Disease relevance of SMAD2

• Lost or very weak expression of SMAD4, SMAD2 and DCC was found in 28, 28, and 30% of serous carcinomas, respectively [1].
• Thus, we propose that the frequent allelic loss at 18q is because of the effect of multiple genes, and there is at least one as yet unidentified tumor suppressor gene at 18q residing distal to SMAD4, SMAD2, and DCC involved in serous ovarian carcinoma [1].
• Disruption of transforming growth factor beta-Smad signaling pathway in head and neck squamous cell carcinoma as evidenced by mutations of SMAD2 and SMAD4 [2].
• Immunohistochemical evaluation of phosphorylated SMAD2/SMAD3 and the co-activator P300 in human glomerulonephritis: correlation with renal injury [3].
• Most importantly, among patients with stage II breast cancer, lack of Smad2P expression in the tumor was strongly associated with shorter overall survival [4].

High impact information on SMAD2

• The ubiquitious nuclear protein Transcriptional Intermediary Factor 1gamma (TIF1gamma) selectively binds receptor-phosphorylated Smad2/3 in competition with Smad4 [5].
• Rapid and robust binding of TIF1gamma to Smad2/3 occurs in hematopoietic, mesenchymal, and epithelial cell types in response to TGFbeta [5].
• PPM1A dephosphorylates and promotes nuclear export of TGFbeta-activated Smad2/3 [6].
• Furthermore, tissues derived from affected individuals showed increased expression of both collagen and connective tissue growth factor, as well as nuclear enrichment of phosphorylated Smad2, indicative of increased TGFbeta signaling [7].
• We identified the homeodomain protein TGIF as a Smad2-binding protein and a repressor of transcription [8].

Chemical compound and disease context of SMAD2

• A missense mutation at a conserved arginine residue in the amino-terminal MH1 domain of both Smad2 and Smad4 has been identified in tumors from patients with colorectal and pancreatic cancers, respectively [9].
• As losartan inhibited the expression of Smad2 on the gene level and reduced the concentration of TGF-beta1 in our study, the results of this in vitro study suggest that the use of angiotensin II receptor blockers might represent a possible way to prevent and treat peritoneal fibrosis in PD patients [10].
• When compared with sham-nephrectomized animals, subtotally nephrectomized animals had reduced creatinine clearance, proteinuria, glomerulosclerosis, interstitial fibrosis, tubular atrophy, and evidence of TGF-beta activity, as indicated by the abundant nuclear staining of phosphorylated Smad2 [11].

Biological context of SMAD2

• Immunohistochemical studies in P144-treated mice revealed a remarkable suppression of connective tissue growth factor expression, fibroblast SMAD2/3 phosphorylation, and alpha-smooth muscle actin positive myofibroblast development, whereas mast cell and mononuclear cell infiltration was not modified [12].
• Western blot and immunofluorescence analyses confirmed that the endogenous SMAD2 and phospho-SMAD2 levels were reduced following siRNA transfection [13].
• The persistence of the MEE and the decreased SMAD2/phospho-SMAD2 levels were coincident with increased MEE cell proliferation [13].
• A novel missense mutation of SMAD2, located in exon 8 at codon 276 TCG (ser) -->TTG (leu), was identified in cell line SCC-15 [2].
• We previously have demonstrated by comparative genomic hybridization that 80% of ulcerative colitis-related cancers show loss of all or part of chromosome 18, the site of at least three candidate tumor suppressor genes: DCC, SMAD2, and SMAD4 [14].

Anatomical context of SMAD2

• Furthermore, phosphorylated SMAD2/3 levels were elevated and nuclear localization of phosphorylated SMAD2/3 was increased, suggesting activation of the SMAD pathway in scleroderma fibroblasts [15].
• Involvement of SMAD4, but not of SMAD2, in transforming growth factor-beta1-induced trophoblast expression of matrix metalloproteinase-2 [16].
• We report here that DPC4 is essential for the function of Smad1 and Smad2 in pathways that signal mesoderm induction and patterning in Xenopus embryos, as well as antimitogenic and transcriptional responses in breast epithelial cells [17].
• TGF-beta1 induced phosphorylation of Smad2 and Smad3 in Mv1Lu mink lung epithelial cells [18].
• Levels of phospho-Smad2/3 are sensors of the interplay between effects of TGF-beta and retinoic acid on monocytic and granulocytic differentiation of HL-60 cells [19].

