Jump to content

SMAD (protein)

From Wikipedia, the free encyclopedia

This is an old revision of this page, as edited by Citation bot (talk | contribs) at 06:57, 17 September 2021 (Add: doi, doi-access. | Use this bot. Report bugs. | Suggested by Headbomb | Linked from Wikipedia:WikiProject_Academic_Journals/Journals_cited_by_Wikipedia/Sandbox | #UCB_webform_linked 313/603). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Smads (or SMADs) comprise a family of structurally similar proteins that are the main signal transducers for receptors of the transforming growth factor beta (TGF-B) superfamily, which are critically important for regulating cell development and growth. The abbreviation refers to the homologies to the Caenorhabditis elegans SMA ("small" worm phenotype) and MAD family ("Mothers Against Decapentaplegic") of genes in Drosophila.

There are three distinct sub-types of Smads: receptor-regulated Smads (R-Smads), common partner Smads (Co-Smads), and inhibitory Smads (I-Smads). The eight members of the Smad family are divided among these three groups. Trimers of two receptor-regulated SMADs and one co-SMAD act as transcription factors that regulate the expression of certain genes.[1][2]

Sub-types

The R-Smads consist of Smad1, Smad2, Smad3, Smad5 and Smad8/9,[3] and are involved in direct signaling from the TGF-B receptor.[4]

Smad4 is the only known human Co-Smad, and has the role of partnering with R-Smads to recruit co-regulators to the complex.[5]

Finally, Smad6 and Smad7 are I-Smads that work to suppress the activity of R-Smads.[6][7] While Smad7 is a general TGF-B signal inhibitor, Smad6 associates more specifically with BMP signaling. R/Co-Smads are primarily located in the cytoplasm, but accumulate in the nucleus following TGF-β signaling, where they can bind to DNA and regulate transcription. However, I-Smads are predominantly found in the nucleus, where they can act as direct transcriptional regulators.[8]

Discovery and nomenclature

Before Smads were discovered, it was unclear what downstream effectors were responsible for transducing TGF-B signals. Smads were first discovered in Drosophila, in which they are known as mothers against dpp (Mad),[note 1] through a genetic screen for dominant enhancers of decapentaplegic (dpp), the Drosophila version of TGF-B.[10] Studies found that Mad null mutants showed similar phenotypes to dpp mutants, suggesting that Mad played an important role in some aspect of the dpp signaling pathway.[10]

A similar screen done in the Caenorhabditis elegans protein SMA (from gene sma for small body size) revealed three genes, Sma-2, Sma-3, and Sma-4, that had similar mutant phenotypes to those of the TGF-B like receptor Daf-4.[11] The human homologue of Mad and Sma was named Smad1, a portmanteau of the previously discovered genes. When injected into Xenopus embryo animal caps, Smad1 was found to be able to reproduce the mesoderm ventralizing effects that BMP4, a member of the TGF-B family, has on embryos. Furthermore, it was demonstrated that Smad1 had transactivational ability localized at the carboxy terminus, which can be enhanced by adding BMP4. This evidence suggests that Smad1 is responsible in part for transducing TGF-B signals.[12]

