM, Howe DJ, et al. A transforming growth factor
type I receptor that signals to activate gene expression. Science. 1994;263:87–89.
10.Lin HY, Wang X-F, Ng-Eaton E, Weinberg RA, Lodish HF. Expression cloning of the TGFtype II receptor, a functional transmembrane serine/ threonine kinase. Cell. 1992;68:775–785.
632
Signalling Through Receptor Serine/Threonine Kinases
11.ten-Dijke P, Yamashita H, Ichijo H, et al. Characterization of type I receptors for transforming growth factorand activin. Science. 1994;264:101–104.
12.Luo K, Lodish HF. Signaling by chimeric erythropoietin-TGF- receptors: homodimerization of the cytoplasmic domain of the type I TGFreceptor and heterodimerization with the type II receptor are both required for intracellular signal transduction. EMBO J. 1996;15:4485–4496.
13.Hart PJ, Deep S, Taylor AB, Shu Z, Hinck CS, Hinck AP. Crystal structure of the human T R2 ectodomain–TGF- 3 complex. Nat Struct Biol. 2002;9:203–208.
14.Liu F, Hata A, Baker JC, et al. A human Mad protein acting as a BMPregulated transcriptional activator. Nature. 1996;381:620–623.
15.Huse M, Muir TW, Xu L, Chen YG, Kuriyan J, Massagué J. The TGF receptor activation process: an inhibitorto substrate-binding switch. Mol Cell. 2001;8:671–682.
16.Wang X-F, Lin HY, Ng EE, Downward J, Lodish HF, Weinberg RA. Expression cloning and characterization of the TGFtype III receptor. Cell. 1991;67:797–805.
17.Lopez-Casillas F, Cheifetz S, Doody J, Andres JL, Lane WS, Massagué J. Structure and expression of the membrane proteoglycan betaglycan, a component of the TGFreceptor system. Cell. 1991;67:785–795.
18.Lopez-Casillas F, Wrana JL, Massagué J. Betaglycan presents ligand to the TGFsignaling receptor. Cell. 1993;73:1435–1444.
19.Ling N, Ying SY, Ueno N, et al. Pituitary FSH is released by a heterodimer of the -subunits from the two forms of inhibin. Nature. 1986;321:779–782.
20.Lewis KA, Gray PC, Blount AL, et al. Betaglycan binds inhibin and can mediate functional antagonism of activin signalling. Nature. 2000;404:411–414.
21.Wiater E, Harrison CA, Lewis KA, Gray PC, Vale WW. Identification of distinct inhibin and transforming growth factor -binding sites on betaglycan: functional separation of betaglycan co-receptor actions. J Biol Chem. 1999;281:17011–17022.
22.Brown CB, Boyer AS, Runyan RB, Barnett JV. Requirement of type III TGFreceptor for endocardial cell transformation in the heart. Science. 1999;283:2080–2082.
23.Gougos A, Letarte M. Identification of a human endothelial cell antigen with monoclonal antibody 44G4 produced against a pre-B leukemic cell line. J Immunol. 1988;141:1925–1933.
24.Cheifetz S, Bellon T, Cales C, et al. Endoglin is a component of the transforming growth factorreceptor system in human endothelial cells. J Biol Chem. 1992;267:19027–19030.
25.Goumans MJ, Valdimarsdottir G, Itoh S, et al. Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGF /ALK5 signaling. Mol Cell. 2003;12:817–828.
633
Signal Transduction
26.Lebrin F, Goumans MJ, Jonker L, et al. Endoglin promotes endothelial cell proliferation and TGF /ALK1 signal transduction. EMBO J. 2004;23:4018–4028.
27.McAllister KA, Grogg KM, Johnson DW, et al. Endoglin, a TGF binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet. 1994;8:345–351.
28.Shen MM, Schier AF. The EGF-CFC gene family in vertebrate development. Trends Genet. 2000;16:303–309.
29.Gray PC, Shani G, Aung K, Kelber J, Vale W. Cripto binds transforming growth factor (TGF ) and inhibits TGF signaling. Mol Cell Biol. 2006;26:9268–9278.