Associations of SMAD2 with chemical compounds

• This inhibitory function is increased in tumour-derived forms of Smad2 and 4 that carry a missense mutation in a conserved N domain arginine residue [20].
• The crystal structure of a phosphorylated Smad2, at 1.8 A resolution, reveals the formation of a homotrimer mediated by the C-terminal phosphoserine (pSer) residues [21].
• Addition of the inhibitor-of-protein serine/threonine phosphatases, okadaic acid, blocks the ATRA-mediated reduction in TGF-beta-induced phospho-Smad2 and shifts the differentiation toward monocytic end points [19].
• Smad signaling can be regulated by the Ras/Erk/mitogen-activated protein pathway in response to receptor tyrosine kinase activation and the gamma interferon pathway and also by the functional interaction of Smad2 with Ca(2+)-calmodulin [22].
• Thus, in human mesangial cells, the mechanism of decorin-mediated inhibition of TGFbeta signalling may involve activation of Ca(2+) signalling, the subsequent phosphorylation of Smad2 at a key regulatory site, and the sequestration of Smad4 in the nucleus [23].

Physical interactions of SMAD2

• SnoN physically interacted with activated Smad-2 by forming transcriptionally inactive complex and overrode the profibrotic action of TGF-beta1 [24].
• These results suggest that Smad2 phosphorylation results in both tighter binding to Smad4 and increased nuclear concentration; those changes may be responsible for transcriptional activation by Smad2 [25].
• However, under conditions of inhibited endocytosis, Smad2 remains bound to SARA for at least 6 h without a significant decline in associated levels [26].
• We report here that the pathway-specific Smad2 and 3 can form a complex with the activin receptor in a ligand-dependent manner [27].
• Although significantly different in sequence from its Xenopus counterpart, hFAST-1 shared with xFAST-1 the ability to bind to human Smad2 and activate an activin response element (ARE) [28].

Enzymatic interactions of SMAD2

• Numbers of epithelial cell nuclei with Smad4 and phosphorylated Smad2/3 staining were significantly reduced in erythematous oral lichen compared with normal oral mucosa [29].
• TGF-beta signals through its cell surface receptor serine kinases that phosphorylate Smad2 or Smad3 proteins [30].
• Additionally, SARA was found to modulate the self-association of partially phosphorylated Smad2, which suggests an added role for this protein in preventing premature release of a monophosphorylated substrate from the receptor complex [31].
• Activin A significantly increased the expression of phosphorylated Smad2 in JHOC-5 cells [32].

Regulatory relationships of SMAD2

• Dominant-negative Smad3 inhibited the transcriptional synergistic response by Smad2 and Smad4 [18].
• CTGF enhanced TGFbeta-induced phosphorylation and nuclear translocation of Smad 2 and Smad 3 in mesangial cells [33].
• The ability of Smurf2 to promote Smad2 destruction required the HECT catalytic activity of Smurf2 and depended on the proteasome-dependent pathway [34].
• In contrast, ALK5 inhibition effectively blocked Smad2 phosphorylation [35].
• Here, we show that activation of JNK cascade blocked the ability of Smad2 to mediate TGF-beta-dependent activation of the FAST proteins [36].

Other interactions of SMAD2

• This inhibitory function of the N domain is shown here to involve an interaction with the C domain that prevents the association of Smad2 with Smad4 [20].
• In addition, we observed TbetaR-activation-dependent interaction between Smad2 and Smad3 [18].
• Vitamin D(3) also induced phosphorylation of Smad2/3 and monocytic differentiation; however the effects were indirect, dependent on its ability to induce expression of TGF-beta1 [19].
• In contrast to SMAD2 deletion, for which no clinical relevance was observed, hazard ratios (HR) in a multivariate analysis associated with SMAD7 deletion [overall survival (OS): HR = 0.43, p = 0.0012; disease-free survival (DFS): HR = 0.50, p = 0.0033] indicated a favorable outcome for these patients [37].
• Significantly, Smurf2 displayed preference to Smad2 as its target for degradation [34].

Analytical, diagnostic and therapeutic context of SMAD2

• By quantitative PCR analysis, a relative loss of copy number of SMAD2, SMAD4, and DCC were detected in 40%, 57%, and 53%, respectively, of the colitis-related cancers [14].
• Cells were stimulated with TGFbeta1 and the expression of SMAD2, 3, 4, 6 and 7 mRNA was analysed by real time RT-PCR [38].
• Transforming growth factor-beta signal transducer SMAD2 but not SMAD1 moved from the cytoplasm to the nucleus after TGF-beta stimulation [39].
• The results of the screen and subsequent co-immunoprecipitation studies identified Smad2 and Smad3, two transcriptional activators that mediate the type beta transforming growth factor (TGF-beta) response, as Ski-interacting proteins [40].
• Performing electrophoretic mobility shift assay and cotransfection experiments, we were able to delineate DNA-binding complexes and identified Smad3, Smad4, and Smad2 [41].

References