{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSMAD4 is the central intracellular mediator of transforming growth factor‐β (TGF‐β) and bone morphogenetic protein (BMP) signaling. By partnering with receptor‐activated Smads (such as Smad2 and Smad3), SMAD4 enables the formation of transcriptionally active complexes that shuttle continuously between the cytoplasm and nucleus. This dynamic nucleocytoplasmic trafficking ensures that downstream gene expression—including regulation of cell cycle arrest, differentiation, and developmental programs—faithfully mirrors receptor activity. Structural studies further reveal that conserved binding interfaces and contributions from domains originally characterized in other Smad family members help coordinate its interactions with additional cofactors, thereby fine‐tuning TGF‐β–responsive transcription."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAlterations in SMAD4 function play a pivotal role in cancer pathogenesis. In diverse tumor types—including pancreatic, colorectal, breast, prostate, head and neck, ovarian, and bladder cancers—loss or inactivation of SMAD4 is associated with genomic instability, altered responses to TGF‐β signaling, and a shift from growth‐suppressive to prometastatic phenotypes. For instance, in breast and colon cancers, SMAD4 loss correlates with the enhanced expression of factors such as interleukin‑11 and vascular endothelial growth factor, which facilitate osteolytic metastases and invasion. In other settings, such as in natural killer cells, SMAD4 helps restrain noncanonical TGF‐β signals that otherwise compromise antitumor immunity. Germline mutations in SMAD4 also underlie inherited syndromes like juvenile polyposis and the combined juvenile polyposis–hereditary hemorrhagic telangiectasia (JP–HHT), while comprehensive tumor sequencing and innovative tissue‐acquisition approaches have underscored its relevance as a prognostic marker in advanced pancreatic and colorectal cancers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "28"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSMAD4 activity is exquisitely controlled by an array of post‐translational modifications and protein–protein interactions that determine its stability and transcriptional output. Sumoylation of SMAD4 by enzymes such as PIAS enhances its stability and transcriptional potential, whereas ubiquitin‐mediated degradation—often triggered by adaptor functions of inhibitory Smads in conjunction with E3 ligases like the Smurfs—attenuates its signaling. In addition, ADP‑ribosylation by poly(ADP‑ribose) polymerase‑1 (PARP‑1) reduces SMAD4’s association with DNA, and oncogenic microRNAs (for example, miR‑224 and miR‑182‑5p) target SMAD4 mRNA to modulate its expression in contexts such as ovarian and bladder cancers. Other regulatory proteins, including DACH1 and factors implicated in developmental syndromes (as seen in Myhre syndrome), further influence SMAD4 function by modulating its complex formation and turnover. These multifaceted regulatory inputs underscore SMAD4’s dual capacity to maintain cellular homeostasis under normal conditions and to drive cancer progression when its control is lost or subverted."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "29", "end_ref": "36"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Y Shi, Y F Wang, L Jayaraman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-beta signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (1998)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0092-8674(00)81600-1"}], "href": "https://doi.org/10.1016/s0092-8674(00"}, {"type": "t", "text": "81600-1) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "9741623"}], "href": "https://pubmed.ncbi.nlm.nih.gov/9741623"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Xaralabos Varelas, Rui Sakuma, Payman Samavarchi-Tehrani, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Cell Biol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncb1748"}], "href": "https://doi.org/10.1038/ncb1748"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18568018"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18568018"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Gareth J Inman, Francisco J Nicolás, Caroline S Hill "}, {"type": "b", "children": [{"type": "t", "text": "Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s1097-2765(02)00585-3"}], "href": "https://doi.org/10.1016/s1097-2765(02"}, {"type": "t", "text": "00585-3) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12191474"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12191474"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Rachel Anna Evans, Ya Chung Tian, Robert Steadman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TGF-beta1-mediated fibroblast-myofibroblast terminal differentiation-the role of Smad proteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Cell Res (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0014-4827(02)00015-0"}], "href": "https://doi.org/10.1016/s0014-4827(02"}, {"type": "t", "text": "00015-0) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12531695"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12531695"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Jia Wei Wu, Ariel R Krawitz, Jijie Chai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural mechanism of Smad4 recognition by the nuclear oncoprotein Ski: insights on Ski-mediated repression of TGF-beta signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0092-8674(02)01006-1"}], "href": "https://doi.org/10.1016/s0092-8674(02"}, {"type": "t", "text": "01006-1) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12419246"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12419246"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Anny Kretschmer, Kristin Moepert, Sibylle Dames, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Differential regulation of TGF-beta signaling through Smad2, Smad3 and Smad4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1206791"}], "href": "https://doi.org/10.1038/sj.onc.1206791"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14555988"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14555988"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Francisco J Nicolás, Karolien De Bosscher, Bernhard Schmierer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Analysis of Smad nucleocytoplasmic shuttling in living cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.01289"}], "href": "https://doi.org/10.1242/jcs.01289"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15280432"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15280432"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Christine A Iacobuzio-Donahue, Baojin Fu, Shinichi Yachida, et al. "}, {"type": "b", "children": [{"type": "t", "text": "DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Oncol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1200/JCO.2008.17.7188"}], "href": "https://doi.org/10.1200/JCO.2008.17.7188"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19273710"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19273710"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Yibin Kang, Wei He, Shaun Tulley, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0506517102"}], "href": "https://doi.org/10.1073/pnas.0506517102"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16172383"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16172383"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Zhihu Ding, Chang-Jiun Wu, Gerald C Chu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature09677"}], "href": "https://doi.org/10.1038/nature09677"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21289624"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21289624"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Amanda Blackford, Oscar K Serrano, Christopher L Wolfgang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-09-0227"}], "href": "https://doi.org/10.1158/1078-0432.CCR-09-0227"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19584151"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19584151"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Nicholas I Fleming, Robert N Jorissen, Dmitri Mouradov, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-12-2706"}], "href": "https://doi.org/10.1158/0008-5472.CAN-12-2706"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23139211"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23139211"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Victor S Cortez, Tyler K Ulland, Luisa Cervantes-Barragan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SMAD4 impedes the conversion of NK cells into ILC1-like cells by curtailing non-canonical TGF-β signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Immunol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ni.3809"}], "href": "https://doi.org/10.1038/ni.3809"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28759002"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28759002"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Guidong Yao, Mianmian Yin, Jie Lian, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-224 is involved in transforming growth factor-beta-mediated mouse granulosa cell proliferation and granulosa cell function by targeting Smad4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Endocrinol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/me.2009-0432"}], "href": "https://doi.org/10.1210/me.2009-0432"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20118412"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20118412"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "J R Howe, M G Sayed, A F Ahmed, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Med Genet (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/jmg.2004.018598"}], "href": "https://doi.org/10.1136/jmg.2004.018598"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15235019"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15235019"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Minoru Oshima, Keiichi Okano, Shinobu Muraki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Immunohistochemically detected expression of 3 major genes (CDKN2A/p16, TP53, and SMAD4/DPC4) strongly predicts survival in patients with resectable pancreatic cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann Surg (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/SLA.0b013e3182827a65"}], "href": "https://doi.org/10.1097/SLA.0b013e3182827a65"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23470568"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23470568"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Sophia Bornstein, Ruth White, Stephen Malkoski, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI38854"}], "href": "https://doi.org/10.1172/JCI38854"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19841536"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19841536"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "C J Gallione, J A Richards, T G W Letteboer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SMAD4 mutations found in unselected HHT patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Med Genet (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/jmg.2006.041517"}], "href": "https://doi.org/10.1136/jmg.2006.041517"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16613914"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16613914"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Panagiotis Papageorgis, Kuanghung Cheng, Sait Ozturk, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Smad4 inactivation promotes malignancy and drug resistance of colon cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-09-3269"}], "href": "https://doi.org/10.1158/0008-5472.CAN-09-3269"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21245094"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21245094"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "M Shintani, H Yagi, T Nakayama, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Med Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/jmg.2008.062703"}], "href": "https://doi.org/10.1136/jmg.2008.062703"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19211612"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19211612"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Hafid Alazzouzi, Pia Alhopuro, Reijo Salovaara, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SMAD4 as a prognostic marker in colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-04-1458"}], "href": "https://doi.org/10.1158/1078-0432.CCR-04-1458"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15814640"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15814640"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Waltraut Friedl, Siegfried Uhlhaas, Karsten Schulmann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Juvenile