30.Onichtchouk D, Chen YG, Dosch R, et al. Silencing of TGF signalling by the pseudoreceptor BAMBI. Nature. 1999;401:480–485.
31.Spencer FA, Hoffmann FM, Gelbart WM. Decapentaplegic: a gene complex affecting morphogenesis in Drosophila melanogaster. Cell. 1982;28:451–461.
32.Raftery LA, Twombly V, Wharton K, Gelbart WM. Genetic screens to identify elements of the decapentaplegic signaling pathway in Drosophila. Genetics. 1995;139:241–254.
33.Newfeld SJ, Chartoff EH, Graff JM, Melton DA, Gelbart WM. Mothers against dpp encodes a conserved cytoplasmic protein required in DPP/TGFresponsive cells. Development. 1996;122:2099–2108.
34.Estevez M, Attisano L, Wrana JL, et al. The daf-4 gene encodes a bone morphogenetic protein receptor controlling C. elegans dauer larva development. Nature. 1993;365:644–649.
35.Georgi LL, Albert PS, Riddle DL. daf-1, a C. elegans gene controlling dauer larva development, encodes a novel receptor protein kinase. Cell. 1990;61:635–645.
36.Savage C, Das P, Finelli AL, et al. Caenorhabditis elegans genes sma-2, sma-3, and sma-4 define a conserved family of transforming growth factor pathway components. Proc Natl Acad Sci USA. 1996;93:790–794.
37.Heldin CH, Miyazono K, ten-Dijke P. TGFsignalling from cell membrane to nucleus through SMAD proteins. Nature. 1997;390:465–471.
38.Kretzschmar M, Massagué J. SMADs: mediators and regulators of TGFsignaling. Curr Opin Genet Dev. 1998;8:103–111.
39.Chai J, Wu JW, Yan N, Massagué J, Pavletich NP, Shi Y. Features of a Smad3 MH1-DNA complex. Roles of water and zinc in DNA binding. J Biol Chem. 2003;278:20327–20331.
40.Wu JW, Hu M, Chai J, et al. Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF signaling. Mol Cell. 2001;8:1277–1289.
41.Chen YG, Hata A, Lo RS, et al. Determinants of specificity in TGFsignal transduction. Genes Dev. 1998;12:2144–2152.
634
Signalling Through Receptor Serine/Threonine Kinases
42.Feng XH, Derynck R. A kinase subdomain of transforming growth factorbeta (TGF- ) type I receptor determines the TGFintracellular signaling specificity. EMBO J. 1997;16:3912–3923.
43.Durocher D, Taylor IA, Sarbassova D, et al. The molecular basis of FHA domain:phosphopeptide binding specificity and implications for phospho-dependent signaling mechanisms. Mol Cell. 2000;6:1169–1182.
44.Pierreux CE, Nicolas FJ, Hill CS. Transforming growth factor -independent shuttling of Smad4 between the cytoplasm and nucleus. Mol Cell Biol. 2000;20:9041–9054.
45.Tsukazaki T, Chiang TA, Davison AF, Attisano L, Wrana JL. SARA, a FYVE domain protein that recruits Smad2 to the TGF receptor. Cell. 1998;95:779–791.
46.Wu G, Chen YG, Ozdamar B, et al. Structural basis of Smad2 recognition by the Smad anchor for receptor activation. Science. 2000;287:92–97.
47.Misra S, Hurley JH. Crystal structure of a phosphatidylinositol 3-phosphate-specific membrane-targeting motif, the FYVE domain of Vps27p. Cell. 1999;97:657–666.
48.Di Guglielmo GM, Le RC, Goodfellow AF, Wrana JL. Distinct endocytic pathways regulate TGFreceptor signalling and turnover. Nat Cell Biol. 2003;5:410–421.
49.Inman GJ, Nicolas FJ, Hill CS. Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF receptor activity. Mol Cell. 2002;10:283–294.
50.Xu L, Alarcon C, Col S, Massagué J. Distinct domain utilization by Smad3 and Smad4 for nucleoporin interaction and nuclear import. J Biol Chem. 2003;278:42569–42577.
51.Chacko BM, Qin BY, Tiwari A, et al. Structural basis of heteromeric smad protein assembly in TGF signaling. Mol Cell. 2004;15:813–823.