Protein

Smads are roughly between 400 and 500 amino acids long, and consist of two globular regions at the amino and carboxy termini, connected by a linker region. These globular regions are highly conserved in R-Smads and Co-Smads, and are called Mad homology 1 (MH1) at the N-terminus, and MH2 at the C-terminus. The MH2 domain is also conserved in I-Smads. The MH1 domain is primarily involved in DNA binding, while the MH2 is responsible for the interaction with other Smads and also for the recognition of transcriptional co-activators and co-repressors.[13] R-Smads and Smad4 interact with several DNA motifs though the MH1 domain. These motifs include the CAGAC and its CAGCC variant, as well as the 5-bp consensus sequence GGC(GC)|(CG).[14][15] Receptor-phosphorylated R-Smads can form homotrimers, as well as heterotrimers with Smad4 in vitro, via interactions between the MH2 domains. Trimers of one Smad4 molecule and two receptor-phosphorylated R-Smad molecules are thought to be the predominant effectors of TGF-β transcriptional regulation.[13] The linker region between MH1 and MH2 is not just a connector, but also plays a role in protein function and regulation. Specifically, R-Smads are phosphorylated in the nucleus at the linker domain by CDK8 and 9, and these phosphorylations modulate the interaction of Smad proteins with transcriptional activators and repressors. Furthermore, after this phosphorylation step, the linker undergoes a second round of phosphorylations by GSK3, labelling Smads for their recognition by ubiquitin ligases, and targeting them for proteasome-mediated degradation.[16] The transcription activators and the ubiquitin ligases both contain pairs of WW domains.[17] These domains interact with the PY motif present in the R-Smad linker, as well as with the phosphorylated residues located in the proximity of the motif. Indeed, the different phosphorylation patterns generated by CDK8/9 and GSK3 define the specific interactions with either transcription activators or with ubiquitin ligases.[18][19] Remarkably, the linker region has the highest concentration of amino acid differences among metazoans, although the phosphorylation sites and the PY motif are highly conserved.

Sequence conservation

The components of the TGF-beta pathway and in particular, the R-Smads, Co-Smad and I-Smads, are represented in the genome of all metazoans sequenced to date. The level of sequence conservation of the Co-Smad and of R-Smads proteins across species is extremely high. This level of conservation of components -and sequences- suggests that the general functions of the TGF-beta pathway have remained generally intact ever since.[20][21] I-Smads have conserved MH2 domains, but divergent MH1 domains as compared to R-Smads and Co-Smads.[22]

Role in TGF-β signalling pathway

R/Co-Smads

TGF-B ligands bind receptors consisting of type 1 and type 2 serine/threonine kinases, which serve to propagate the signal intracellularly. Ligand binding stabilizes a receptor complex consisting of two type 1 receptors, and two type 2 receptors.[23] Type 2 receptors then can phosphorylate type 1 receptors at locations on the GS domain, located N-terminally to the type 1 kinase domain.[23] This phosphorylation event activates the type 1 receptors, making them capable of further propagating the TGF-B signal via Smads. Type 1 receptors phosphorylate R-Smads at two C-terminal serines, which are arranged in an SSXS motif. Smads are localized at the cell surface by Smad anchor for receptor activation (SARA) proteins, placing them in proximity of type 1 receptor kinases to facilitate phosphorylation.[24] Phosphorylation of the R-Smad causes it to dissociate from SARA, exposing a nuclear import sequence, as well as promoting its association with a Co-Smad. This Smad complex is then localized to the nucleus, where it is able to bind their target genes, with the help of other associated proteins.[25]

I-Smads

I-Smads disrupt TGF-B signaling through a variety of mechanisms, including preventing association of R-Smads with type 1 receptors and Co-Smads, down-regulating type 1 receptors, and making transcriptional changes in the nucleus. The conserved MH2 domain of I-Smads is capable of binding to type 1 receptors, thus making it a competitive inhibitor of R-Smad binding. Following R-Smad activation, it forms a heteromeric complex with an I-Smad, which prevents its association with a Co-Smad. In addition, the I-Smad recruits a ubiquitin ligase to target the activate R-Smad for degradation, effectively silencing the TGF-β signal.[8] I-Smads in the nucleus also compete with R/Co-Smad complexes for association with DNA binding elements.[26] Reporter assays show that fusing I-Smads to the DNA-binding region of reporter genes decreases their expression, suggesting that I-Smads function as transcriptional repressors.[27]

Role in cell cycle control

In adult cells, TGF-β inhibits cell cycle progression, stopping cells from making the G1/S phase transition.[28] This phenomenon is present in the epithelial cells of many organs, and is regulated in part by the Smad signaling pathway. The precise mechanism of control differs slightly between cell types.

