In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8. Acts synergistically with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression. Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions. Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is required for the TGF-mediated signaling. Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. May act as a tumor suppressor. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator.

1. ENG, ACVRL1, and SMAD4 mutations result in different phenotypes in hereditary hemorrhagic telangiectasia PMID: 30251589
2. Our results demonstrated that SMAD4 and NF1 mutations can serve as potential biomarkers for poor prognosis to cetuximab-based therapy in Chinese mCRC patients. PMID: 29703253
3. miRNA-34a suppressed the TGF-beta-induced epithelial mesenchymal transformation, invasion, and migration of nasopharyngeal carcinoma cells by directly targeting SMAD4. PMID: 29960168
4. miR-205 functions as an oncogenic miRNA by directly binding to SMAD4 and PTEN, providing a novel target for the molecular treatment of ovarian cancer. PMID: 28145479
5. Smad4 deletion may inhibit lipogenesis, stimulate beta-oxidation, improve lipid metabolism and liver function, alleviate inflammation and fibrosis, and reduce cell apoptosis in nonalcoholic steatohepatitis. PMID: 29696816
6. a constructed SMAD4 RNA interference experiment confirmed that the function of KCNQ1OT1 was to act on lens epithelial cell proliferation and EMT, and this was achieved via the SMAD4 signaling pathway. The findings of the present study may provide a novel target for molecular therapy of cataracts disease. PMID: 29749509
7. Serum BMP2 and Smad4 levels in patients with senile osteoporotic fracture were significantly lower than those in normal controls PMID: 29938690
8. The tumor suppressor gene SMAD4 (DPC4) may help predict which surgical patients are at higher risk for failure after definitive management and may benefit from intensified adjuvant therapy. PMID: 29329157
9. Smad4 could be considered as a central component of EMT transition in human colorectal cancer that combines with transcriptional factors to reduce E-cadherin and alter the expression of the epithelial phenotype. PMID: 29468299
10. LPS mediates intercellular tight junction destruction among TECs and RhoT1/SMAD-4/JAM-3 is a pivotal pathway to mediate the phenomenon. PMID: 29725250
11. the results indicated that miR3147 may serve an oncogenic role in vulvar squamous cell carcinoma (VSCC) by targeting Smad4. miR3147 may represent a novel potential therapeutic target marker for VSCC. PMID: 29512734
12. Data indicate that in pancreatic cancer cells, the expression of ENG may be controlled by a pathway mediated by SMAD4. PMID: 29393426
13. Results demonstrated that SMAD4 is the direct target of miR-19b-3p in colon cancer. Its expression is downregulated in colon cancer contributing to oxaliplatin resistance. PMID: 28938919
14. We found expression of pSmad2/3 and Smad4 in different liver tissues, with up-regulated expression of both antibodies in chronic hepatitis C with higher stage of fibrosis and higher grade of activity. Smad4 expression up-regulated in hepatocellular carcinoma compared to chronic hepatitis C lesions, so it could identify patients with high risk for hepatocellular carcinoma. PMID: 29924446
15. SMAD4 mutation is independently associated with worse outcomes among patients undergoing resection of colorectal liver metastases. PMID: 29551247
16. Our study demonstrates that loss of SMAD4 expression is a signature characterizing the cetuximab-resistant phenotype and suggests that SMAD4 expression may be a determinant of sensitivity/resistance to EGFR/MAPK or EGFR/JNK inhibition in HPV-negative head and neck squamous cell carcinoma tumors PMID: 28522603
17. Whole-genome sequencing and confirmatory Sanger sequencing of junction PCR products were used to show that in each of the 5 cases, the SMAD4 processed gene was integrated at the same position on chromosome 9, located within the last intron of the SCAI gene PMID: 28867604
18. SMAD4 which can form a SMAD3/SMAD4 complex induced by TGFbeta. PMID: 28901475
19. High Expression of smad4 is associated with liver cancer. PMID: 28415588
20. miR-224 mediates HCT116 colorectal carcinoma cell line proliferation by targeting Smad4. PMID: 28924364
21. These results demonstrate that Smad4 suppresses the tumorigenesis and aggressiveness of neuroblastoma through repressing the HPSE expression. PMID: 27595937
22. SMAD4 gene mutation in hereditary hemorrhagic telangiectasia patients is independently associated with a higher risk of aortic root and ascending aorta dilation. PMID: 28874282
23. Smad4 expression negatively correlated with VEGF-A and VEGF-C in colon cancer PMID: 28445620
24. we demonstrated that SMAD4 rs12455792 CT, TT genotypes might increase the risk of TAAD by promoting proteoglycans degradation and SMCs apoptosis. PMID: 28666732
25. reduced Smad4 expression may predict responsiveness to regimens that contain DNA topoisomerase inhibitors in human non-small cell lung cancer PMID: 28577946
26. Our study showed that miR-205 decreased SMAD4 expression, thus promoting NSCLC cell growth. PMID: 28199217