52.Qin BY, Chacko BM, Lam SS, de Caestecker MP, Correia JJ, Lin K. Structural basis of Smad1 activation by receptor kinase phosphorylation. Mol Cell. 2001;8:1303–1312.
53.Lim SK, Hoffmann FM. Smad4 cooperates with lymphoid enhancerbinding factor 1/T cell-specific factor to increase c-myc expression in the absence of TGF signaling. Proc Natl Acad Sci USA. 2006;103:18580– 18585.
54.Shiou SR, Singh AB, Moorthy K, et al. Smad4 regulates claudin-1 expression in a transforming growth factor- -independent manner in colon cancer cells. Cancer Res. 2007;67:1571–1579.
55.He W, Dorn DC, Erdjument-Bromage H, Tempst P, Moore MA, Massagué J. Hematopoiesis controlled by distinct TIF1 and Smad4 branches of the TGF pathway. Cell. 2006;125:929–941.
56.Xu L, Kang Y, Col S, Massagué J. Smad2 nucleocytoplasmic shuttling by nucleoporins CAN/Nup214 and Nup153 feeds TGF signaling complexes in the cytoplasm and nucleus. Mol Cell. 2002;10:271–282.
635
Signal Transduction
57.Seoane J, Le HV, Shen L, Anderson SA, Massagué J. Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell. 2004;117:211–223.
58.Shi Y, Wang YF, Jayaraman L, Yang H, Massagué J, Pavletich NP. Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF signaling. Cell. 1998;94:585–594.
59.Chen X, Rubock MJ, Whitman M. A transcriptional partner for MAD proteins in TGFsignalling. Nature. 1996;383:691–696.
60.Hanai J, Chen LF, Kanno T, et al. Interaction and functional cooperation of PEBP2/CBF with Smads. Synergistic induction of the immunoglobulin germline C promoter. J Biol Chem. 1999;274:31577–31582.
61.Alliston T, Choy L, Ducy P, Karsenty G, Derynck R. TGF -induced repression of CBFA1 by Smad3 decreases cbfa1 and osteocalcin expression and inhibits osteoblast differentiation. EMBO J. 2001;20:2254–2272.
62.Germain S, Howell M, Esslemont GM, Hill CS. Homeodomain and wingedhelix transcription factors recruit activated Smads to distinct promoter elements via a common Smad interaction motif. Genes Dev. 2000;14:435– 451.
63.Hata A, Seoane J, Lagna G, Montalvo E, Hemmati-Brivanlou A, Massagué J. OAZ uses distinct DNAand protein-binding zinc fingers in separate BMPSmad and Olf signaling pathways. Cell. 2000;100:229–240.
64.Zhang Y, Feng XH, Derynck R. Smad3 and Smad4 cooperate with c-Jun/c- Fos to mediate TGF- -induced transcription. Nature. 1998;394:909–913.
65.Chen CR, Kang Y, Siegel PM, Massagué J. E2F4/5 and p107 as Smad cofactors linking the TGF receptor to c-myc repression. Cell. 2002;110:19–32.
66.Kang Y, Chen CR, Massagué J. A self-enabling TGF response coupled to stress signaling: Smad engages stress response factor ATF3 for Id1 repression in epithelial cells. Mol Cell. 2003;11:915–926.
67.Ogryzko VV, Schiltz RL, Russanova V, Howard BH, Nakatani Y. The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell. 1996;87:953–959.
68.Janknecht R, Wells NJ, Hunter T. TGF -stimulated cooperation of smad proteins with the coactivators CBP/p300. Genes Dev. 1998;12:2114–2119.
69.Valcourt U, Kowanetz M, Niimi H, Heldin CH, Moustakas A. TGF and the Smad signaling pathway support transcriptomic reprogramming during epithelial-mesenchymal cell transition. Mol Biol Cell. 2005;16:1987–2002.
70.Nicolas E, Roumillac C, Trouche D. Balance between acetylation and methylation of histone H3 lysine 9 on the E2F-responsive dihydrofolate reductase promoter. Mol Cell Biol. 2003;23:1614–1622.