One mechanism by which Smads facilitate TGF-B induced cytostasis is by downregulating Myc, which is a transcription factor that promotes cell growth. Myc also represses p15(Ink4b) and p21(Cip1), which are inhibitors of Cdk4 and Cdk2 respectively.[29] When there is no TGF-β present, a repressor complex composed of Smad3, and the transcription factors E2F4 and p107 exist in the cytoplasm. However, when TGF-B signal is present, this complex localizes to the nucleus, where it associates with Smad4 and binds to the TGF-B inhibitory element (TIE) of the Myc promoter to repress its transcription.[30]

In addition to Myc, Smads are also involved in the downregulation of Inhibitor of DNA Binding (ID) proteins. IDs are transcription factors that regulate genes involved in cell differentiation, maintaining multi-potency in stem cells, and promoting continuous cell cycling.[31] Therefore, downregulating ID proteins is a pathway by which TGF-B signaling could arrest the cell cycle. In a DNA microarray screen, Id2 and Id3 were found to be repressed by TGF-B, but induced by BMP signaling. Knocking out Id2 and Id3 genes in epithelial cells enhances cell cycle inhibition by TGF-B, showing that they are important in mediating this cytostatic effect.[32] Smads are both a direct and indirect inhibitor of Id expression. TGF-B signal triggers Smad3 phosphorylation, which in turn activates ATF3, a transcription factor that is induced during cellular stress. Smad3 and ATF3 then coordinate to repress Id1 transcription, resulting in its downregulation.[33] Indirectly, Id downregulation is a secondary effect of Myc repression by Smad3. Since Myc is an inducer of Id2, downregulating Myc will also result in reduced Id2 signaling, which contributes to cell cycle arrest.[31]

Studies show that Smad3, but not Smad2, is an essential effector for the cytostatic effects of TGF-B. Depleting endogeneous Smad3 via RNA interference was sufficient to interfere with TGF-B cytostasis. However, depleting Smad2 in a similar manner enhanced, rather than halted, TGF-B induced cell cycle arrest. This suggests while Smad3 is necessary for TGF-B cytostatic effect, the ratio of Smad3 to Smad2 modulates the intensity of the response. However, overexpressing Smad2 to change this ratio had no effect on the cytostatic response. Therefore, further experiments are necessary to definitely prove that the ratio of Smad3 to Smad2 regulates intensity of cytostatic effect in response to TGF-B.[34]

Smad proteins have also been found to be direct transcriptional regulators of Cdk4. Reporter assays in which luciferase was placed under a Cdk4 promoter showed increased luciferase expression when Smad4 was targeted with siRNAs. Repression of Smad2 and 3 did not have any significant effect, suggesting that Cdk4 is directly regulated by Smad4.[35]

Clinical significance

Role of Smad in cancer

Defects in Smad signaling can result in TGF-B resistance, causing dysregulation of cell growth. Deregulation of TGF-B signaling has been implicated in many cancer types, including pancreatic, colon, breast, lung, and prostate cancer.[36] Smad4 is most commonly mutated in human cancers, particularly pancreatic and colon cancer. Smad4 is inactivated in nearly half of all pancreatic cancers. As a result, Smad4 was first termed Deleted in Pancreatic Cancer Locus 4 (DPC4) upon its discovery.[37] Germline Smad4 mutations are partially responsible for genetic disposition for human familial juvenile polyposis, which puts a person at high risk of developing potentially cancerous gastrointestinal polyps. Experimental supporting evidence for this observation comes from a study showing that heterozygous Smad4 knockout mice (+/-) uniformly developed gastrointestinal polyps by 100 weeks.[38] Many familial Smad4 mutants occur on the MH2 domain, which disrupts the protein’s ability to form homo- or hetero-oligomers, thus impairing TGF-B signal transduction.[39]