27. Significantly, miR-4260 was increased in human colorectal cancer tissues with simultaneous downregulation of MCC and SMAD4. PMID: 28638476
28. Lung metastases from colorectal cancer patients revealed that CCL15 expression correlated with loss of SMAD4. In a mouse model, CCL15 secreted from SMAD4-deficient colorectal cancer cells recruited CCR1(+) cells, promoting their metastatic activities to the lung. PMID: 27492974
29. The stimulation of epithelial-mesenchymal transition (EMT) by miR196a5p in cancer stem-like cells was abolished by overexpression of Smad4. Collectively, these data demonstrate that miR196a5p has a key role in EMT and invasion by targeting Smad4 in gastric cancer stem cells(GCSCs). miR196a5p may serve as a potential target for gastric cancer therapy. PMID: 28440445
30. Biomarker expression in pancreatic ductal adenocarcinoma (PDAC) of CXCR4, SMAD4, SOX9 and IFIT3 will be prospectively assessed by immunohistochemistry and verified by rt.-PCR from tumor and adjacent healthy pancreatic tissue of surgical specimen. PMID: 28356064
31. Epstein Barr virus-encoded BARF1 promotes cell proliferation in stomach cancer by upregulating NFkappaB and miR-146a and downregulating SMAD4, thereby contributing to EBV-induced stomach cancer progression. PMID: 27438138
32. miR-20a-5p, as an onco-miRNA, promoted the invasion and metastasis ability by suppressing Smad4 expression in colorectal cancer cells. PMID: 27286257
33. Findings illustrate the innovative mechanism by which PSG9 drives the progression of colorectal cancer and tumor angiogenesis. This occurs via nuclear translocation of PSG9/SMAD4, which activates angiogenic cytokines. PMID: 27528036
34. results characterized miR-1305-Smad4 axis as a major downstream functional mechanism of lncRNA DANCR in promoting the chondrogenesis in synovium-derived mesenchymal stem cells. PMID: 28674107
35. the role of SIRT7 in inhibiting SMAD4-mediated breast cancer metastasis providing a possible therapeutic avenue. PMID: 28827661
36. we propose that the Smad4-Pitx2-PPP2R2A axis, a new signaling pathway, suppresses the pancreatic carcinogenesis PMID: 26848620
37. By downregulating TRAIL-R1, TGFbeta1 may not only promote tumor escape from immune surveillance but also negatively impact on TRAIL- or TRAIL-R1-based therapy regimens for treatment of Pancreatic ductal adenocarcinoma. PMID: 27492861
38. miR-483 suppresses chondrogenic differentiation of bone marrow-derived mesenchymal stem cells by targeting SMAD4 PMID: 28244607
39. The chromosome 18q21 deletion in nearly one third of pancreatic adenocarcinomas eliminates not only the tumor suppressor SMAD4, but also neighboring genes with important cellular roles, such as ME2 PMID: 28174172
40. Our data indicated that colon cancer cell induced the expression of miR-27a in HLECs, which promoted lymphangiogenesis by targeting SMAD4. Our finding implicated miR-27a as a potential target for new anticancer therapies in colon cancer PMID: 29065177
41. Results provide evidence that not only epithelial SMAD4 loss, but also stromal features, may regulate the risk of malignant transformation of oral leukoplakia. PMID: 28256094
42. mechanistic study revealed that miR-224 functions by inhibiting the tumor suppressor, SMAD4, to support the proliferation and migration of osteosarcoma (OS) cells. Our findings indicate that targeting TAZ and miR-224 could be a promising approach for the treatment of OS. PMID: 28055015
43. We hypothesize that the expanded spectrum of cardiovascular abnormalities relates to the ability of the SMAD4 protein to integrate diverse signaling pathways. The co-occurrence of congenital and acquired phenotypes demonstrates that the gene product of SMAD4 is required for both developmental and postnatal cardiovascular homeostasis. PMID: 27302097
44. Loss of heterozygosity and high cytoplasmic localization of SMAD4 expression in Stage II and low nuclear SMAD4 in Stage III are associated with colorectal cancer. PMID: 28423626
45. miR-558 facilitates the progression of gastric cancer through directly targeting the HPSE promoter to attenuate Smad4-mediated repression of HPSE expression. PMID: 27685626
46. Smad4 may not directly induce thoracic aortic aneurysms; rather it may contribute to TAA in combination with other risk factors. PMID: 28716708
47. Genetic status of DPC4 contributes to the recurrence patterns in pancreatic ductal adenocarcinoma following pancreatectomy, and patients with an initially expressed DPC4 gene receive a greater benefit from intensive local control for locoregional recurrence PMID: 28160547
48. NK cells from a SMAD4-deficient person affected by polyposis were hyper-responsive to TGF-beta PMID: 28759002
49. SMAD4 mutation was commonly detected in pancreatic juice samples from patients with Pancreatic Ductal Adenocarcinoma, mutant SMAD4 concentrations could distinguish PDAC from Intraductal Papillary Mucinous neoplasm. PMID: 27432539
50. Phosphorylation of SMAD4 is associated with Breast Cancer Metastasis. PMID: 28115363

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Cytoplasm. Nucleus.

Dwarfin/SMAD family

HGNC: 6770

OMIM: 114500

KEGG: hsa:4089

STRING: 9606.ENSP00000341551

UniGene: Hs.75862