71.Melhuish TA, Wotton D. The interaction of the carboxyl terminusbinding protein with the Smad corepressor TGIF is disrupted by a holoprosencephaly mutation in TGIF. J Biol Chem. 2000;275:39762–39766.
636
Signalling Through Receptor Serine/Threonine Kinases
72.Seoane J, Pouponnot C, Staller P, Schader M, Eilers M, Massagué J. TGF influences Myc, Miz-1 and Smad to control the CDK inhibitor p15INK4b. Nat Cell Biol. 2001;3:400–408.
73.Frederick JP, Liberati NT, Waddell DS, Shi Y, Wang XF. Transforming growth factor -mediated transcriptional repression of c-myc is dependent on direct binding of Smad3 to a novel repressive Smad binding element. Mol Cell Biol. 2004;24:2546–2559.
74.Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF family signalling. Nature. 2003;425:577–584.
75.Nishita M, Hashimoto MK, Ogata S, et al. Interaction between Wnt and TGF signalling pathways during formation of Spemann’s organizer. Nature. 2000;403:781–785.
76.Nakashima K, Yanagisawa M, Arakawa H, et al. Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science. 1999;284:479–482.
77.Matsuura I, Denissova NG, Wang G, He D, Long J, Liu F. Cyclin-dependent kinases regulate the antiproliferative function of Smads. Nature. 2004;430:226–231.
78.Sapkota G, Alarcon C, Spagnoli FM, Brivanlou AH, Massagué J. Balancing BMP signaling through integrated inputs into the Smad1 linker. Mol Cell. 2007;25:441–454.
79.Kretzschmar M, Doody J, Massagué J. Opposing BMP and EGF signalling pathways converge on the TGF family mediator Smad1. Nature. 1997;389:618–622.
80.Pera EM, Ikeda A, Eivers E, De Robertis EM. Integration of IGF. FGF, and anti-BMP signals via Smad1 phosphorylation in neural induction. Genes Dev. 2003;17:3023–3028.
81.De Robertis EM, Larrain J, Oelgeschlager M, Wessely O. The establishment of Spemann’s organizer and patterning of the vertebrate embryo. Nat Rev Genet. 2000;1:171–181.
82.Streit A, Berliner AJ, Papanayotou C, Sirulnik A, Stern CD. Initiation of neural induction by FGF signalling before gastrulation. Nature. 2000;406:74–78.
83.Delaune E, Lemaire P, Kodjabachian L. Neural induction in Xenopus requires early FGF signalling in addition to BMP inhibition. Development. 2005;132:299–310.
84.Spemann H. http://nobelprizeorg/nobel_prizes/medicine/ laureates/1935/ 11935.
85.Spemann H, Mangold H. Über induktion von embryonalanlagen durch implantation artfremder organisatoren. Wilhelm Roux Arch Entw Mech Org. 1924;100:599–638.
86.Nakashima N, Reddi AH. The application of bone morphogenetic proteins to dental tissue engineering. Nature Biotech. 2003;21:1025–1032.
637
Signal Transduction
87.Yakymovych I, ten Dijke P, Heldin CH, Souchelnytskyi S. Regulation of Smad signaling by protein kinase C. FASEB J. 2001;15:553–555.
88.Scherer A, Graff JM. Calmodulin differentially modulates Smad1 and Smad2 signaling. J Biol Chem. 2000;275:41430–41438.
89.Bonni S, Wang HR, Causing CG, et al. TGF induces assembly of a Smad2Smurf2 ubiquitin ligase complex that targets SnoN for degradation. Nat Cell Biol. 2001;3:587–595.
90.Nakao A, Afrakhte M, Moren A, et al. Identification of Smad7, a TGF - inducible antagonist of TGFsignalling. Nature. 1997;389:631–635.
91.Afrakhte M, Moren A, Jossan S, et al. Induction of inhibitory Smad6 and Smad7 mRNA by TGF family members. Biochem Biophys Res Commun. 1998;249:505–511.
92.Hata A, Lagna G, Massagué J, Hemmati-Brivanlou A. Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev. 1998;12:186–197.
93.Ogunjimi AA, Briant DJ, Pece-Barbara N, et al. Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain. Mol Cell. 2005;19:297–308.