Despite evidence showing that Smad3 is more critical than Smad2 in TGF-B signaling, the rate of Smad3 mutations in cancer is lower than that of Smad2.[40][41] Choriocarcinoma tumor cells are TGF-B signaling resistant, as well as lacking Smad3 expression. Studies show that reintroducing Smad3 into choriocarcinoma cells is sufficient to increase TIMP-1 (tissue inhibitor of metalloprotease-1) levels, a mediator of TGF-B’s anti-invasive effect, and thus restore TGF-B signaling. However, reintroducing Smad3 was not sufficient to rescue the anti-invasive effect of TGF-B. This suggests that other signaling mechanisms in addition to Smad3 are defective in TGF-B resistant choriocarcinoma.[37]

Role of Smad in Alzheimer’s

Alzheimer’s patients display elevated levels of TGF-B and phosphorylated Smad2 in their hippocampal neurons.[42] This finding is seemingly paradoxical, as TGF-B has previously been shown to have neuroprotective effects on Alzheimer’s patients. This suggests that some aspect of TGF-B signaling is defective, causing TGF-B to lose its neuroprotective effects. Research has shown that phosphorylated Smad2 is ectopically localized to cytoplasmic granules rather than the nucleus, in hippocampal neurons of patients with Alzheimer’s disease. Specifically, the ectopically located phosphorylated Smad2s were found within amyloid plaques, and attached to neurofibrillary tangles. These data suggest that Smad2 is involved in the development of Alzheimer’s disease.[43] Recent studies show that the peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) is involved in promoting the abnormal localization of Smad2. Pin1 was found to co-localize with Smad2/3 and phosphorylated tau proteins within the cytoplasmic granules, suggesting a possible interaction. Transfecting Smad2 expressing cells with Pin1 causes proteasome-mediated Smad2 degradation, as well as increased association of Smad2 with phosphorylated tau. This feedback loop is bidirectional; Smad2 is also capable of increasing Pin1 mRNA synthesis. Thus, the two proteins could be caught in a “vicious cycle” of regulation. Pin1 causes both itself and Smad2 to be associated in insoluble neurofibrillary tangles, resulting in low levels of both soluble proteins. Smad2 then promotes Pin1 RNA synthesis to try and compensate, which only drives more Smad2 degradation and association with neurofibrillary tangles.[44]

TGF-β/Smad signaling in kidney disease

Dysregulation of TGF-B/Smad signaling is a possible pathogenic mechanism of chronic kidney disease. In the kidneys, TGF-B1 promotes accumulation of the extracellular matrix (ECM) by increasing its production and inhibiting its degradation, which is characteristic of renal fibrosis.[45] TGF-B1 signal is transduced by the R-Smads Smad2 and Smad3, both of which are found to be overexpressed in diseased kidneys.[46] Smad3 knockout mice display reduced progression of renal fibrosis, suggesting its importance in regulating the disease.[47] Conversely, inhibiting Smad2 in kidney cells (full Smad2 knockouts are embryonic lethal) actually leads to more severe fibrosis, suggesting that Smad2 works antagonistically to Smad3 in the progression of renal fibrosis.[48] Unlike the R-Smads, Smad7 protein is typically under-expressed in diseased kidney cells. This loss of TGF-B inhibition results in increased amounts of active Smad2/3, which contribute to the progression of renal fibrosis as described above.[49]

Notes

  1. ^ Mad mutations can be placed in an allelic series based on the relative severity of the maternal effect enhancement of weak dpp alleles, thus explaining the name "mothers against dpp".[9]