polyposis: massive gastric polyposis is more common in MADH4 mutation carriers than in BMPR1A mutation carriers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Genet (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00439-002-0748-9"}], "href": "https://doi.org/10.1007/s00439-002-0748-9"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12136244"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12136244"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Erlinda E Embuscado, Daniel Laheru, Francesca Ricci, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Immortalizing the complexity of cancer metastasis: genetic features of lethal metastatic pancreatic cancer obtained from rapid autopsy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Biol Ther (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4161/cbt.4.5.1663"}], "href": "https://doi.org/10.4161/cbt.4.5.1663"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15846069"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15846069"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Yoshikuni Kawaguchi, Scott Kopetz, Timothy E Newhook, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet A (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.a.33206"}], "href": "https://doi.org/10.1002/ajmg.a.33206"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20101697"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20101697"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Hiroshi Hirata, Koji Ueno, Varahram Shahryari, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Oncogenic miRNA-182-5p targets Smad4 and RECK in human bladder cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0051056"}], "href": "https://doi.org/10.1371/journal.pone.0051056"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23226455"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23226455"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Yoshiro Itatani, Kenji Kawada, Teruaki Fujishita, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of SMAD4 from colorectal cancer cells promotes CCL15 expression to recruit CCR1+ myeloid cells and facilitate liver metastasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.gastro.2013.07.033"}], "href": "https://doi.org/10.1053/j.gastro.2013.07.033"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23891973"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23891973"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Blanca Herrera, Maarten van Dinther, Peter Ten Dijke, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Autocrine bone morphogenetic protein-9 signals through activin receptor-like kinase-2/Smad1/Smad4 to promote ovarian cancer cell proliferation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-09-2912"}], "href": "https://doi.org/10.1158/0008-5472.CAN-09-2912"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19996292"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19996292"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Anita Morén, Takeshi Imamura, Kohei Miyazono, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "SUMO-1/Ubc9 promotes nuclear accumulation and metabolic stability of tumor suppressor Smad4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.C300112200"}], "href": "https://doi.org/10.1074/jbc.C300112200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12813045"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12813045"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Tanner J Freeman, J Joshua Smith, Xi Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Smad4-mediated signaling inhibits intestinal neoplasia by inhibiting expression of β-catenin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Gastroenterology (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/j.gastro.2011.11.026"}], "href": "https://doi.org/10.1053/j.gastro.2011.11.026"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22115830"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22115830"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Kongming Wu, Ying Yang, Chenguang Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "DACH1 inhibits transforming growth factor-beta signaling through binding Smad4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M310021200"}], "href": "https://doi.org/10.1074/jbc.M310021200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14525983"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14525983"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Francisco J Nicolás, Caroline S Hill "}, {"type": "b", "children": [{"type": "t", "text": "Attenuation of the TGF-beta-Smad signaling pathway in pancreatic tumor cells confers resistance to TGF-beta-induced growth arrest."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1206420"}], "href": "https://doi.org/10.1038/sj.onc.1206420"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12802277"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12802277"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Peter Lönn, Lars P van der Heide, Markus Dahl, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PARP-1 attenuates Smad-mediated transcription."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2010.10.029"}], "href": "https://doi.org/10.1016/j.molcel.2010.10.029"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21095583"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21095583"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "K Ueno, H Hirata, V Shahryari, et al. "}, {"type": "b", "children": [{"type": "t", "text": "microRNA-183 is an oncogene targeting Dkk-3 and SMAD4 in prostate cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Cancer (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/bjc.2013.125"}], "href": "https://doi.org/10.1038/bjc.2013.125"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23538390"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23538390"}]}, {"type": "r", "ref": 36, "children": [{"type": "t", "text": "Takayuki Ohshima, Kunitada Shimotohno "}, {"type": "b", "children": [{"type": "t", "text": "Transforming growth factor-beta-mediated signaling via the p38 MAP kinase pathway activates Smad-dependent transcription through SUMO-1 modification of Smad4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M307533200"}], "href": "https://doi.org/10.1074/jbc.M307533200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14514699"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14514699"}]}]}]}