94.Wahl SM, Wen J, Moutsopoulos N. TGF : a mobile purveyor of immune privilege. Immunol Rev. 2006;213:213–227.
95.Han G, Li AG, Liang YY, et al. Smad7-induced -catenin degradation alters epidermal appendage development. Dev Cell. 2006;11:301–312.
96.Degen WG, Weterman MA, van Groningen JJ, et al. Expression of nma, a novel gene, inversely correlates with the metastatic potential of human melanoma cell lines and xenografts. Int J Cancer. 1996;65:460–465.
97.Das AK, Helps NR, Cohen PT, Barford D. Crystal structure of the protein serine/threonine phosphatase 2C at 2.0 A resolution. EMBO J. 1996;15:6798–6809.
98.Lin X, Duan X, Liang YY, et al. PPM1A functions as a Smad phosphatase to terminate TGF signaling. Cell. 2006;125:915–928.
99.Chen HB, Shen J, Ip YT, Xu L. Identification of phosphatases for Smad in the BMP/DPP pathway. Genes Dev. 2006;20:648–653.
100.Sapkota G, Knockaert M, Alarcon C, Montalvo E, Brivanlou AH, Massagué J. Dephosphorylation of the linker regions of Smad1 and Smad2/3 by small C-terminal domain phosphatases has distinct outcomes for bone morphogenetic protein and transforming growth factorpathways.
J Biol Chem. 2006;281:40412–40419.
101.Meinhart A, Kamenski T, Hoeppner S, Baumli S, Cramer P. A structural perspective of CTD function. Genes Dev. 2005;19:1401–1415.
102.Hahn SA, Schutte M, Hoque AT, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21. Science. 1996;271:350–353.
103.Miyaki M, Iijima T, Konishi M, et al. Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis. Oncogene. 1999;18:3098–3103.
638
Signalling Through Receptor Serine/Threonine Kinases
104.Alberici P, Jagmohan-Changur S, De Pater E, Van Der Valk M, Smits R, Hohenstein P, Fodde R. Smad4 haploinsufficiency in mouse models for intestinal cancer. Oncogene. 2006;25:1841–1851.
105.Deckers M, van Dinther M, Buijs J, et al. The tumor suppressor Smad4 is required for transforming growth factor -induced epithelial to mesenchymal transition and bone metastasis of breast cancer cells. Cancer Res. 2006;66:2202–2209.
106.Schniewind B, Groth S, Sebens MS, et al. Dissecting the role of TGF type I receptor/ALK5 in pancreatic ductal adenocarcinoma: Smad activation
is crucial for both the tumor suppressive and prometastatic function. Oncogene. 2007;26:4850–4862.
107.Oft M, Akhurst RJ, Balmain A. Metastasis is driven by sequential elevation of H-ras and Smad2 levels. Nat Cell Biol. 2002;4:487–494.
108.Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat Rev Immunol. 2006;6:715– 727.
109.Bhat R, Watzl C. Serial killing of tumor cells by human natural killer cells – enhancement by therapeutic antibodies. PLoS ONE. 2007;2:e326.
110.Thomas DA, Massagué J. TGF directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell. 2005;8:369– 380.
111.Shook D, Keller R. Mechanisms, mechanics and function of epithelial-mesenchymal transitions in early development. Mech Dev. 2003;120:1351–1383.
112.Zavadil J, Bitzer M, Liang D, et al. Genetic programs of epithelial cell plasticity directed by transforming growth factor- . Proc Natl Acad Sci USA. 2001;98:6686–6691.
113.Nieto MA, Sargent MG, Wilkinson DG, Cooke J. Control of cell behavior during vertebrate development by Slug, a zinc finger gene. Science. 1994;264:835–839.
114.Luo W, Peterson A, Garcia BA, et al. Protein phosphatase 1 regulates assembly and function of the -catenin degradation complex. EMBO J. 2007;26:1511–1521.
115.Barrallo-Gimeno A, Nieto MA. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development. 2005;132:3151–3161.
116.Ozdamar B, Bose R, Barrios-Rodiles M, Wang HR, Zhang Y, Wrana JL. Regulation of the polarity protein Par6 by TGF receptors controls epithelial cell plasticity. Science. 2005;307:1603–1609.
639