References

  1. ^ Derynck R, Zhang Y, Feng XH (December 1998). "Smads: transcriptional activators of TGF-beta responses". Cell. 95 (6): 737–40. doi:10.1016/S0092-8674(00)81696-7. PMID 9865691. S2CID 17711163.
  2. ^ Massagué J, Seoane J, Wotton D (December 2005). "Smad transcription factors". Genes & Development. 19 (23): 2783–810. doi:10.1101/gad.1350705. PMID 16322555.
  3. ^ Wu JW, Hu M, Chai J, Seoane J, Huse M, Li C, Rigotti DJ, Kyin S, Muir TW, Fairman R, Massagué J, Shi Y (December 2001). "Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-beta signaling". Molecular Cell. 8 (6): 1277–89. doi:10.1016/S1097-2765(01)00421-X. PMID 11779503.
  4. ^ Massagué J (October 2012). "TGFβ signalling in context". Nature Reviews Molecular Cell Biology. 13 (10): 616–30. doi:10.1038/nrm3434. PMC 4027049. PMID 22992590.
  5. ^ Shi Y, Hata A, Lo RS, Massagué J, Pavletich NP (July 1997). "A structural basis for mutational inactivation of the tumour suppressor Smad4". Nature. 388 (6637): 87–93. Bibcode:1997Natur.388R..87S. doi:10.1038/40431. PMID 9214508. S2CID 4424997.
  6. ^ Macias MJ, Martin-Malpartida P, Massagué J (June 2015). "Structural determinants of Smad function in TGF-β signaling". Trends in Biochemical Sciences. 40 (6): 296–308. doi:10.1016/j.tibs.2015.03.012. PMC 4485443. PMID 25935112.
  7. ^ Itoh F, Asao H, Sugamura K, Heldin CH, ten Dijke P, Itoh S (August 2001). "Promoting bone morphogenetic protein signaling through negative regulation of inhibitory Smads". The EMBO Journal. 20 (15): 4132–42. doi:10.1093/emboj/20.15.4132. PMC 149146. PMID 11483516.
  8. ^ a b Yan X, Liao H, Cheng M, Shi X, Lin X, Feng XH, Chen YG (January 2016). "Smad7 Protein Interacts with Receptor-regulated Smads (R-Smads) to Inhibit Transforming Growth Factor-β (TGF-β)/Smad Signaling". The Journal of Biological Chemistry. 291 (1): 382–92. doi:10.1074/jbc.M115.694281. PMC 4697173. PMID 26555259.
  9. ^ "Gene name - Mothers against dpp". Interactive Fly, Drosophila. Society for Developmental Biology.
  10. ^ a b Sekelsky JJ, Newfeld SJ, Raftery LA, Chartoff EH, Gelbart WM (March 1995). "Genetic characterization and cloning of mothers against dpp, a gene required for decapentaplegic function in Drosophila melanogaster". Genetics. 139 (3): 1347–58. doi:10.1093/genetics/139.3.1347. PMC 1206461. PMID 7768443.
  11. ^ Savage C, Das P, Finelli AL, Townsend SR, Sun CY, Baird SE, Padgett RW (January 1996). "Caenorhabditis elegans genes sma-2, sma-3, and sma-4 define a conserved family of transforming growth factor beta pathway components". Proceedings of the National Academy of Sciences of the United States of America. 93 (2): 790–4. Bibcode:1996PNAS...93..790S. doi:10.1073/pnas.93.2.790. PMC 40134. PMID 8570636.
  12. ^ Liu F, Hata A, Baker JC, Doody J, Cárcamo J, Harland RM, Massagué J (June 1996). "A human Mad protein acting as a BMP-regulated transcriptional activator". Nature. 381 (6583): 620–3. Bibcode:1996Natur.381..620L. doi:10.1038/381620a0. PMID 8637600. S2CID 4367462.
  13. ^ a b Shi Y, Massagué J (June 2003). "Mechanisms of TGF-β Signaling from Cell Membrane to the Nucleus". Cell. 113 (6): 685–700. doi:10.1016/S0092-8674(03)00432-X. PMID 12809600. S2CID 16860578.
  14. ^ Macias MJ, Martin-Malpartida P, Massagué J (June 2015). "Structural determinants of Smad function in TGF-β signaling". Trends in Biochemical Sciences. 40 (6): 296–308. doi:10.1016/j.tibs.2015.03.012. PMC 4485443. PMID 25935112.
  15. ^ Martin-Malpartida P, Batet M, Kaczmarska Z, Freier R, Gomes T, Aragón E, Zou Y, Wang Q, Xi Q, Ruiz L, Vea A, Márquez JA, Massagué J, Macias MJ (December 2017). "Structural basis for genome wide recognition of 5-bp GC motifs by SMAD transcription factors". Nature Communications. 8 (1): 2070. Bibcode:2017NatCo...8.2070M. doi:10.1038/s41467-017-02054-6. PMC 5727232. PMID 29234012.
  16. ^ Alarcón C, Zaromytidou AI, Xi Q, Gao S, Yu J, Fujisawa S, Barlas A, Miller AN, Manova-Todorova K, Macias MJ, Sapkota G, Pan D, Massagué J (November 2009). "Nuclear CDKs drive Smad transcriptional activation and turnover in BMP and TGF-beta pathways". Cell. 139 (4): 757–69. doi:10.1016/j.cell.2009.09.035. PMC 2818353. PMID 19914168.
  17. ^ Macias MJ, Wiesner S, Sudol M (February 2002). "WW and SH3 domains, two different scaffolds to recognize proline-rich ligands". FEBS Letters. 513 (1): 30–7. doi:10.1016/S0014-5793(01)03290-2. PMID 11911877. S2CID 8224830.
  18. ^ Aragón E, Goerner N, Zaromytidou AI, Xi Q, Escobedo A, Massagué J, Macias MJ (June 2011). "A Smad action turnover switch operated by WW domain readers of a phosphoserine code". Genes & Development. 25 (12): 1275–88. doi:10.1101/gad.2060811. PMC 3127429. PMID 21685363..
  19. ^ Aragón E, Goerner N, Xi Q, Gomes T, Gao S, Massagué J, Macias MJ (October 2012). "Structural basis for the versatile interactions of Smad7 with regulator WW domains in TGF-β Pathways". Structure. 20 (10): 1726–36. doi:10.1016/j.str.2012.07.014. PMC 3472128. PMID 22921829.
  20. ^ Huminiecki L, Goldovsky L, Freilich S, Moustakas A, Ouzounis C, Heldin CH (February 2009). "Emergence, development and diversification of the TGF-beta signalling pathway within the animal kingdom". BMC Evolutionary Biology. 9: 28. doi:10.1186/1471-2148-9-28. PMC 2657120. PMID 19192293.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  21. ^ Richards GS, Degnan BM (2009). "The dawn of developmental signaling in the metazoa". Cold Spring Harbor Symposia on Quantitative Biology. 74: 81–90. doi:10.1101/sqb.2009.74.028. PMID 19903747.
  22. ^ Souchelnytskyi S, Nakayama T, Nakao A, Morén A, Heldin CH, Christian JL, ten Dijke P (September 1998). "Physical and functional interaction of murine and Xenopus Smad7 with bone morphogenetic protein receptors and transforming growth factor-beta receptors". The Journal of Biological Chemistry. 273 (39): 25364–70. doi:10.1074/jbc.273.39.25364. PMID 9738003.
  23. ^ a b Shi Y, Massagué J (June 2003). "Mechanisms of TGF-beta signaling from cell membrane to the nucleus". Cell. 113 (6): 685–700. doi:10.1016/s0092-8674(03)00432-x. PMID 12809600. S2CID 16860578.
  24. ^ Qin BY, Chacko BM, Lam SS, de Caestecker MP, Correia JJ, Lin K (December 2001). "Structural basis of Smad1 activation by receptor kinase phosphorylation". Molecular Cell. 8 (6): 1303–12. doi:10.1016/s1097-2765(01)00417-8. PMID 11779505.
  25. ^ Xu L, Kang Y, Cöl S, Massagué J (August 2002). "Smad2 nucleocytoplasmic shuttling by nucleoporins CAN/Nup214 and Nup153 feeds TGFbeta signaling complexes in the cytoplasm and nucleus". Molecular Cell. 10 (2): 271–82. doi:10.1016/s1097-2765(02)00586-5. PMID 12191473.
  26. ^ Zhang S, Fei T, Zhang L, Zhang R, Chen F, Ning Y, Han Y, Feng XH, Meng A, Chen YG (June 2007). "Smad7 antagonizes transforming growth factor beta signaling in the nucleus by interfering with functional Smad-DNA complex formation". Molecular and Cellular Biology. 27 (12): 4488–99. doi:10.1128/MCB.01636-06. PMC 1900056. PMID 17438144.
  27. ^ Pulaski L, Landström M, Heldin CH, Souchelnytskyi S (April 2001). "Phosphorylation of Smad7 at Ser-249 does not interfere with its inhibitory role in transforming growth factor-beta-dependent signaling but affects Smad7-dependent transcriptional activation". The Journal of Biological Chemistry. 276 (17): 14344–9. doi:10.1074/jbc.M011019200. PMID 11278814.
  28. ^ Siegel PM, Massagué J (November 2003). "Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer". Nature Reviews. Cancer. 3 (11): 807–21. doi:10.1038/nrc1208. PMID 14557817. S2CID 22700076.
  29. ^ Warner BJ, Blain SW, Seoane J, Massagué J (September 1999). "Myc downregulation by transforming growth factor beta required for activation of the p15(Ink4b) G(1) arrest pathway". Molecular and Cellular Biology. 19 (9): 5913–22. doi:10.1128/mcb.19.9.5913. PMC 84444. PMID 10454538.
  30. ^ Chen CR, Kang Y, Siegel PM, Massagué J (July 2002). "E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression". Cell. 110 (1): 19–32. doi:10.1016/s0092-8674(02)00801-2. PMID 12150994. S2CID 8945574.
  31. ^ a b Lasorella A, Benezra R, Iavarone A (February 2014). "The ID proteins: master regulators of cancer stem cells and tumour aggressiveness". Nature Reviews. Cancer. 14 (2): 77–91. doi:10.1038/nrc3638. PMID 24442143. S2CID 31055227.
  32. ^ Kowanetz M, Valcourt U, Bergström R, Heldin CH, Moustakas A (May 2004). "Id2 and Id3 define the potency of cell proliferation and differentiation responses to transforming growth factor beta and bone morphogenetic protein". Molecular and Cellular Biology. 24 (10): 4241–54. doi:10.1128/mcb.24.10.4241-4254.2004. PMC 400464. PMID 15121845.
  33. ^ Kang Y, Chen CR, Massagué J (April 2003). "A self-enabling TGFbeta response coupled to stress signaling: Smad engages stress response factor ATF3 for Id1 repression in epithelial cells". Molecular Cell. 11 (4): 915–26. doi:10.1016/s1097-2765(03)00109-6. PMID 12718878.
  34. ^ Kim SG, Kim HA, Jong HS, Park JH, Kim NK, Hong SH, Kim TY, Bang YJ (October 2005). "The endogenous ratio of Smad2 and Smad3 influences the cytostatic function of Smad3". Molecular Biology of the Cell. 16 (10): 4672–83. doi:10.1091/mbc.E05-01-0054. PMC 1237073. PMID 16093355.
  35. ^ Ueberham U, Hilbrich I, Ueberham E, Rohn S, Glöckner P, Dietrich K, Brückner MK, Arendt T (December 2012). "Transcriptional control of cell cycle-dependent kinase 4 by Smad proteins--implications for Alzheimer's disease". Neurobiology of Aging. 33 (12): 2827–40. doi:10.1016/j.neurobiolaging.2012.01.013. PMID 22418736. S2CID 5853206.
  36. ^ Samanta D, Datta PK (January 2012). "Alterations in the Smad pathway in human cancers". Frontiers in Bioscience. 17: 1281–93. doi:10.2741/3986. PMC 4281477. PMID 22201803.
  37. ^ a b Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE (January 1996). "DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1". Science. 271 (5247): 350–3. Bibcode:1996Sci...271..350H. doi:10.1126/science.271.5247.350. PMID 8553070. S2CID 37694954.
  38. ^ Takaku K, Miyoshi H, Matsunaga A, Oshima M, Sasaki N, Taketo MM (December 1999). "Gastric and duodenal polyps in Smad4 (Dpc4) knockout mice". Cancer Research. 59 (24): 6113–7. PMID 10626800.
  39. ^ Woodford-Richens KL, Rowan AJ, Gorman P, Halford S, Bicknell DC, Wasan HS, Roylance RR, Bodmer WF, Tomlinson IP (August 2001). "SMAD4 mutations in colorectal cancer probably occur before chromosomal instability, but after divergence of the microsatellite instability pathway". Proceedings of the National Academy of Sciences of the United States of America. 98 (17): 9719–23. Bibcode:2001PNAS...98.9719W. doi:10.1073/pnas.171321498. PMC 55519. PMID 11481457.
  40. ^ Levy L, Hill CS (February 2006). "Alterations in components of the TGF-beta superfamily signaling pathways in human cancer". Cytokine & Growth Factor Reviews. 17 (1–2): 41–58. doi:10.1016/j.cytogfr.2005.09.009. PMID 16310402.
  41. ^ Sjöblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE (October 2006). "The consensus coding sequences of human breast and colorectal cancers". Science. 314 (5797): 268–74. Bibcode:2006Sci...314..268S. doi:10.1126/science.1133427. PMID 16959974. S2CID 10805017.
  42. ^ Lee HG, Ueda M, Zhu X, Perry G, Smith MA (December 2006). "Ectopic expression of phospho-Smad2 in Alzheimer's disease: uncoupling of the transforming growth factor-beta pathway?". Journal of Neuroscience Research. 84 (8): 1856–61. doi:10.1002/jnr.21072. PMID 16998902. S2CID 19941825.
  43. ^ Ueberham U, Ueberham E, Gruschka H, Arendt T (October 2006). "Altered subcellular location of phosphorylated Smads in Alzheimer's disease". The European Journal of Neuroscience. 24 (8): 2327–34. doi:10.1111/j.1460-9568.2006.05109.x. PMID 17074053. S2CID 21442932.
  44. ^ Li Y, Li ZX, Jin T, Wang ZY, Zhao P (2017). "Tau Pathology Promotes the Reorganization of the Extracellular Matrix and Inhibits the Formation of Perineuronal Nets by Regulating the Expression and the Distribution of Hyaluronic Acid Synthases". Journal of Alzheimer's Disease. 57 (2): 395–409. doi:10.3233/JAD-160804. PMC 5366250. PMID 28234253.
  45. ^ Eddy AA, Neilson EG (November 2006). "Chronic kidney disease progression". Journal of the American Society of Nephrology. 17 (11): 2964–6. doi:10.1681/ASN.2006070704. PMID 17035605.
  46. ^ Huang XR, Chung AC, Wang XJ, Lai KN, Lan HY (July 2008). "Mice overexpressing latent TGF-beta1 are protected against renal fibrosis in obstructive kidney disease". American Journal of Physiology. Renal Physiology. 295 (1): F118–27. doi:10.1152/ajprenal.00021.2008. PMC 2494503. PMID 18448597.
  47. ^ Neelisetty S, Alford C, Reynolds K, Woodbury L, Nlandu-Khodo S, Yang H, Fogo AB, Hao CM, Harris RC, Zent R, Gewin L (September 2015). "Renal fibrosis is not reduced by blocking transforming growth factor-β signaling in matrix-producing interstitial cells". Kidney International. 88 (3): 503–14. doi:10.1038/ki.2015.51. PMC 4556568. PMID 25760325.
  48. ^ Yuan W, Varga J (October 2001). "Transforming growth factor-beta repression of matrix metalloproteinase-1 in dermal fibroblasts involves Smad3". The Journal of Biological Chemistry. 276 (42): 38502–10. doi:10.1074/jbc.M107081200. PMID 11502752.
  49. ^ Böttinger EP, Bitzer M (October 2002). "TGF-beta signaling in renal disease". Journal of the American Society of Nephrology. 13 (10): 2600–10. doi:10.1097/01.asn.0000033611.79556.ae. PMID 12239251.
Retrieved from "https://en.wikipedia.org/w/index.php?title=SMAD_(protein)&oldid=1044817640"